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Malaria skin: Malaria and its skin signs

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Malaria and its skin signs

Authors: Ellie Dodson, Medical Student, University of Bristol, United Kingdom; Dr Lauren Thomas, RMO, Royal Darwin Hospital, Darwin, NT, Australia; Niket Shah, Medical Student, University of Otago, Wellington, New Zealand. Copy edited by Gus Mitchell. November 2020.


What is malaria?

Malaria is a blood-borne tropical infection caused by parasitic protozoa of the genus Plasmodium transmitted between people via infected female Anopheles mosquitoes.

Who gets malaria?

Malaria only occurs in the 91 tropical and subtropical countries where the Anopheles mosquitoes can survive, multiply, and complete their growth cycle. Disease incidence within these countries further depends on environmental factors including altitude, climate, and vegetation. In 2016, the World Health Organisation (WHO) estimated 90% of malaria cases in the world occurred in sub-Saharan Africa, but other regions at risk included South-East Asia, Central and South America, and parts of the Middle East. The WHO World Malaria Report for 2019 estimated 229 million cases and 409,000 deaths in that year.

Children under 5, pregnant women, and the immunosuppressed are at the highest risk of contracting malaria.

As malaria is a blood-borne disease, it is possible to contract it from blood transfusions and the sharing of needles, but this is rare.

What causes malaria?

Malaria is caused by just four of the many species of Plasmodium protozoa. These are:

  • P. falciparum
  • P. vivax
  • P. malariae
  • P. ovale.

The Plasmodium protozoa are spread by the female Anopheles mosquito which bites between dusk and dawn. The mosquito deposits the protozoa in the intervascular skin matrix, from where the microorganisms invade the bloodstream and rapidly establish infection in the liver. The parasites mature and multiply in the liver over several days before entering red blood cells for their final growth phase. The infected red cells burst open to release protozoa into the bloodstream where another mosquito can incidentally collect them during a blood-feed. This phase of parasitaemia, when many parasites are circulating in the blood, corresponds to an acute attack of symptoms.

What are the clinical features of malaria?

Symptoms of malaria usually develop 10–15 days after an infectious mosquito bite (range 7 days to 3 months). An acute attack of uncomplicated malaria lasts 6–10 hours and presents with fever, chills, headache, cough, myalgia, abdominal pain, vomiting, and diarrhoea. Progression to severe malaria involves organs including the brain, kidney, or lungs, or blood disturbances such as severe anaemia, metabolic acidosis, hypoglycaemia, or disseminated intravascular coagulation (DIC).

What are the cutaneous features of malaria?

Apart from the visible mosquito bites, cutaneous findings are rare and non-specific in malaria, but have been reported with P. falciparum and P. vivax malaria. Reported cutaneous findings include:

Mucosal involvement has not been reported.

Skin signs may indicate complications such as jaundice, anaemia, and DIC.

Skin side effects of malaria treatment and chemoprophylaxis

Tetracyclines can cause photosensitivity including photo-onycholysis. Photosensitivity is an important adverse effect in tropical countries, and appropriate sun protection should be recommended when doxycycline is prescribed for chemoprophylaxis in travellers.

Hydroxychloroquine can cause morbilliform or psoriasiform rashes in up to 10% of people.

What are the complications of malaria?

Uncomplicated malaria can progress to severe disease, with organ involvement including:

  • Pulmonary oedema and acute respiratory distress
  • Acute renal failure
  • Cerebral malaria, epilepsy, reversible post-malaria neurological syndrome, and permanent visual, motor, or language disorders
  • Hyper-reactive malarial splenomegaly (very enlarged spleen) and splenic rupture.

P. falciparum malaria in pregnancy can cause severe disease in the mother resulting in premature delivery or low birth-weight baby. Congenital malaria is due to transplacental infection from the mother or during delivery and presents in the first 48 hours after birth. Neonatal malaria presents three weeks after birth following an infected mosquito bite. Both forms carry a high mortality rate.

Relapses can occur months or years after P. vivax or P. ovale infection following reactivation of dormant liver parasites.

How is malaria diagnosed?

Malaria should be considered in anyone with a febrile illness in an endemic area, or after visiting an endemic area in the previous 12 months.

Malaria is diagnosed on microscopic examination of a blood film. Thick blood film examination provides sensitivity. Thin blood film examination allows speciation and quantitation. If the initial film is negative, blood should be reassessed every 6–12 hours for 36–48 hours before malaria can be confidently excluded.

Antigen-based rapid diagnostic tests (RDT) detect specific antigens produced by the parasite. Some are species specific, while others can detect multiple species.

What is the differential diagnosis for malaria?

Malaria presents as a nonspecific acute febrile illness. The differential diagnosis therefore is long and includes many other tropical infectious febrile illnesses, including:

What is the treatment for malaria?

The best treatment option for malaria is prophylaxis including clothing, netting over beds, mosquito repellents, and chemoprophylaxis with medications such as doxycycline and hydroxychloroquine, depending on the geographic location. Work on vaccine development continues.

Vector control to prevent the spread of mosquitoes can include:

  • The destruction of areas of stagnant water where mosquitoes breed
  • Treatment of houses and netting with insecticide
  • Release of sterile male mosquitoes
  • Genetic modification of mosquitoes to reduce disease susceptibility.

General measures

Treatment may be required for:

  • Secondary infection
  • Electrolyte and fluid imbalance
  • Anaemia
  • Hypoglycaemia.

Antihistamines have been reported to ease the symptoms of cutaneous involvement.

Supportive measures for complications may also include ventilation and/or dialysis.

Specific measures

The medication used for prophylaxis and treatment will depend on drug resistance and severity of disease. Drugs used include:

  • Doxycycline
  • Clindamycin
  • Hydroxychloroquine and chloroquine
  • Artemisinin derivatives, such as artesunate and artemether.

What is the outcome for malaria?

Full recovery from malaria is expected with appropriate prompt treatment. However, treatment is not always curative due to drug resistance, high parasite density, treatment noncompliance, low host immunity, and poor drug bioavailability. Recurrent symptoms with detectable parasitaemia can occur 2–6 weeks after apparently successful treatment.

Urticaria is reported to subside 12–48 hours after starting antimalarial treatment. All skin symptoms resolve within days of treatment without recurrence.

Cerebral malaria and anaemia in children can result in persistent movement disorders, speech difficulties, deafness, blindness, behavioural issues, and epilepsy.

Severe malaria can deteriorate rapidly, with death within hours or days due to missed or delayed diagnosis, but also sometimes despite appropriate treatment and intensive care.

P. falciparum malaria can be rapidly fatal within 24–48 hours of presentation, especially in children.

In 2018, there were an estimated 228 million cases of malaria, and 405,000 deaths (mostly children) worldwide.

Where Malaria Infection and the Host Immune Response Begin

Semin Immunopathol. Author manuscript; available in PMC 2014 Feb 25.

Published in final edited form as:

PMCID: PMC3934925

NIHMSID: NIHMS411807

Johns Hopkins Bloomberg School of Public Health, Malaria Research Institute, 615 North Wolfe St. , Baltimore, MD 21205

See other articles in PMC that cite the published article.

Abstract

Infection by malaria parasites begins with the inoculation of sporozoites into the skin of the host. The early events following sporozoite deposition in the dermis are critical for both the establishment of malaria infection and for the induction of protective immune responses. The initial sporozoite inoculum is generally low and only a small percentage of these sporozoites successfully reach the liver and grow to the next life cycle stage, making this a significant bottleneck for the parasite. Recent studies highlight the importance of sporozoite motility and host cell traversal in dermal exit. Importantly, protective immune responses against sporozoites and liver stages of Plasmodium are induced by dendritic cells in the lymph node draining the skin inoculation site. The cellular, molecular and immunological events that occur in the skin and associated lymph nodes are the topic of this review.

Keywords: malaria, dermis, sporozoites, plasmodium, dendritic cells, CD8+ T cells

Introduction

Malaria, one of the most important infectious diseases worldwide, is caused by protozoan parasites of the genus Plasmodium. These parasites cycle between a vertebrate and mosquito host and experience a significant reduction in numbers during transmission. Sexual or asexual reproductive cycles follow transmission and restore parasite numbers in the mosquito or vertebrate host, respectively. Thus, infection in the vertebrate host has two phases: an asymptomatic pre-erythrocytic stage, when parasite numbers are low, and a symptomatic erythrocytic stage, composed of iterative cycles of replication in host red blood cells. The pre-erythrocytic stage is short-lived, yet critical for the establishment of malaria infection. It is comprised of sporozoites, which are inoculated by infected mosquitoes, and the liver stages (or exoerythrocytic stages) into which they develop. In this review we will focus on the early stages of malaria infection, following the fate of inoculated sporozoites and outlining how the immune response to these stages is initiated and sustained. We will conclude with some thoughts as to how this knowledge can inform the generation of improved malaria vaccine candidates.

The skin stage of malaria infection

Until recently, our knowledge of the molecular interactions between host and parasite during the early stage of malaria infection was limited due to the small numbers of sporozoites and liver stages present in the mammalian host. Indeed, a review of the literature between 1970 to 1995 indicates that malariologists labored under the assumption that sporozoites rapidly left the inoculation site and significant interactions between host and parasite did not begin until sporozoites invaded hepatocytes and began to develop. Recent studies have now shown that sporozoites spend several hours at the inoculation site [1] and initiate an immune response in the lymph nodes which drain this site [2], thus bringing this early stage of infection into the limelight.

Sporozoites reside in mosquito salivary glands and exit with the mosquito’s saliva into the skin of the vertebrate host as the mosquito probes for blood. Salivation stops when the mosquito locates and begins to imbibe blood, thus sporozoites are primarily deposited into the skin and are not inoculated directly into the blood circulation [3, 4]. In most cases, the skin compartment into which sporozoites are inoculated is the dermis since this is the depth to which the mosquito’s proboscis reaches. However, skin thickness varies from one location to another and a minority of sporozoites likely find themselves in the epidermis or sub-cutaneous tissue. The average number of sporozoites inoculated by a single infected mosquito varies enormously and is, to some extent, a function of the salivary gland load [5]. Studies using mosquitoes infected with rodent malaria parasites showed that a single infected mosquito injects between 0 and 1,300 sporozoites with the average inoculum being approximately 125 sporozoites [5]. These studies, however, used laboratory-raised mosquitoes where infection is optimized and salivary gland sporozoite numbers tend to be high. In the field, mosquitoes harbor lower numbers of parasites and it is likely that the inoculum is generally under 100 sporozoites [6, 7].

After their deposition in the skin, sporozoites must locate and penetrate blood vessels in order to reach the liver. Intra-vital microscopy studies show that sporozoites move randomly in the skin until they contact either endothelial cells of the blood or lymphatic system [8, 9]. Sporozoites glide around and along these vessels, enter by an as yet unknown mechanism and are carried away, either rapidly by the blood circulation, or slowly by the lymphatic system [8]. Although some sporozoites rapidly leave the injection site, many take hours to exit and enter the bloodstream. That transit to the bloodstream could take hours was initially suggested by experiments in monkeys with the primate malaria parasite Plasmodium cynomolgi, in which it was demonstrated that transplantation of skin containing the inoculation site, up to 2 hours after sporozoite injection, resulted in infection of naïve recipients [10]. More recently, using the rodent malaria parasite Plasmodium yoelii, which enables a more quantitative and comprehensive analysis, it was demonstrated that sporozoites exit the dermis and enter the blood circulation in a slow trickle extending for 2 to 3 hours after their inoculation [1]. Some sporozoites do not enter the bloodstream and instead enter the lymphatic circulation and go to the draining lymph node. Studies have shown that approximately 15–20% of the inoculum ends up in the draining lymph node [1, 2, 8]. These sporozoites, though at least initially alive, ultimately do not continue further and likely become fodder for the immune response [2, 8].

It is likely that the remainder of the inoculum is destroyed at the site of deposition, likely by the innate immune response of the host, although this has, to date, not been well-studied. Recently, however, it was shown that a small proportion, between 0.5 and 5%, of the inoculated sporozoites remain and begin to develop into exoerythrocytic stages at the inoculation site [11, 12]. Thus far this has only been studied using rodent malaria parasites so it is possible that the development of exoerythrocytic stages in an aberrant location may result from a non-optimal host-parasite combination since the natural hosts of rodent malaria parasites are African thicket rats. Equally possible is that this may be an evolutionary relic since the avian malaria parasites, with whom the rodent and primate parasites share a common ancestor, develop into exoerythrocytic stages in mesodermal tissue including the skin. Importantly, these aberrantly developing parasites are not able to initiate a blood stage infection [12]. This is possibly because the merozoites within the exoerythrocytic forms do not fully mature although imaging data argues that this is not the case [11]. More likely it is because these parasites cannot easily access the blood circulation from this location: the liver sinusoids with their fenestrated endothelia provide a more direct route to the blood circulation than the closed endothelia of the blood. Nonetheless, it will be important to determine whether these skin exoerythrocytic stages contribute to the adaptive immune response that targets infected hepatocytes and whether this is a feature of malaria infection that is shared by all Plasmodium species.

Sporozoite exit from the dermis

Two sporozoite behaviors are required for dermal exit: motility and an ability to traverse cells. Sporozoites move by gliding motility, which is powered by an actin-myosin motor beneath their plasma membrane (reviewed in [13]. This motor is connected to the sporozoite surface via the cytoplasmic domain of a transmembrane surface protein called TRAP, (thrombospondin related anonymous protein) which has extracellular adhesive domains that bind to matrix such that the force of the motor translocates TRAP posteriorly, propelling the sporozoite forward. Previous studies have demonstrated that sporozoites actively invade hepatocytes and gliding motility is required for cell invasion [14]. More recently it has been shown that robust gliding is critical for sporozoite exit from the skin: sporozoites with mutations in TRAP which result in slow staccato movement have a much more pronounced effect on infectivity after intradermal inoculation than after intravenous injection [15]. Another critical property for dermal exit is the ability of sporozoites to traverse host cells, wounding these cells as they enter and exit [16, 17]. Mutants deficient in proteins required for cell traversal have normal infectivity when placed directly on hepatocytes in vitro yet are substantially less infective in vivo where they must exit the dermis and traverse the liver sinusoid to reach their target cell [16, 18–20]. In vivo imaging of fluorescent cell traversal mutants demonstrates that they are not able to efficiently move through the skin, becoming immobilized after contacting cells [16]. These data raise the possibility that cell traversal may also be a mechanism by which sporozoites escape phagocytic cells that arrive at the site in response to the mosquito’s saliva [16]. Importantly migrating sporozoites must switch to an invasive phenotype once they reach the liver. Recent studies have shown that the major surface protein of sporozoites, the circumsporozoite protein or CSP, is critical for this switch [21]. CSP has a cell adhesive domain in its carboxy-terminus which is masked in salivary gland sporozoites. This domain remains masked as sporozoites migrate through the skin and then upon contact with hepatocytes, CSP is proteolytically processed by a parasite protease, revealing this domain and changing a migratory sporozoite into an invasive one. Although the signal for CSP cleavage and the switch to an invasive phenotype are incompletely understood, the highly sulfated heparan sulfate proteoglycans specific to hepatocytes likely play a role [17]. Thus, shortly after their arrival in the liver, cell traversal activity is stopped and invasion, with development into the next life cycle stage, proceeds.

Induction of protective anti-Plasmodium CD8+ T cell responses

Early studies using experimental models clearly demonstrated that protective immunity against sporozoite-induced infection requires antigen-specific CD8+ T cells [22, 23]. Some of these CD8+ T cells were specific for defined epitopes in CSP, and these T cells strongly inhibited the development of liver stage parasites [24]. Subsequent studies using T-cell receptor transgenic CD8+ T cells specific for a CSP epitope, demonstrated that these T cells were primed primarily in lymph nodes draining the skin where sporozoites were deposited [2]. Forty-eight hours after immunization, either by the bites of irradiated infected mosquitoes or via intradermal inoculation of irradiated sporozoites, epitope-specific CD8+ T cells producing IFN-γ were first detected only in the lymph nodes draining the inoculation site. Once CD8+ T cells are activated in lymph nodes, they migrate to other lymphoid and non-lymphoid organs including the liver. The importance of T cell priming in skin draining lymph nodes was demonstrated in experiments in which these lymph nodes were surgically ablated or through pharmacological inhibition of T-cell egress from lymph nodes. Under these experimental conditions the number of T cells reaching the liver was drastically reduced and the protective capacity of the anti-parasite CD8+ T cell-mediated protection was diminished.

An intriguing observation made in early studies indicated that protective immunity could be induced with irradiated yet live sporozoites [25]. Consistent with this observation, it was later shown that the induction of effector CD8+ T cell responses also requires immunization with live sporozoites [2, 26]. The strict requirement of viable sporozoites was previously interpreted as evidence that sporozoite invasion of hepatocytes was required for the induction of protective immune responses and this led to the idea that liver stage antigens were critical to induce protective immunity. However, the demonstration that protective CD8+ T cells are induced in the skin draining lymph node suggests that these responses are induced after complex interactions between professional antigen presenting cells and sporozoites.

Antigen presentation by dendritic cells (DCs)

It is well established that CD11c+ DCs play a critical role in the priming of Plasmodium specific CD8+ T cells. Studies have shown that DCs incubated in vitro with sporozoites or obtained from lymph nodes of mice previously injected with sporozoites present parasite epitopes to T cells [2, 27, 28]. Moreover, in vivo depletion of the CD11c+ DCs abolishes the induction of parasite specific CD8+ T cell responses [29]. The skin is a tissue that harbors large numbers of DCs belonging to phenotypically and functionally distinct groups which are likely to interact with parasites. In addition, there are large numbers of lymph node-resident DCs which may also play a role in inducing T cell responses, particularly considering that a significant number of parasites migrate to lymph nodes draining the inoculation site.

The mechanisms by which DCs acquire antigen from live parasites is an intriguing yet poorly understood process. It is well known that the CSP and other parasite molecules are shed as sporozoites move and conceivably, these secreted molecules may be endocytosed and processed by DCs, and peptides within these antigens eventually presented to T cells. Alternatively, as was outlined earlier, the critical role of cell traversal for exit from the dermis means that sporozoites may also directly deposit antigen in the cytosol of DCs.

While the precise mechanisms of DC antigen uptake are unknown, experimental evidence indicates that DC priming of CD8+ T cells occurs by antigen cross-presentation. This notion is supported by studies in which Toll-like receptor ligands administered prior to sporozoite immunization, inhibit the induction of CD8+ T cell responses [2]. It is known that TLR ligands hasten the maturation of DCs, a process that is accompanied by an inhibition of their endocytic activity [30, 31]. Recently, these studies were expanded using new methodological approaches and novel transgenic parasites. P. berghei parasites expressing mutant CSP containing the H-2Kb SIINFEKL epitope have enabled studies in genetically modified C57Bl/6 (H-2b) mice deficient in molecules involved in antigen processing and presentation [32]. These studies demonstrated that priming of CD8+ T cells required intact endocytic function as experiments performed in mice lacking the endosomal protein Unc93B1 failed to develop robust CD8+ T cell responses. Unc93B1 is believed to mediate translocation of endocytosed molecules to the ER which are subsequently transported to the cytosol where they are processed to generate peptide epitopes [33]. A critical role for cross-presentation is further supported by in vivo experiments in which treatment of mice with cytochrome-c resulted in a severely reduced CD8+ T cell response [32]. Studies in other systems show that after cytochrome-c is internalized by endocytosis, it is translocated to the cytosol where it induces apoptosis, thus depleting antigen cross-presenting cells [34–36]. Finally, no CD8+ T cell responses were observed in mice lacking the TAP1 molecule which mediates the transport of the proteosome-processed CSP peptides from the cytosol to the ER. This clearly indicates that CSP must reach the cytosol where it is processed, generating epitope-containing peptides that are transported by TAP from the ER to where they bind to class l MHC molecules.

The precise tissue compartment where the capture of parasite antigen occurs and the identity of the DC subpopulation involved in this process, are critical matters that remain to be defined. As discussed in the preceding sections, intradermally inoculated sporozoites remain in the skin for over one hour and exit the skin in a slow trickle [1]. In addition a significant proportion of sporozoites migrate to the draining lymph nodes [1, 2, 8]. These findings raise an important question: where do DCs acquire sporozoite antigen? An obvious possibility is that sporozoite antigen is acquired in the dermis by skin-resident DCs that then migrate to the lymph nodes where they present antigen directly to naive CD8+ T cells. At least three distinct subsets of skin-resident migratory DCs have been characterized: Langerhans cells, dermal DCs, and langerin+CD103+ dermal DCs [37]. Langerin+CD103+ dermal DCs are a subset of migratory DCs that play a key role in cross-presenting viral and self antigens [37–40] and their possible involvement in cross-presentation of sporozoite antigens requires further investigation. Alternatively, dermal DCs could transfer skin-derived antigen to lymph node resident DCs for CD8+ T cell priming as shown in studies using herpes simplex virus [41]. Finally, it is also possible that CD8+ T cell priming does not require skin-derived DCs, but instead occurs via direct acquisition of sporozoite antigen by lymph-node resident DCs. In this regard it is important that skin-inoculated sporozoites can be found associated with DCs in the lymph nodes [8].

Antigen persistence and maintenance of memory responses: another role for skin draining lymph nodes

Prolonged antigen presentation is crucial for maximal expansion of effector CD8+ T cell responses and recently it was demonstrated that continuous antigen presentation occurs for up to two months after immunization with irradiated sporozoites [42]. This observation is quite striking considering that irradiated sporozoites are not able to undergo proliferation and do not differentiate beyond early liver stages [43, 44]. Apparently, the parasite antigen does not persist as a dormant form of the parasite because treatment with primaquine to eliminate early liver stage parasites has no effect on continuous antigen presentation [42]. Antigen-presenting cells are responsible for trapping antigens, although the precise identity of the cell types involved in presenting persisting antigens is unclear and remains an area of further investigation. Persistent antigen is detected mostly in skin draining lymph nodes although it can also be found in spleen and liver. Continuous antigen presentation to CD8+ T cells is required for renewing and maintaining the memory CD8+ T cell population and in fact naive cells such as recent thymic emigrants, are primed by persisting antigens. It is important that this prolonged antigen presentation does not induce CD8+ T cell exhaustion as described in some chronic viral infection models [45, 46], on the contrary, persistent antigen induces effector T cell differentiation and is necessary to develop or maintain optimal memory responses.

Relevance of the skin stage to the malaria vaccine effort

Several decades ago it was demonstrated that immunization with attenuated sporozoites could protective rodents, primates and humans from challenge with infected mosquito bites. Initially studies in rodents utilized irradiated sporozoites inoculated intravenously. In humans, immunization has always relied upon the bites of irradiated infected mosquitoes with ≥ 950 infected bites required for protection [47]. Calculations based upon the demonstration that individual mosquitoes inoculate on average 125 sporozoites [5], indicate that the dose required for protection in humans is not significantly different from rodent models. Thus, studies in humans clearly demonstrate that sporozoites inoculated into the skin can induce protective immune responses. More recently it has also been shown in the rodent models that sporozoites delivered by mosquito bite or intradermal injection can induce protection equivalent to that observed after intravenous immunization [2, 48, 49].

That attenuated sporozoites inoculated into the dermis induce protection should not be surprising given what we now know of sporozoite biology and priming of the immune response in the dermis and in the lymph nodes that drain this site. Moreover, a significant number of sporozoites, perhaps as high as 50%, may remain in the skin as non-viable parasites or undergoing further development to exoerythrocytic stages [1, 8, 11, 12]. Of the parasites that reach the bloodstream, most do not productively infect hepatocytes; studies with the rodent malaria parasites P. yoelii and P. berghei suggest that at most 25% and 10% of the inoculum, respectively, develops into liver stages [50, 51]. The skin, therefore, is the site where sporozoites may have their greatest exposure to the host immune system and it is not unexpected that a strong immune response is induced first in lymphoid organs associated with this tissue compartment.

Conclusions

Research conducted in several laboratories over the past 10 years has demonstrated that the skin, a compartment originally thought to be irrelevant to malaria infection, is a critical barrier for the sporozoite. Both robust gliding motility as well as the ability to traverse cells are required for dermal exit, yet even under optimal conditions, well-over 50% of sporozoites do not leave the inoculation site. Thus, this is a vulnerable time for the parasite suggesting that antibodies targeting critical processes such as gliding and cell traversal, could have a dramatic impact on infection. The recent explosion in our understanding of sporozoite biology at the inoculation site sets the stage for discovering and testing these new antibody targets.

This initial stage of malaria infection is also critical for the induction of T cell responses that ultimately target infected hepatocytes as priming occurs in the lymph node draining the inoculation site. Ultimately, the immunogenic properties of sporozoites combined with the rich array of immunologically active cells in the skin, confers upon give the dermis a critical role in determining the magnitude and quality of the anti-parasite immune response. As we move forward with candidate malaria vaccines, the biological and immunological importance of this early stage of infection is likely to play a role in vaccine design.

Acknowledgments

PS is supported by NIH R01 AI056840 and FZ by NIH R01 AI44375. The authors are grateful for the support of the Bloomberg Family Foundation.

Footnotes

1This article is published as part of the Special Issue on Immunoparasitology [35:1]

The authors declare no financial conflicts of interest.

References

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Where Malaria Infection and the Host Immune Response Begin

Semin Immunopathol. Author manuscript; available in PMC 2014 Feb 25.

Published in final edited form as:

PMCID: PMC3934925

NIHMSID: NIHMS411807

Johns Hopkins Bloomberg School of Public Health, Malaria Research Institute, 615 North Wolfe St. , Baltimore, MD 21205

See other articles in PMC that cite the published article.

Abstract

Infection by malaria parasites begins with the inoculation of sporozoites into the skin of the host. The early events following sporozoite deposition in the dermis are critical for both the establishment of malaria infection and for the induction of protective immune responses. The initial sporozoite inoculum is generally low and only a small percentage of these sporozoites successfully reach the liver and grow to the next life cycle stage, making this a significant bottleneck for the parasite. Recent studies highlight the importance of sporozoite motility and host cell traversal in dermal exit. Importantly, protective immune responses against sporozoites and liver stages of Plasmodium are induced by dendritic cells in the lymph node draining the skin inoculation site. The cellular, molecular and immunological events that occur in the skin and associated lymph nodes are the topic of this review.

Keywords: malaria, dermis, sporozoites, plasmodium, dendritic cells, CD8+ T cells

Introduction

Malaria, one of the most important infectious diseases worldwide, is caused by protozoan parasites of the genus Plasmodium. These parasites cycle between a vertebrate and mosquito host and experience a significant reduction in numbers during transmission. Sexual or asexual reproductive cycles follow transmission and restore parasite numbers in the mosquito or vertebrate host, respectively. Thus, infection in the vertebrate host has two phases: an asymptomatic pre-erythrocytic stage, when parasite numbers are low, and a symptomatic erythrocytic stage, composed of iterative cycles of replication in host red blood cells. The pre-erythrocytic stage is short-lived, yet critical for the establishment of malaria infection. It is comprised of sporozoites, which are inoculated by infected mosquitoes, and the liver stages (or exoerythrocytic stages) into which they develop. In this review we will focus on the early stages of malaria infection, following the fate of inoculated sporozoites and outlining how the immune response to these stages is initiated and sustained. We will conclude with some thoughts as to how this knowledge can inform the generation of improved malaria vaccine candidates.

The skin stage of malaria infection

Until recently, our knowledge of the molecular interactions between host and parasite during the early stage of malaria infection was limited due to the small numbers of sporozoites and liver stages present in the mammalian host. Indeed, a review of the literature between 1970 to 1995 indicates that malariologists labored under the assumption that sporozoites rapidly left the inoculation site and significant interactions between host and parasite did not begin until sporozoites invaded hepatocytes and began to develop. Recent studies have now shown that sporozoites spend several hours at the inoculation site [1] and initiate an immune response in the lymph nodes which drain this site [2], thus bringing this early stage of infection into the limelight.

Sporozoites reside in mosquito salivary glands and exit with the mosquito’s saliva into the skin of the vertebrate host as the mosquito probes for blood. Salivation stops when the mosquito locates and begins to imbibe blood, thus sporozoites are primarily deposited into the skin and are not inoculated directly into the blood circulation [3, 4]. In most cases, the skin compartment into which sporozoites are inoculated is the dermis since this is the depth to which the mosquito’s proboscis reaches. However, skin thickness varies from one location to another and a minority of sporozoites likely find themselves in the epidermis or sub-cutaneous tissue. The average number of sporozoites inoculated by a single infected mosquito varies enormously and is, to some extent, a function of the salivary gland load [5]. Studies using mosquitoes infected with rodent malaria parasites showed that a single infected mosquito injects between 0 and 1,300 sporozoites with the average inoculum being approximately 125 sporozoites [5]. These studies, however, used laboratory-raised mosquitoes where infection is optimized and salivary gland sporozoite numbers tend to be high. In the field, mosquitoes harbor lower numbers of parasites and it is likely that the inoculum is generally under 100 sporozoites [6, 7].

After their deposition in the skin, sporozoites must locate and penetrate blood vessels in order to reach the liver. Intra-vital microscopy studies show that sporozoites move randomly in the skin until they contact either endothelial cells of the blood or lymphatic system [8, 9]. Sporozoites glide around and along these vessels, enter by an as yet unknown mechanism and are carried away, either rapidly by the blood circulation, or slowly by the lymphatic system [8]. Although some sporozoites rapidly leave the injection site, many take hours to exit and enter the bloodstream. That transit to the bloodstream could take hours was initially suggested by experiments in monkeys with the primate malaria parasite Plasmodium cynomolgi, in which it was demonstrated that transplantation of skin containing the inoculation site, up to 2 hours after sporozoite injection, resulted in infection of naïve recipients [10]. More recently, using the rodent malaria parasite Plasmodium yoelii, which enables a more quantitative and comprehensive analysis, it was demonstrated that sporozoites exit the dermis and enter the blood circulation in a slow trickle extending for 2 to 3 hours after their inoculation [1]. Some sporozoites do not enter the bloodstream and instead enter the lymphatic circulation and go to the draining lymph node. Studies have shown that approximately 15–20% of the inoculum ends up in the draining lymph node [1, 2, 8]. These sporozoites, though at least initially alive, ultimately do not continue further and likely become fodder for the immune response [2, 8].

It is likely that the remainder of the inoculum is destroyed at the site of deposition, likely by the innate immune response of the host, although this has, to date, not been well-studied. Recently, however, it was shown that a small proportion, between 0.5 and 5%, of the inoculated sporozoites remain and begin to develop into exoerythrocytic stages at the inoculation site [11, 12]. Thus far this has only been studied using rodent malaria parasites so it is possible that the development of exoerythrocytic stages in an aberrant location may result from a non-optimal host-parasite combination since the natural hosts of rodent malaria parasites are African thicket rats. Equally possible is that this may be an evolutionary relic since the avian malaria parasites, with whom the rodent and primate parasites share a common ancestor, develop into exoerythrocytic stages in mesodermal tissue including the skin. Importantly, these aberrantly developing parasites are not able to initiate a blood stage infection [12]. This is possibly because the merozoites within the exoerythrocytic forms do not fully mature although imaging data argues that this is not the case [11]. More likely it is because these parasites cannot easily access the blood circulation from this location: the liver sinusoids with their fenestrated endothelia provide a more direct route to the blood circulation than the closed endothelia of the blood. Nonetheless, it will be important to determine whether these skin exoerythrocytic stages contribute to the adaptive immune response that targets infected hepatocytes and whether this is a feature of malaria infection that is shared by all Plasmodium species.

Sporozoite exit from the dermis

Two sporozoite behaviors are required for dermal exit: motility and an ability to traverse cells. Sporozoites move by gliding motility, which is powered by an actin-myosin motor beneath their plasma membrane (reviewed in [13]. This motor is connected to the sporozoite surface via the cytoplasmic domain of a transmembrane surface protein called TRAP, (thrombospondin related anonymous protein) which has extracellular adhesive domains that bind to matrix such that the force of the motor translocates TRAP posteriorly, propelling the sporozoite forward. Previous studies have demonstrated that sporozoites actively invade hepatocytes and gliding motility is required for cell invasion [14]. More recently it has been shown that robust gliding is critical for sporozoite exit from the skin: sporozoites with mutations in TRAP which result in slow staccato movement have a much more pronounced effect on infectivity after intradermal inoculation than after intravenous injection [15]. Another critical property for dermal exit is the ability of sporozoites to traverse host cells, wounding these cells as they enter and exit [16, 17]. Mutants deficient in proteins required for cell traversal have normal infectivity when placed directly on hepatocytes in vitro yet are substantially less infective in vivo where they must exit the dermis and traverse the liver sinusoid to reach their target cell [16, 18–20]. In vivo imaging of fluorescent cell traversal mutants demonstrates that they are not able to efficiently move through the skin, becoming immobilized after contacting cells [16]. These data raise the possibility that cell traversal may also be a mechanism by which sporozoites escape phagocytic cells that arrive at the site in response to the mosquito’s saliva [16]. Importantly migrating sporozoites must switch to an invasive phenotype once they reach the liver. Recent studies have shown that the major surface protein of sporozoites, the circumsporozoite protein or CSP, is critical for this switch [21]. CSP has a cell adhesive domain in its carboxy-terminus which is masked in salivary gland sporozoites. This domain remains masked as sporozoites migrate through the skin and then upon contact with hepatocytes, CSP is proteolytically processed by a parasite protease, revealing this domain and changing a migratory sporozoite into an invasive one. Although the signal for CSP cleavage and the switch to an invasive phenotype are incompletely understood, the highly sulfated heparan sulfate proteoglycans specific to hepatocytes likely play a role [17]. Thus, shortly after their arrival in the liver, cell traversal activity is stopped and invasion, with development into the next life cycle stage, proceeds.

Induction of protective anti-Plasmodium CD8+ T cell responses

Early studies using experimental models clearly demonstrated that protective immunity against sporozoite-induced infection requires antigen-specific CD8+ T cells [22, 23]. Some of these CD8+ T cells were specific for defined epitopes in CSP, and these T cells strongly inhibited the development of liver stage parasites [24]. Subsequent studies using T-cell receptor transgenic CD8+ T cells specific for a CSP epitope, demonstrated that these T cells were primed primarily in lymph nodes draining the skin where sporozoites were deposited [2]. Forty-eight hours after immunization, either by the bites of irradiated infected mosquitoes or via intradermal inoculation of irradiated sporozoites, epitope-specific CD8+ T cells producing IFN-γ were first detected only in the lymph nodes draining the inoculation site. Once CD8+ T cells are activated in lymph nodes, they migrate to other lymphoid and non-lymphoid organs including the liver. The importance of T cell priming in skin draining lymph nodes was demonstrated in experiments in which these lymph nodes were surgically ablated or through pharmacological inhibition of T-cell egress from lymph nodes. Under these experimental conditions the number of T cells reaching the liver was drastically reduced and the protective capacity of the anti-parasite CD8+ T cell-mediated protection was diminished.

An intriguing observation made in early studies indicated that protective immunity could be induced with irradiated yet live sporozoites [25]. Consistent with this observation, it was later shown that the induction of effector CD8+ T cell responses also requires immunization with live sporozoites [2, 26]. The strict requirement of viable sporozoites was previously interpreted as evidence that sporozoite invasion of hepatocytes was required for the induction of protective immune responses and this led to the idea that liver stage antigens were critical to induce protective immunity. However, the demonstration that protective CD8+ T cells are induced in the skin draining lymph node suggests that these responses are induced after complex interactions between professional antigen presenting cells and sporozoites.

Antigen presentation by dendritic cells (DCs)

It is well established that CD11c+ DCs play a critical role in the priming of Plasmodium specific CD8+ T cells. Studies have shown that DCs incubated in vitro with sporozoites or obtained from lymph nodes of mice previously injected with sporozoites present parasite epitopes to T cells [2, 27, 28]. Moreover, in vivo depletion of the CD11c+ DCs abolishes the induction of parasite specific CD8+ T cell responses [29]. The skin is a tissue that harbors large numbers of DCs belonging to phenotypically and functionally distinct groups which are likely to interact with parasites. In addition, there are large numbers of lymph node-resident DCs which may also play a role in inducing T cell responses, particularly considering that a significant number of parasites migrate to lymph nodes draining the inoculation site.

The mechanisms by which DCs acquire antigen from live parasites is an intriguing yet poorly understood process. It is well known that the CSP and other parasite molecules are shed as sporozoites move and conceivably, these secreted molecules may be endocytosed and processed by DCs, and peptides within these antigens eventually presented to T cells. Alternatively, as was outlined earlier, the critical role of cell traversal for exit from the dermis means that sporozoites may also directly deposit antigen in the cytosol of DCs.

While the precise mechanisms of DC antigen uptake are unknown, experimental evidence indicates that DC priming of CD8+ T cells occurs by antigen cross-presentation. This notion is supported by studies in which Toll-like receptor ligands administered prior to sporozoite immunization, inhibit the induction of CD8+ T cell responses [2]. It is known that TLR ligands hasten the maturation of DCs, a process that is accompanied by an inhibition of their endocytic activity [30, 31]. Recently, these studies were expanded using new methodological approaches and novel transgenic parasites. P. berghei parasites expressing mutant CSP containing the H-2Kb SIINFEKL epitope have enabled studies in genetically modified C57Bl/6 (H-2b) mice deficient in molecules involved in antigen processing and presentation [32]. These studies demonstrated that priming of CD8+ T cells required intact endocytic function as experiments performed in mice lacking the endosomal protein Unc93B1 failed to develop robust CD8+ T cell responses. Unc93B1 is believed to mediate translocation of endocytosed molecules to the ER which are subsequently transported to the cytosol where they are processed to generate peptide epitopes [33]. A critical role for cross-presentation is further supported by in vivo experiments in which treatment of mice with cytochrome-c resulted in a severely reduced CD8+ T cell response [32]. Studies in other systems show that after cytochrome-c is internalized by endocytosis, it is translocated to the cytosol where it induces apoptosis, thus depleting antigen cross-presenting cells [34–36]. Finally, no CD8+ T cell responses were observed in mice lacking the TAP1 molecule which mediates the transport of the proteosome-processed CSP peptides from the cytosol to the ER. This clearly indicates that CSP must reach the cytosol where it is processed, generating epitope-containing peptides that are transported by TAP from the ER to where they bind to class l MHC molecules.

The precise tissue compartment where the capture of parasite antigen occurs and the identity of the DC subpopulation involved in this process, are critical matters that remain to be defined. As discussed in the preceding sections, intradermally inoculated sporozoites remain in the skin for over one hour and exit the skin in a slow trickle [1]. In addition a significant proportion of sporozoites migrate to the draining lymph nodes [1, 2, 8]. These findings raise an important question: where do DCs acquire sporozoite antigen? An obvious possibility is that sporozoite antigen is acquired in the dermis by skin-resident DCs that then migrate to the lymph nodes where they present antigen directly to naive CD8+ T cells. At least three distinct subsets of skin-resident migratory DCs have been characterized: Langerhans cells, dermal DCs, and langerin+CD103+ dermal DCs [37]. Langerin+CD103+ dermal DCs are a subset of migratory DCs that play a key role in cross-presenting viral and self antigens [37–40] and their possible involvement in cross-presentation of sporozoite antigens requires further investigation. Alternatively, dermal DCs could transfer skin-derived antigen to lymph node resident DCs for CD8+ T cell priming as shown in studies using herpes simplex virus [41]. Finally, it is also possible that CD8+ T cell priming does not require skin-derived DCs, but instead occurs via direct acquisition of sporozoite antigen by lymph-node resident DCs. In this regard it is important that skin-inoculated sporozoites can be found associated with DCs in the lymph nodes [8].

Antigen persistence and maintenance of memory responses: another role for skin draining lymph nodes

Prolonged antigen presentation is crucial for maximal expansion of effector CD8+ T cell responses and recently it was demonstrated that continuous antigen presentation occurs for up to two months after immunization with irradiated sporozoites [42]. This observation is quite striking considering that irradiated sporozoites are not able to undergo proliferation and do not differentiate beyond early liver stages [43, 44]. Apparently, the parasite antigen does not persist as a dormant form of the parasite because treatment with primaquine to eliminate early liver stage parasites has no effect on continuous antigen presentation [42]. Antigen-presenting cells are responsible for trapping antigens, although the precise identity of the cell types involved in presenting persisting antigens is unclear and remains an area of further investigation. Persistent antigen is detected mostly in skin draining lymph nodes although it can also be found in spleen and liver. Continuous antigen presentation to CD8+ T cells is required for renewing and maintaining the memory CD8+ T cell population and in fact naive cells such as recent thymic emigrants, are primed by persisting antigens. It is important that this prolonged antigen presentation does not induce CD8+ T cell exhaustion as described in some chronic viral infection models [45, 46], on the contrary, persistent antigen induces effector T cell differentiation and is necessary to develop or maintain optimal memory responses.

Relevance of the skin stage to the malaria vaccine effort

Several decades ago it was demonstrated that immunization with attenuated sporozoites could protective rodents, primates and humans from challenge with infected mosquito bites. Initially studies in rodents utilized irradiated sporozoites inoculated intravenously. In humans, immunization has always relied upon the bites of irradiated infected mosquitoes with ≥ 950 infected bites required for protection [47]. Calculations based upon the demonstration that individual mosquitoes inoculate on average 125 sporozoites [5], indicate that the dose required for protection in humans is not significantly different from rodent models. Thus, studies in humans clearly demonstrate that sporozoites inoculated into the skin can induce protective immune responses. More recently it has also been shown in the rodent models that sporozoites delivered by mosquito bite or intradermal injection can induce protection equivalent to that observed after intravenous immunization [2, 48, 49].

That attenuated sporozoites inoculated into the dermis induce protection should not be surprising given what we now know of sporozoite biology and priming of the immune response in the dermis and in the lymph nodes that drain this site. Moreover, a significant number of sporozoites, perhaps as high as 50%, may remain in the skin as non-viable parasites or undergoing further development to exoerythrocytic stages [1, 8, 11, 12]. Of the parasites that reach the bloodstream, most do not productively infect hepatocytes; studies with the rodent malaria parasites P. yoelii and P. berghei suggest that at most 25% and 10% of the inoculum, respectively, develops into liver stages [50, 51]. The skin, therefore, is the site where sporozoites may have their greatest exposure to the host immune system and it is not unexpected that a strong immune response is induced first in lymphoid organs associated with this tissue compartment.

Conclusions

Research conducted in several laboratories over the past 10 years has demonstrated that the skin, a compartment originally thought to be irrelevant to malaria infection, is a critical barrier for the sporozoite. Both robust gliding motility as well as the ability to traverse cells are required for dermal exit, yet even under optimal conditions, well-over 50% of sporozoites do not leave the inoculation site. Thus, this is a vulnerable time for the parasite suggesting that antibodies targeting critical processes such as gliding and cell traversal, could have a dramatic impact on infection. The recent explosion in our understanding of sporozoite biology at the inoculation site sets the stage for discovering and testing these new antibody targets.

This initial stage of malaria infection is also critical for the induction of T cell responses that ultimately target infected hepatocytes as priming occurs in the lymph node draining the inoculation site. Ultimately, the immunogenic properties of sporozoites combined with the rich array of immunologically active cells in the skin, confers upon give the dermis a critical role in determining the magnitude and quality of the anti-parasite immune response. As we move forward with candidate malaria vaccines, the biological and immunological importance of this early stage of infection is likely to play a role in vaccine design.

Acknowledgments

PS is supported by NIH R01 AI056840 and FZ by NIH R01 AI44375. The authors are grateful for the support of the Bloomberg Family Foundation.

Footnotes

1This article is published as part of the Special Issue on Immunoparasitology [35:1]

The authors declare no financial conflicts of interest.

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Where Malaria Infection and the Host Immune Response Begin

Semin Immunopathol. Author manuscript; available in PMC 2014 Feb 25.

Published in final edited form as:

PMCID: PMC3934925

NIHMSID: NIHMS411807

Johns Hopkins Bloomberg School of Public Health, Malaria Research Institute, 615 North Wolfe St., Baltimore, MD 21205

See other articles in PMC that cite the published article.

Abstract

Infection by malaria parasites begins with the inoculation of sporozoites into the skin of the host. The early events following sporozoite deposition in the dermis are critical for both the establishment of malaria infection and for the induction of protective immune responses. The initial sporozoite inoculum is generally low and only a small percentage of these sporozoites successfully reach the liver and grow to the next life cycle stage, making this a significant bottleneck for the parasite. Recent studies highlight the importance of sporozoite motility and host cell traversal in dermal exit. Importantly, protective immune responses against sporozoites and liver stages of Plasmodium are induced by dendritic cells in the lymph node draining the skin inoculation site. The cellular, molecular and immunological events that occur in the skin and associated lymph nodes are the topic of this review.

Keywords: malaria, dermis, sporozoites, plasmodium, dendritic cells, CD8+ T cells

Introduction

Malaria, one of the most important infectious diseases worldwide, is caused by protozoan parasites of the genus Plasmodium. These parasites cycle between a vertebrate and mosquito host and experience a significant reduction in numbers during transmission. Sexual or asexual reproductive cycles follow transmission and restore parasite numbers in the mosquito or vertebrate host, respectively. Thus, infection in the vertebrate host has two phases: an asymptomatic pre-erythrocytic stage, when parasite numbers are low, and a symptomatic erythrocytic stage, composed of iterative cycles of replication in host red blood cells. The pre-erythrocytic stage is short-lived, yet critical for the establishment of malaria infection. It is comprised of sporozoites, which are inoculated by infected mosquitoes, and the liver stages (or exoerythrocytic stages) into which they develop. In this review we will focus on the early stages of malaria infection, following the fate of inoculated sporozoites and outlining how the immune response to these stages is initiated and sustained. We will conclude with some thoughts as to how this knowledge can inform the generation of improved malaria vaccine candidates.

The skin stage of malaria infection

Until recently, our knowledge of the molecular interactions between host and parasite during the early stage of malaria infection was limited due to the small numbers of sporozoites and liver stages present in the mammalian host. Indeed, a review of the literature between 1970 to 1995 indicates that malariologists labored under the assumption that sporozoites rapidly left the inoculation site and significant interactions between host and parasite did not begin until sporozoites invaded hepatocytes and began to develop. Recent studies have now shown that sporozoites spend several hours at the inoculation site [1] and initiate an immune response in the lymph nodes which drain this site [2], thus bringing this early stage of infection into the limelight.

Sporozoites reside in mosquito salivary glands and exit with the mosquito’s saliva into the skin of the vertebrate host as the mosquito probes for blood. Salivation stops when the mosquito locates and begins to imbibe blood, thus sporozoites are primarily deposited into the skin and are not inoculated directly into the blood circulation [3, 4]. In most cases, the skin compartment into which sporozoites are inoculated is the dermis since this is the depth to which the mosquito’s proboscis reaches. However, skin thickness varies from one location to another and a minority of sporozoites likely find themselves in the epidermis or sub-cutaneous tissue. The average number of sporozoites inoculated by a single infected mosquito varies enormously and is, to some extent, a function of the salivary gland load [5]. Studies using mosquitoes infected with rodent malaria parasites showed that a single infected mosquito injects between 0 and 1,300 sporozoites with the average inoculum being approximately 125 sporozoites [5]. These studies, however, used laboratory-raised mosquitoes where infection is optimized and salivary gland sporozoite numbers tend to be high. In the field, mosquitoes harbor lower numbers of parasites and it is likely that the inoculum is generally under 100 sporozoites [6, 7].

After their deposition in the skin, sporozoites must locate and penetrate blood vessels in order to reach the liver. Intra-vital microscopy studies show that sporozoites move randomly in the skin until they contact either endothelial cells of the blood or lymphatic system [8, 9]. Sporozoites glide around and along these vessels, enter by an as yet unknown mechanism and are carried away, either rapidly by the blood circulation, or slowly by the lymphatic system [8]. Although some sporozoites rapidly leave the injection site, many take hours to exit and enter the bloodstream. That transit to the bloodstream could take hours was initially suggested by experiments in monkeys with the primate malaria parasite Plasmodium cynomolgi, in which it was demonstrated that transplantation of skin containing the inoculation site, up to 2 hours after sporozoite injection, resulted in infection of naïve recipients [10]. More recently, using the rodent malaria parasite Plasmodium yoelii, which enables a more quantitative and comprehensive analysis, it was demonstrated that sporozoites exit the dermis and enter the blood circulation in a slow trickle extending for 2 to 3 hours after their inoculation [1]. Some sporozoites do not enter the bloodstream and instead enter the lymphatic circulation and go to the draining lymph node. Studies have shown that approximately 15–20% of the inoculum ends up in the draining lymph node [1, 2, 8]. These sporozoites, though at least initially alive, ultimately do not continue further and likely become fodder for the immune response [2, 8].

It is likely that the remainder of the inoculum is destroyed at the site of deposition, likely by the innate immune response of the host, although this has, to date, not been well-studied. Recently, however, it was shown that a small proportion, between 0.5 and 5%, of the inoculated sporozoites remain and begin to develop into exoerythrocytic stages at the inoculation site [11, 12]. Thus far this has only been studied using rodent malaria parasites so it is possible that the development of exoerythrocytic stages in an aberrant location may result from a non-optimal host-parasite combination since the natural hosts of rodent malaria parasites are African thicket rats. Equally possible is that this may be an evolutionary relic since the avian malaria parasites, with whom the rodent and primate parasites share a common ancestor, develop into exoerythrocytic stages in mesodermal tissue including the skin. Importantly, these aberrantly developing parasites are not able to initiate a blood stage infection [12]. This is possibly because the merozoites within the exoerythrocytic forms do not fully mature although imaging data argues that this is not the case [11]. More likely it is because these parasites cannot easily access the blood circulation from this location: the liver sinusoids with their fenestrated endothelia provide a more direct route to the blood circulation than the closed endothelia of the blood. Nonetheless, it will be important to determine whether these skin exoerythrocytic stages contribute to the adaptive immune response that targets infected hepatocytes and whether this is a feature of malaria infection that is shared by all Plasmodium species.

Sporozoite exit from the dermis

Two sporozoite behaviors are required for dermal exit: motility and an ability to traverse cells. Sporozoites move by gliding motility, which is powered by an actin-myosin motor beneath their plasma membrane (reviewed in [13]. This motor is connected to the sporozoite surface via the cytoplasmic domain of a transmembrane surface protein called TRAP, (thrombospondin related anonymous protein) which has extracellular adhesive domains that bind to matrix such that the force of the motor translocates TRAP posteriorly, propelling the sporozoite forward. Previous studies have demonstrated that sporozoites actively invade hepatocytes and gliding motility is required for cell invasion [14]. More recently it has been shown that robust gliding is critical for sporozoite exit from the skin: sporozoites with mutations in TRAP which result in slow staccato movement have a much more pronounced effect on infectivity after intradermal inoculation than after intravenous injection [15]. Another critical property for dermal exit is the ability of sporozoites to traverse host cells, wounding these cells as they enter and exit [16, 17]. Mutants deficient in proteins required for cell traversal have normal infectivity when placed directly on hepatocytes in vitro yet are substantially less infective in vivo where they must exit the dermis and traverse the liver sinusoid to reach their target cell [16, 18–20]. In vivo imaging of fluorescent cell traversal mutants demonstrates that they are not able to efficiently move through the skin, becoming immobilized after contacting cells [16]. These data raise the possibility that cell traversal may also be a mechanism by which sporozoites escape phagocytic cells that arrive at the site in response to the mosquito’s saliva [16]. Importantly migrating sporozoites must switch to an invasive phenotype once they reach the liver. Recent studies have shown that the major surface protein of sporozoites, the circumsporozoite protein or CSP, is critical for this switch [21]. CSP has a cell adhesive domain in its carboxy-terminus which is masked in salivary gland sporozoites. This domain remains masked as sporozoites migrate through the skin and then upon contact with hepatocytes, CSP is proteolytically processed by a parasite protease, revealing this domain and changing a migratory sporozoite into an invasive one. Although the signal for CSP cleavage and the switch to an invasive phenotype are incompletely understood, the highly sulfated heparan sulfate proteoglycans specific to hepatocytes likely play a role [17]. Thus, shortly after their arrival in the liver, cell traversal activity is stopped and invasion, with development into the next life cycle stage, proceeds.

Induction of protective anti-Plasmodium CD8+ T cell responses

Early studies using experimental models clearly demonstrated that protective immunity against sporozoite-induced infection requires antigen-specific CD8+ T cells [22, 23]. Some of these CD8+ T cells were specific for defined epitopes in CSP, and these T cells strongly inhibited the development of liver stage parasites [24]. Subsequent studies using T-cell receptor transgenic CD8+ T cells specific for a CSP epitope, demonstrated that these T cells were primed primarily in lymph nodes draining the skin where sporozoites were deposited [2]. Forty-eight hours after immunization, either by the bites of irradiated infected mosquitoes or via intradermal inoculation of irradiated sporozoites, epitope-specific CD8+ T cells producing IFN-γ were first detected only in the lymph nodes draining the inoculation site. Once CD8+ T cells are activated in lymph nodes, they migrate to other lymphoid and non-lymphoid organs including the liver. The importance of T cell priming in skin draining lymph nodes was demonstrated in experiments in which these lymph nodes were surgically ablated or through pharmacological inhibition of T-cell egress from lymph nodes. Under these experimental conditions the number of T cells reaching the liver was drastically reduced and the protective capacity of the anti-parasite CD8+ T cell-mediated protection was diminished.

An intriguing observation made in early studies indicated that protective immunity could be induced with irradiated yet live sporozoites [25]. Consistent with this observation, it was later shown that the induction of effector CD8+ T cell responses also requires immunization with live sporozoites [2, 26]. The strict requirement of viable sporozoites was previously interpreted as evidence that sporozoite invasion of hepatocytes was required for the induction of protective immune responses and this led to the idea that liver stage antigens were critical to induce protective immunity. However, the demonstration that protective CD8+ T cells are induced in the skin draining lymph node suggests that these responses are induced after complex interactions between professional antigen presenting cells and sporozoites.

Antigen presentation by dendritic cells (DCs)

It is well established that CD11c+ DCs play a critical role in the priming of Plasmodium specific CD8+ T cells. Studies have shown that DCs incubated in vitro with sporozoites or obtained from lymph nodes of mice previously injected with sporozoites present parasite epitopes to T cells [2, 27, 28]. Moreover, in vivo depletion of the CD11c+ DCs abolishes the induction of parasite specific CD8+ T cell responses [29]. The skin is a tissue that harbors large numbers of DCs belonging to phenotypically and functionally distinct groups which are likely to interact with parasites. In addition, there are large numbers of lymph node-resident DCs which may also play a role in inducing T cell responses, particularly considering that a significant number of parasites migrate to lymph nodes draining the inoculation site.

The mechanisms by which DCs acquire antigen from live parasites is an intriguing yet poorly understood process. It is well known that the CSP and other parasite molecules are shed as sporozoites move and conceivably, these secreted molecules may be endocytosed and processed by DCs, and peptides within these antigens eventually presented to T cells. Alternatively, as was outlined earlier, the critical role of cell traversal for exit from the dermis means that sporozoites may also directly deposit antigen in the cytosol of DCs.

While the precise mechanisms of DC antigen uptake are unknown, experimental evidence indicates that DC priming of CD8+ T cells occurs by antigen cross-presentation. This notion is supported by studies in which Toll-like receptor ligands administered prior to sporozoite immunization, inhibit the induction of CD8+ T cell responses [2]. It is known that TLR ligands hasten the maturation of DCs, a process that is accompanied by an inhibition of their endocytic activity [30, 31]. Recently, these studies were expanded using new methodological approaches and novel transgenic parasites. P. berghei parasites expressing mutant CSP containing the H-2Kb SIINFEKL epitope have enabled studies in genetically modified C57Bl/6 (H-2b) mice deficient in molecules involved in antigen processing and presentation [32]. These studies demonstrated that priming of CD8+ T cells required intact endocytic function as experiments performed in mice lacking the endosomal protein Unc93B1 failed to develop robust CD8+ T cell responses. Unc93B1 is believed to mediate translocation of endocytosed molecules to the ER which are subsequently transported to the cytosol where they are processed to generate peptide epitopes [33]. A critical role for cross-presentation is further supported by in vivo experiments in which treatment of mice with cytochrome-c resulted in a severely reduced CD8+ T cell response [32]. Studies in other systems show that after cytochrome-c is internalized by endocytosis, it is translocated to the cytosol where it induces apoptosis, thus depleting antigen cross-presenting cells [34–36]. Finally, no CD8+ T cell responses were observed in mice lacking the TAP1 molecule which mediates the transport of the proteosome-processed CSP peptides from the cytosol to the ER. This clearly indicates that CSP must reach the cytosol where it is processed, generating epitope-containing peptides that are transported by TAP from the ER to where they bind to class l MHC molecules.

The precise tissue compartment where the capture of parasite antigen occurs and the identity of the DC subpopulation involved in this process, are critical matters that remain to be defined. As discussed in the preceding sections, intradermally inoculated sporozoites remain in the skin for over one hour and exit the skin in a slow trickle [1]. In addition a significant proportion of sporozoites migrate to the draining lymph nodes [1, 2, 8]. These findings raise an important question: where do DCs acquire sporozoite antigen? An obvious possibility is that sporozoite antigen is acquired in the dermis by skin-resident DCs that then migrate to the lymph nodes where they present antigen directly to naive CD8+ T cells. At least three distinct subsets of skin-resident migratory DCs have been characterized: Langerhans cells, dermal DCs, and langerin+CD103+ dermal DCs [37]. Langerin+CD103+ dermal DCs are a subset of migratory DCs that play a key role in cross-presenting viral and self antigens [37–40] and their possible involvement in cross-presentation of sporozoite antigens requires further investigation. Alternatively, dermal DCs could transfer skin-derived antigen to lymph node resident DCs for CD8+ T cell priming as shown in studies using herpes simplex virus [41]. Finally, it is also possible that CD8+ T cell priming does not require skin-derived DCs, but instead occurs via direct acquisition of sporozoite antigen by lymph-node resident DCs. In this regard it is important that skin-inoculated sporozoites can be found associated with DCs in the lymph nodes [8].

Antigen persistence and maintenance of memory responses: another role for skin draining lymph nodes

Prolonged antigen presentation is crucial for maximal expansion of effector CD8+ T cell responses and recently it was demonstrated that continuous antigen presentation occurs for up to two months after immunization with irradiated sporozoites [42]. This observation is quite striking considering that irradiated sporozoites are not able to undergo proliferation and do not differentiate beyond early liver stages [43, 44]. Apparently, the parasite antigen does not persist as a dormant form of the parasite because treatment with primaquine to eliminate early liver stage parasites has no effect on continuous antigen presentation [42]. Antigen-presenting cells are responsible for trapping antigens, although the precise identity of the cell types involved in presenting persisting antigens is unclear and remains an area of further investigation. Persistent antigen is detected mostly in skin draining lymph nodes although it can also be found in spleen and liver. Continuous antigen presentation to CD8+ T cells is required for renewing and maintaining the memory CD8+ T cell population and in fact naive cells such as recent thymic emigrants, are primed by persisting antigens. It is important that this prolonged antigen presentation does not induce CD8+ T cell exhaustion as described in some chronic viral infection models [45, 46], on the contrary, persistent antigen induces effector T cell differentiation and is necessary to develop or maintain optimal memory responses.

Relevance of the skin stage to the malaria vaccine effort

Several decades ago it was demonstrated that immunization with attenuated sporozoites could protective rodents, primates and humans from challenge with infected mosquito bites. Initially studies in rodents utilized irradiated sporozoites inoculated intravenously. In humans, immunization has always relied upon the bites of irradiated infected mosquitoes with ≥ 950 infected bites required for protection [47]. Calculations based upon the demonstration that individual mosquitoes inoculate on average 125 sporozoites [5], indicate that the dose required for protection in humans is not significantly different from rodent models. Thus, studies in humans clearly demonstrate that sporozoites inoculated into the skin can induce protective immune responses. More recently it has also been shown in the rodent models that sporozoites delivered by mosquito bite or intradermal injection can induce protection equivalent to that observed after intravenous immunization [2, 48, 49].

That attenuated sporozoites inoculated into the dermis induce protection should not be surprising given what we now know of sporozoite biology and priming of the immune response in the dermis and in the lymph nodes that drain this site. Moreover, a significant number of sporozoites, perhaps as high as 50%, may remain in the skin as non-viable parasites or undergoing further development to exoerythrocytic stages [1, 8, 11, 12]. Of the parasites that reach the bloodstream, most do not productively infect hepatocytes; studies with the rodent malaria parasites P. yoelii and P. berghei suggest that at most 25% and 10% of the inoculum, respectively, develops into liver stages [50, 51]. The skin, therefore, is the site where sporozoites may have their greatest exposure to the host immune system and it is not unexpected that a strong immune response is induced first in lymphoid organs associated with this tissue compartment.

Conclusions

Research conducted in several laboratories over the past 10 years has demonstrated that the skin, a compartment originally thought to be irrelevant to malaria infection, is a critical barrier for the sporozoite. Both robust gliding motility as well as the ability to traverse cells are required for dermal exit, yet even under optimal conditions, well-over 50% of sporozoites do not leave the inoculation site. Thus, this is a vulnerable time for the parasite suggesting that antibodies targeting critical processes such as gliding and cell traversal, could have a dramatic impact on infection. The recent explosion in our understanding of sporozoite biology at the inoculation site sets the stage for discovering and testing these new antibody targets.

This initial stage of malaria infection is also critical for the induction of T cell responses that ultimately target infected hepatocytes as priming occurs in the lymph node draining the inoculation site. Ultimately, the immunogenic properties of sporozoites combined with the rich array of immunologically active cells in the skin, confers upon give the dermis a critical role in determining the magnitude and quality of the anti-parasite immune response. As we move forward with candidate malaria vaccines, the biological and immunological importance of this early stage of infection is likely to play a role in vaccine design.

Acknowledgments

PS is supported by NIH R01 AI056840 and FZ by NIH R01 AI44375. The authors are grateful for the support of the Bloomberg Family Foundation.

Footnotes

1This article is published as part of the Special Issue on Immunoparasitology [35:1]

The authors declare no financial conflicts of interest.

References

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Malaria: Symptoms & Types

What Is Malaria?

Malaria is a serious and sometimes life-threatening tropical disease that is caused by a parasite and spreads through mosquitoes. It kills more than 445,000 people a year, many of them children in Africa.

Although malaria is almost wiped out in the United States, you can still get the disease when you travel to other parts of the world. The United States has about 1,700 malaria cases every year from immigrants and travelers returning from countries where malaria is more common.

These countries have climates that are hot enough for the malaria parasites and the mosquitoes that carry them to thrive. Before you travel, check the CDC’s website to see whether your destination is a hotspot for malaria. You may have to take pills before, during, and after your trip to lower your chances of getting it.

Malaria Causes and Risk Factors

Malaria is caused by plasmodium parasites, which are carried by anophelesmosquitoes.

Only female mosquitoes spread the malaria parasites. When a mosquito bites a person who has malaria, it drinks the person’s blood, which contains the parasites. When the mosquito bites another person, it injects the parasites into that person. That’s how the disease spreads.

Once the parasites enter your body, they travel to your liver, where they multiply. They invade your red blood cells, which carry oxygen. The parasites get inside them, lay their eggs, and multiply until the red blood cell bursts. This releases more parasites into your bloodstream. As they attack more of your healthy red blood cells, this infection can make you very sick.

Malaria isn’t contagious, meaning it can’t be spread from person to person. But it can be spread in the following ways:

  • From a pregnant mother to their unborn baby
  • Sharing needles
  • Blood transfusions
  • Organ transplant

Malaria is most common in warm-weather climates. It’s found most often in:

  • Africa
  • South and Southeast Asia
  • The Middle East
  • Central and South America 
  • Oceania

Types of Malaria

There are five species of plasmodiumparasites that affect humans. Two of them are considered the most dangerous:

P. falciparum.This is the most common malaria parasite in Africa, and it causes the most malaria-related deaths in the world. P. falciparum multiplies very quickly, causing serious blood loss and clogged blood vessels.

P. vivax. This is the malaria parasite most commonly found outside of sub-Saharan Africa, especially in Asia and Latin America. This species can lie dormant, then rise up to infect your blood months or years after the mosquito bite.

Symptoms

Symptoms for malaria usually start about 10-15 days after the infected mosquito bite. Along with high fever, shaking chills, and sweating, they can include:

Throwing up or feeling like you’re going to

Here are some things to keep in mind:

  • Because the signs are so similar to cold or flu symptoms, it might be hard to tell what you have at first.
  • Malaria symptoms don’t always show up within 2 weeks, especially if it’s a P. vivax infection.
  • People who live in areas with lots of malaria cases may become partially immune after being exposed to it throughout their lives. But this can change if they move to a place where they’re not around the parasite.

When to Call a Doctor About Malaria

Given how quickly malaria can become life-threatening, it’s important to get medical care as quickly as possible. Young children, infants, and pregnant women have an especially high chance for severe cases of malaria.

Seek care if you get a high fever while living in or traveling to an area that has a high chance for malaria. You should still get medical help even if you see the symptoms many weeks, months, or a year after your travel.

Malaria Diagnosis

Your doctor will ask you about your medical history and any recent travel and do a physical exam.

You’ll also get a blood test, which can tell your doctor:

  • If the parasite is in your blood
  • If certain medications will work against the parasite
  • If your body has ever made antibodies to fight off malaria 

Types of blood tests for malaria include:

Thick and thin blood smears. These are the most common and accurate malaria tests. A lab technician, doctor, or nurse will take some of your blood and send it to a lab to be stained to make any parasites show clearly. The technician spreads it on a glass slide and looks at it with a microscope. A thin blood smear, also called a blood film, is one drop of blood spread across most of the slide. A thick smear drops the blood on a small area. A normal test does two of each.

The number of malaria parasites in your blood can change each day. So your test might say you don’t have malaria even if you do. For that reason, you may need your blood drawn several times over 2 or 3 days for the best results.

Rapid diagnostic test. Also called RDT or antigen testing, this is a quick option when blood draws and smears aren’t available. Blood taken from a prick on your finger is put on a test strip that changes color to show whether you have malaria or not.

This test usually can’t tell which of the four common species of malaria parasites caused your infection. It also can’t tell whether the infection is minor or major. Your doctor should follow up all results with blood smears.

Molecular test. Also known as polymerase chain reaction test, it can identify the type of parasite, which helps your doctor decide which drugs to prescribe. This test is a good choice if your blood has low number of parasites or if the results of your blood smear are vague.

Antibody test. Doctors use this to find out if you’ve had malaria before. It looks for antibodies that show up in the blood after an infection.

Drug resistance test. Some malaria parasites are resistant to drugs. But doctors can test your blood to see if certain drugs will work.

Other blood tests. You may also have blood taken for a blood count and chemistry panel. This can tell your doctor how serious your infection is and if it’s causing other problems, like anemia or kidney failure.

Malaria Treatment

The treatment your doctor recommends will depend on things like:

  • The type of parasite you have
  • How bad your symptoms are
  • The geographic area where you got infected
  • Your age 
  • Whether you’re pregnant

Medications doctors use to treat malaria include:

  • Chloroquine or hydroxychloroquine. Your doctor may recommend one of these drugs if your symptoms aren’t serious and you’re in an area where the parasite hasn’t become resistant to chloroquine. 
  • Artemisinin-based combination therapy (ACT). This combines two medicines that work in different ways. They’re used to treat milder cases of malaria or as part of a treatment plan for more serious cases. 
  • Atovaquone-proguanil, artemether-lumefantrine. These combinations are other options in areas where the parasite has become resistant to chloroquine. They also can be given to children.
  • Mefloquine. This medication is another option if chloroquine can’t be used, but it’s been linked to rare but serious side effects related to your brain and is only used as a last resort.
  • Artesunate. If your symptoms are severe, your doctor may recommend this drug as treatment for the first 24 hours, then follow it with 3 days of artemisinin-based combination therapy. 

Some parasites that cause malaria have become resistant to almost all the medicines used to treat the illness, so researchers are always looking for new drugs that work.

Malaria Complications

Some people are more likely to have serious health problems if they get malaria, including:

  • Young children and infants
  • Older adults
  • People who travel from places that don’t have the vaccine
  • Pregnant women and their unborn children

These health problems can include:

Malaria symptoms & treatments – Illnesses & conditions

About malaria

Malaria is a serious tropical disease spread by mosquitoes. If it isn’t diagnosed and treated quickly, it can be fatal.

A single mosquito bite is all it takes for someone to become infected.

Symptoms of malaria

It’s important to be aware of the symptoms of malaria if you’re travelling to areas where there’s a high risk of the disease. This means that you can get medical attention quickly.

Symptoms are similar to those of flu and usually appear 6 to 30 days after the mosquito bite, but it can sometimes take up to a year for symptoms to start.

The initial symptoms of malaria include:

  • a high temperature (fever)
  • headache
  • sweats
  • chills
  • muscle aches or pains
  • vomiting and or diarrhoea

These symptoms can start mild and may be difficult to identify as malaria.

When to seek medical attention

Malaria is a serious illness that can get worse very quickly. It can be fatal if not treated quickly.

The effects of malaria are usually more severe in:

  • babies
  • young children
  • pregnant women
  • older people




Urgent advice:

Call 111 or go to A&E if:


  • you or your child develop symptoms of malaria during or after a visit to an area where the disease is found, even if it has been several weeks, months or a year after you return from travelling.

You must tell the healthcare professional that you have been in a country with a risk of malaria, including any brief stopovers.

What causes malaria?

Malaria is caused by the Plasmodium parasite. The parasite is spread to humans through the bites of infected mosquitoes.

There are 5 different types of Plasmodium parasite that cause malaria in humans. They are found in different parts of the world (but do overlap in certain areas) and vary in terms of how severe the infection can be.

All malaria infections cause the same symptoms and require immediate medical attention. It’s not possible to find out which type of malaria you have from symptoms alone.


Types of malaria parasite

  • Plasmodium falciparum – mainly found in Africa, it’s the most common type of malaria parasite and is responsible for most malaria deaths worldwide, though treatment does cure the infection.
  • Plasmodium vivax – mainly found in Asia and South America, this parasite causes milder symptoms but it can stay in the liver for years which can result in symptoms reoccurring if it isn’t treated properly.
  • Plasmodium ovale – fairly uncommon and usually found in West Africa.
  • Plasmodium malariae – this is quite rare and usually only found in Africa.
  • Plasmodium knowlesi – this is very rare and found in parts of southeast Asia.

How malaria is spread

The Plasmodium parasite is spread by mosquitoes. These are known as ‘night-biting’ mosquitoes because they most commonly bite between sunset and sunrise.

When a mosquito bites a person already infected with malaria, it becomes infected and spreads the parasite to the next person it bites. Malaria can’t be spread directly from person to person.

When an infected mosquito bites, the parasite enters the blood and travels to the liver. In the liver, it develops for days to weeks before re-entering the blood. This is the point where symptoms develop and urgent treatment is required.

Although it is very rare, malaria can also be spread from a person with the infection through blood transfusions and sharing needles.

Where is malaria found?

Malaria is found in tropical and subtropical regions of the world. It is not found in the UK or Europe.

The fitfortravel website has more information about the risk of malaria in individual countries.

Complications of malaria

Malaria is a serious illness that can be fatal if not diagnosed and treated quickly. Severe complications of malaria can occur within hours or days of the first symptoms. This means it is important to seek urgent medical help as soon as possible.

Anaemia

The destruction of red blood cells by the malaria parasite can cause severe anaemia.

Anaemia is a condition where the red blood cells are unable to carry enough oxygen to the body’s muscles and organs. This can leave you feeling drowsy, weak and faint.

Cerebral malaria

In rare cases, malaria can affect the brain. This is known as cerebral malaria which can cause your brain to swell, sometimes leading to permanent brain damage. It can also cause fits (seizures) or coma.

Other complications

Other complications that can arise as a result of severe malaria include:

  • liver failure and jaundice – yellowing of the skin and whites of the eyes
  • shock – a sudden drop in blood pressure
  • pulmonary oedema – a build-up of fluid in the lungs
  • acute respiratory distress syndrome (ARDS)
  • abnormally low blood sugar – hypoglycaemia
  • kidney failure
  • swelling and rupturing of the spleen
  • dehydration

Malaria in pregnancy

If you get malaria while pregnant, you and your baby have an increased risk of developing serious complications like:

Pregnant women are advised to avoid travelling to regions with a risk of malaria.

Visit your GP, midwife, obstetrician or travel health advisor for a full discussion if you’re pregnant and are thinking of travelling to a high-risk area. Not all antimalarial tablets are safe in pregnancy and it’s important you get specific advice. 

Preventing and treating malaria

If you travel to an area that has malaria, you are at risk of the infection. It’s very important that you take precautions to prevent the disease and get treatment immediately if symptoms do develop.

Preventing malaria

Malaria can often be avoided using the ABCD approach to prevention, which stands for:

  • Awareness of risk – find out whether you’re at risk of getting malaria
  • Bite prevention – use insect repellent, cover your skin with clothing, and use a mosquito net to avoid mosquito bites
  • Check whether you need to take antimalarial prevention tablets by visiting a travel health clinic – if you do, make sure you take the right antimalarial tablets at the right dose and finish the course
  • Diagnosis – seek immediate medical advice if you have malaria symptoms, including up to a year after you return from travelling

Being aware of the risks

To check whether you are travelling to a malaria risk area see the fitfortravel or National Travel Health Network and Centre (NaTHNaC) websites.

Visit your local travel clinic for malaria advice as soon as you know that you are travelling to a risk area.

If you grew up in a country where malaria is common, any natural protection will be quickly lost when you move. This means you need to protect yourself from infection if you’re now travelling to a risk area, even if that’s where you grew up.

Preventing mosquito bites

Avoiding mosquito bites is one of the best ways to prevent malaria. This is particularly important during early evening and at night when mosquitoes bite.

There are several steps you can take to avoid being bitten.

Do



  • mosquitoes can’t bite through clothing so wear light, loose-fitting clothing that will cover your arms and legs


  • apply insect repellent to all areas of your skin that are not covered by clothing, including your face and neck


  • remember to reapply insect repellent frequently


  • sleep under a mosquito net that’s been treated with an insecticide, or in a room with effective air conditioning

The most effective repellents contain 50% diethyltoluamide (DEET). These are available in:

  • sprays
  • roll-ons
  • sticks
  • creams

There’s no evidence to suggest that other remedies protect against malaria, such as homeopathic remedies, electronic buzzers, vitamins B1 or B12, garlic, yeast extract spread (Marmite), tea tree oils or bath oils.

Further information on mosquito bite prevention is available from the fitfortravel or National Travel Health Network and Centre (NaTHNaC) websites.

Antimalarial tablets

Antimalarial tablets can help prevent you from developing a malaria infection. For the best protection, you must also follow mosquito bite prevention advice.

You must start taking antimalarial tablets before travel and continue taking them whilst travelling in the risk area. Antimalarial tablets must also be taken for a period of time after you have left the risk area.

How long antimalarial tablets should be taken will depend on which tablet is used.

Antimalarial tablets don’t stop malaria from entering your body. However, they do stop the infection from developing inside your body and prevent you from getting ill.

If you stop taking your antimalarial tablets early (even when you are back in the UK) you could still become ill with malaria.

Taking antimalarial medication

You may need to take a short trial course of antimalarial tablets before travelling. This is to check that side effects do not occur and that you do not have an adverse reaction. If you do, alternative antimalarials can be prescribed before you leave.

Do



  • make sure you get the right antimalarial tablets before you go – visit a travel health clinic for advice on which is the best antimalarial for you


  • follow the instructions included with your tablets carefully


  • make sure you complete the full course of tablets

There’s currently no vaccine available that offers protection against malaria.

Types of antimalarial medication

The type of antimalarial tablets that you will be recommended is based on the following information:

  • where you’re going
  • any relevant family medical history
  • your medical history, including any allergies to medication
  • any medication you’re currently taking
  • any problems you’ve had with antimalarial medicines in the past
  • your age
  • whether you’re pregnant

If you’ve taken antimalarial medication in the past, don’t assume it’s suitable for future trips.

The type of antimalarial that you will need to take depends on which strain of malaria is carried by the mosquitoes in an area. It will also depend on whether they’re resistant to certain types of antimalarial medication.

The main types of antimalarials used to prevent malaria are:

  • Atovaquone plus proguanil (also known as Maloff protect or Malarone)
  • Doxycycline (also known as Vibramycin-D)
  • Mefloquine (also known as Lariam)

To find out what type of antimalarial medication is best for you, visit your local travel clinic.

Treating malaria

If malaria is diagnosed and treated quickly, you should fully recover. Treatment should be started as soon as possible.

Treatment begins in a hospital to make sure complications don’t suddenly develop. Treatment is with tablets or capsules. If someone is very ill, treatment will be given through a drip into a vein in the arm (intravenously).

Treatment for malaria can leave you feeling very tired and weak for several weeks.

The type of medicine and how long you need to take it will depend on:

  • the type of malaria you have
  • the severity of your symptoms
  • whether you took preventative antimalarial tablets
  • your age
  • whether you’re pregnant

(PDF) Plasmodium vivax malaria presenting with skin rash

J Vector Borne Dis 48, December 2011, pp. 245–246

Case Reports

Plasmodium vivax malaria presenting with skin rash – a case report

Syed Ahmed Zaki & Preeti Shanbag

Department of Pediatrics, Lokmanya Tilak Municipal General Hospital and Medical College, Sion, Mumbai

Key words Angioedema; antihistaminics; atypical; malaria; rash; skin urticaria

Malaria is a major disease of public health impor-

tance with a high morbidity and mortality. In endemic

regions, malaria can present with unusual features due to

development of immunity, increasing resistance to anti-

malarial drugs, and the indiscriminate use of antimalarial

drugs1. Such unusual presentations of malaria can lead to

delayed diagnosis and complications. We herein report a

girl with vivax malaria presenting with skin rash.

Case report: A 9-yr old Indian girl presented with skin

rash and fever for 2 days. Fever was high grade, continu-

ous and was associated with chills and rigors. There was

no history of any cough, cold, drug intake, abdominal pain,

vomiting, bleeding manifestations, diarrhoea or urinary

complaints. On admission she had a heart rate of 104/min

respiratory rate of 24/min and blood pressure of 104/70

mmHg. Throat examination was normal. Pallor was

present. Skin examination revealed multiple erythematous

and papular skin lesions involving bilateral upper and lower

limb (Fig. 1). Lesions were mildly itchy. Oral mucosa was

normal. Liver was palpable 2 cm below the right costal

margin with a span of 6 cm. Spleen was palpable 1 cm

below the left costal margin. Other systemic examination

was normal. Investigations done on the day of admission

revealed: hemoglobin 8.2 g/dL, total leukocyte count

11,200/mm3, and platelet count 1.7 lac/mm3. Peripheral

blood smear showed trophozoites of P. vivax. OptiMal

test was positive for vivax malaria. Dengue NS1 antigen

test and dark ground microscopy for leptospira were nega-

tive. Her liver function tests, renal function tests, serum

electrolytes and urine microscopy were normal. She was

treated with chloroquine along with antihistamine. Rash

disappeared completely on the third day of admission. The

patient was given primaquine for 14 days for radical cure.

She is well on follow up after six months.

Cutaneous lesions in malaria are rarely reported and

include urticaria, erythema, angioedema, petechiae, pur-

pura, and disseminated intravascular coagulation2. Cuta-

neous lesions have been described with both falciparum

and vivax malaria2. Although the exact pathogenesis of

skin lesions in malaria is not known, these may reflect

part of different immunological consequences during ma-

larial infection. Mast cell activation plays a central role

in the pathophysiology of malaria3. Degranulation of mast

cells during various stages of malarial infection releases a

constellation of mediators like histamine, serotonin, hep-

arin, proteoglycans, prostaglandins, leukotrienes, platelet

activating factor (PAF), cytokines and tumor necrosis fac-

tor2. These mediators cause increased vascular permeability

and vasodilatation. PAF causes aggregation of human

platelets, wheal and flare response with late phase

erythema. Leukotriene-induced wheal-flare response is

long lasting and associated with endothelial activation and

up-regulation of adhesion molecules4,5. Both IgG and IgE

containing immune complexes are elevated in malaria and

probably play a role in pathogenesis6. IgE containing im-

mune complexes are associated with complicated malarial

infection. Deposition of such immune complexes in cuta-

Fig. 1: Clinical photograph showing multiple discrete erythematous

and papular skin lesions involving both the lower limb

Malaria: symptoms, pathogens, treatment, doctor’s advice :: Health :: RBC Style

The article was commented on and checked by Anna Tsygankova, senior consultant at the medical company BestDoctor

What is malaria

Malaria is one of the most common infectious diseases in the world. It is caused by parasites-plasmodia, which are carried by malaria mosquitoes.The incubation period of the disease can last from 11 days to several months. The main symptom is regular bouts of severe fever that occur every two to three days. In severe forms, the disease can lead to dangerous organ damage.

Even 80 years ago, malaria was spread across the globe. However, thanks to the development of economics and medicine, today the disease has been defeated in half of the countries of the world and is rampant only in hot developing countries. Scientists believe that humanity will be able to completely defeat malaria by 2050 – however, this will require spending an additional $ 2 billion a year to combat it [1].

According to the WHO, annually about 228 million people fall ill with malaria, of which 400 thousand die. 94% of malaria cases are reported in Africa, half of them in six countries: Nigeria, Congo, Tanzania, Burkina Faso, Mozambique and Niger. Most of all, children suffer from malaria from six months to five years, who are completely immune to the disease. They account for two thirds of malaria deaths.

Tourists and travelers are often infected with malaria.According to the WHO, annually about 10 thousand people bring the disease from foreign trips.

Causative agents of malaria

The disease is transmitted by mosquitoes of the genus Anopheles, infected with malaria plasmodia – the simplest parasites, which act as direct pathogens of the disease. Malaria mosquitoes live mainly in swamps and in shallow stagnant bodies of water, including puddles. Many countries have eradicated malaria through massive campaigns to drain swamps.

Two hundred species of anopheles mosquitoes can be found all over the planet, with the exception of deserts and territories of the Far North.The species Anopheles Messeae is widespread in Russia. However, he stopped suffering the disease more than 50 years ago. Today, malaria can only be contracted from the Asian and African species of malaria mosquitoes.

The malaria mosquito first drinks the blood of a person infected with malaria. Plasmodium gets into its intestines. He then bites another person and transfers the parasite larvae to him. Those first go to the liver, where they grow and develop. When plasmodia become adults, they pass from the liver into the bloodstream, after which the person shows the first symptoms of malaria.Some species of Plasmodia can doze in the liver for a long time.

Malaria can also be transmitted from person to person without the involvement of mosquitoes: from mother to child (very rare), through blood transfusions and by sharing injection needles.

Types of malaria

Of several hundred malaria plasmodia, only five are dangerous to humans. Each of them causes a different kind of disease.

Three-day malaria

Plasmodium vivax causes three-day malaria (vivax-malaria) – a relatively mild form with a long course. It is characterized by the fact that malarial attacks of fever occur every two days, often at the same time of the day, from 11 to 16 hours. Another type of pathogen – P. ovale – causes ovale malaria, which is similar to three days old.

P. Vivax is distributed in Tajikistan, Afghanistan, Pakistan and Nepal, as well as in Central America and northern South America.Previously, this particular type of plasmoids was widespread in Europe and Russia. P. ovale is found mainly in Africa, in the same place as the Plasmodium, which causes tropical fever.

Four-day malaria

P. malariae causes four-day malaria, in which attacks occur every 70 to 72 hours. This form is not so severe, but in rare cases it can cause serious kidney damage – nephrological syndrome. Plasmodia of this type can covertly live in the human body for decades, even after recovery.They cause a rather rare type of malaria that occurs in India, Indonesia, Cambodia and Laos.

Tropical malaria

P. falciparum causes tropical malaria. This is the most dangerous type of disease, and at the same time the most common – it accounts for more than 90% of infections. The attacks occur irregularly, and the disease affects the vessels, which can lead first to hypoxia, and then to organ failure. The disease is dominant throughout Africa, and in countries such as India, Vietnam and Thailand, it occurs about as often as three-day malaria.

Knowlesi Malaria

The possibility of human infection with P. knowlesi was discovered only in 2004 – it was previously believed that it infects only macaques. This type of malaria develops the fastest and is therefore very dangerous if treatment is delayed [2]. The features of the course of this type of malaria are still poorly understood, but researchers call this form no less severe than tropical [3]. This type of malaria is common in Southeast Asia, primarily in Malaysia, the Philippines and Indonesia.

Symptoms of malaria

Most often, the first symptoms of malaria appear 11-30 days after infection, although both types of plasmodia, causing the three-day form, can sleep in the liver for up to 15 months.

At the first stage of the disease, pathogens multiply and accumulate in the blood, and the symptomatology resembles general poisoning – a person is shivering, nauseous, weak, body aches and pains in joints and limbs. Distinguishing malaria from other infectious diseases is very difficult at this stage.

When there are a lot of plasmodia in the blood, the height of the disease sets in, which consists of repeated malarial attacks, or paroxysms. Depending on the type of disease, attacks occur every other day or every two to three days.

The attack lasts from 15 minutes to two hours. Symptoms resemble flu: the temperature rises sharply to 39-41 °, the pressure drops, breathing becomes more frequent. The person is sick or vomiting, he can be delirious. Then the temperature drops sharply, the patient feels severe weakness and quickly falls asleep.Herpes-like rashes may appear on the lips. Waking up, a person feels healthy, but after a while the attack is repeated. As the patient begins to recover, the seizures become less severe and eventually disappear altogether.

In all patients with malaria, by the fifth or seventh day of the disease, the liver and spleen are enlarged, and in addition, anemia (anemia) develops.

According to the clinical picture, malaria is divided into uncomplicated and severe, in which the disease causes not only attacks, but also organ damage.

Major complications of malaria include:

Nephrotic syndrome

This is a dangerous, almost untreatable kidney injury that can occur with four days of malaria.

Cerebral malaria

Brain damage, which most often develops due to inadequate treatment. It begins with headache and mild impairment of consciousness, and if untreated can lead to coma and death.

Algid form of malaria

Toxic shock, which occurs due to the huge content of parasites in the blood.It starts with symptoms of severe intoxication, can lead to coma and death.

Hemoglobinuric (black water) fever

An extremely severe complication of tropical fever that most often occurs with late initiation of treatment. After taking drugs in a person’s blood at the same time, there are too many dead plasmodia and dead erythrocytes, which die due to drugs. The most characteristic manifestations are vomiting of black bile and black urine. Some studies have associated this complication with the use of quinine, a drug used to treat severe malaria.

Tears and organ failure

Malaria can severely damage the kidneys, liver or spleen, the latter even to the point of rupture.

Diagnostics of malaria

In the vast majority of cases, malaria in Europeans is diagnosed after visiting tropical countries where the disease is present.

In the early stages, malaria develops in the same way as many other infectious diseases. The main method for accurate diagnosis is blood smear microscopy, which allows you to detect parasites.Only after their identification can the doctor make a final diagnosis.

Less often, less accurate methods of immunological diagnostics are used, in which specific antibodies or antigens of plasmodia are searched for in the blood.

There are also rapid tests for parasite antigens, but they are not very accurate.

Treatment of malaria

In Russia and other countries that are not endemic for malaria, it is treated only in a hospital.

To cure the disease, it is necessary to kill the plasmodia in the blood. For this, antiparasitic drugs are used.

Combination therapy is most commonly used today in the treatment of uncomplicated malaria. Most often, it contains artemisinin or its derivatives – this is an antiparasitic drug that is made from wormwood (artemisia). It is effective against all types of Plasmodium malaria, but treatment with it alone often leads to relapse. Therefore, artemisinin is supplemented with other, more specific antimalarial drugs.In addition, if malaria is massively treated with artemisinin alone, plasmodia will inevitably develop resistance to it over time, and humanity will be almost unarmed before the disease. In Russia, drugs based on artemisinin are not registered. Malaria ovale is treated with a combination of primaquine and chloroquine.

Main drugs used in the treatment of malaria:

  • chloroquine;
  • hydroxychloroquine;
  • primaquine;
  • quinine;
  • mefloquine;
  • artemisinin;
  • artesunate;
  • artemether;
  • arteter;
  • proguan;
  • tetracycline;
  • doxycycline.

The choice of medication depends on the form of malaria, as well as on the region in which the infection occurred [4]. For example, the malarial plasmodia of Afghanistan and Pakistan developed resistance to chloroquine, while the Thai and Myanmar Plasmodium also developed resistance to mefloquine [5].

In the treatment of malaria with complications, antimalarial drugs are supplemented with specific drugs for the affected organs.

Vaccination against malaria and immunity against malaria

The only working vaccine against malaria – RTS, S – was created in the late 1980s, but received EU approval only in 2015.It has a rather low efficiency – RTS, S gives 27% protection against all forms of malaria and 58% against severe [6]. Today, it is being vaccinated for children in countries where malaria is most prevalent, and for travelers and residents of developed countries, it is not available.

People living in countries where malaria is present may have an innate immunity to it. Populations of West Africa and African Americans carry the Duffy gene, which makes them immune to 3-day malaria. Other genetic traits can make them more resistant to tropical malaria as well.Also, the risk of developing malaria is lower in people suffering from sickle cell anemia, a rare genetic disease that also occurs mainly in the Negroid race [7].

After an illness, a person develops an unstable acquired immunity, which grows stronger with each re-infection. In an acquired immune patient, malaria can be almost invisible, with very low levels of parasites in the blood. In societies where people are in constant contact with malaria and contract it several times a year, many develop strong immunity to the disease by the time they reach puberty [8].

Prevention of malaria

Prevention of malaria is mainly limited to protection from mosquito bites. WHO recommends wearing clothing that completely covers the body and using insect repellants from the skin and living quarters. For repellents, it is best to use products that contain DEET, IR3535, or icaridin. In countries with malaria, international organizations distribute mosquito nets impregnated with mosquito repellent – they are considered one of the most convenient, simple and effective ways to protect against the disease [9].

There is also a group of antimalarial drugs that are effective for the prevention of the disease. Doctors advise taking antimalarial drugs before traveling to a malaria country, and during and after travel. In Russia, mefloquine and chloroquine are most often prescribed. Only a doctor can choose the right drug.

Rospotrebnadzor recommends that tourists returning from countries with malaria monitor their temperature for three years after the trip.

Malaria in Russia

From prehistoric times to the middle of the 20th century, malaria was spread throughout the world (with the exception of the Far North), including in most of Russia.

In Russia, the disease was called “shake”, “pale” or “dead”. In the mid-1930s, a large-scale malaria epidemic swept across the Soviet Union, which affected the Volga region, the Urals and Ukraine. However, industrialization, drainage of swamps and the development of medicine gradually helped to cope with malaria.In 1962, the authorities announced that the disease had been completely eradicated.

After the collapse of the Soviet Union, the disease returned to Central Asia. In the 2000s, most cases of importation of infection into Russia were associated with migrants from Tajikistan, Azerbaijan and Uzbekistan. However, the situation there quickly improved – today the only post-Soviet state where endemic malaria is present is Tajikistan, but it is also close to completely defeating the disease [10].

For the last decade, 80-120 cases of malaria have been registered in Russia per year.All of them are imported – most often from Africa, as well as from India, Thailand, Latin America and the Middle East [11].

In 2020, Tanzania became the main supplier of malaria to Russia, one of the few countries that did not close borders for tourists. According to the head of Rospotrebnadzor Anna Popova, 11 cases of malaria were brought from there. It is known that two cases have died.

Expert commentary

Anna Tsygankova, senior doctor-consultant of the medical company BestDoctor

How toxic are malaria drugs? What side effects can they have?

With the use of any drug, side effects may occur.In the case of malaria chemoprophylaxis, drugs are used that are supposed to kill the parasite, and they are quite toxic. However, there is a concept of risk – benefit, that is, chemoprophylaxis for a European is potentially much less harmful than malaria. All registered prophylactic drugs have undergone post-marketing studies and have been proven to be effective and safe. Mild nausea, occasional vomiting, and frequent loose stools should not stop prophylaxis, but if these symptoms persist, seek medical advice.A rare complication (1 in 10 thousand travelers) is described when taking mefloquine: the development of neurological symptoms, seizures, psychosis.

Can complications of malaria fatally disrupt organ functions, lead to disability or disability?

If you seek medical help on time and start treatment, malaria will go away completely. Severe forms of the disease are individual, in some cases they are fatal. Four-day malaria has a specific complication.It may not cause acute symptoms, but low-level parasitemia (the presence of plasmodia in the blood) can persist for many decades and lead to immune complex-mediated nephritis with the development of nephrotic syndrome. This is a serious condition that can make a person disabled: protein is lost through the kidneys, pronounced edema is formed, lipid metabolism is disturbed, and the risk of developing infectious diseases increases. This condition occurs in children in endemic areas in Africa.

90,000 Malaria

Malaria (Middle Ages Italian mala aria – “bad air”, formerly known as “swamp fever”) – a group of vector-borne infectious diseases transmitted to humans by the bites of mosquitoes of the genus Anopheles (“malaria mosquitoes”) and accompanied by fever, chills, splenomegaly (an increase in the size of the spleen), hepatomegaly (an increase in the size of the liver), anemia.It is characterized by a chronic recurrent course.

Each year, 350-500 million cases of human malaria infection are recorded, of which 1.3-3 million end in death. 85-90% of cases of infection occur in sub-Saharan Africa, the overwhelming majority of children under the age of 5 become infected.

History

It has been suggested that humans have had malaria for 50,000 years. Malaria is believed to be native to West Africa (P.falciparum) and Central Africa (P. vivax). Molecular genetic data indicate that the preparasitic ancestor of Plasmodium was a free-living protozoan, capable of photosynthesis, which adapted to live in the intestines of aquatic invertebrates. He could also live in the larvae of the first blood-sucking insects of the order Diptera, which appeared 150-200 million years ago, quickly acquiring the ability to have two hosts. The oldest mosquito fossils found with the remains of malaria parasites are 30 million years old.With the advent of man, malaria parasites have developed, capable of changing hosts between humans and mosquitoes of the Anopheles genus.

Finding out the cause of the disease

In 1880, the French military doctor Charles Louis Alphonse Laveran, working in Algeria, found a living single-celled organism in the blood corpuscles of a malaria patient. A year later, the scientist published an article in the medical press “The Parasitic Nature of Malaria: A Description of a New Parasite Found in the Blood of Malaria Patients.”This was the first time that protozoa were identified as the cause of the disease. For this and other discoveries, he was awarded the 1907 Nobel Prize in Physiology or Medicine. The name of the genus of the parasite Plasmodium was proposed in 1895 by the Italian scientists Ettore Marchiafava and Angelo Celli [10]. In 1894, parasitologist Patrick Manson first suggested that mosquitoes could transmit malaria to humans. In 1896, the Cuban physician Carlos Finlay, who treated yellow fever patients in Havana, expressed the same hypothesis.Sir Ronald Ross, an Englishman who worked in India, showed in 1898 that certain species of mosquitoes transmit malaria to birds, and isolated the parasites from the salivary glands of the mosquito. He also managed to find parasites in the intestines of mosquitoes feeding on the blood of sick people, but was unable to trace the transmission of parasites from mosquitoes to humans. Giovanni Batista Grassi in 1898 managed to experimentally infect humans with malaria through a mosquito bite (he experimented on volunteers, including himself).He also proved that only mosquitoes of the genus Anopheles are carriers of malaria in Italy, developed and implemented measures to prevent malaria. However, in 1902 only Ronald Ross received the Nobel Prize in Medicine for describing the life cycle of the malaria parasite. The data obtained by Finlay and Ross in 1900 were confirmed by the medical board, headed by Walter Reed. The advice of this council was used by William C. Gordas for the wellness activities carried out on the construction of the Panama Canal.

In the early 20th century, before the discovery of antibiotics, it was practiced to deliberately infect patients with syphilis with malaria. Malaria provided an increased body temperature, at which syphilis, if not completely resolved, then in any case decreased its activity and passed into the latent stage. By controlling the course of the fever with quinine, doctors in this way tried to minimize the negative effects of syphilis. Although some patients died, this was considered preferable to inevitable death from syphilitic infection.

Discovery of the dormant stage of the parasite

Although the stages of the life cycle of the parasite, which take place in the human bloodstream and in the body of a mosquito, were described as early as the late 19th and early 20th centuries, it was not until the 1980s that the existence of the dormant stage became known. The discovery of this form of the parasite finally explained how people who recovered from malaria could get sick again years after the disappearance of plasmodium cells from the bloodstream.

Range

Malaria mosquitoes live in almost all climatic zones, with the exception of the subarctic, arctic zones and deserts.In Russia, they inhabit the entire European territory of the country and in Western Siberia, except for the polar and circumpolar latitudes. They don’t live in Eastern Siberia: winters are too harsh there, and mosquitoes do not survive.

However, for there to be a risk of contracting malaria, in addition to malaria mosquitoes, conditions are required for their rapid reproduction and transfer of malaria plasmodium. Such conditions are achieved in areas where there are no low temperatures, there are swamps and a lot of precipitation. Therefore, malaria is most widespread in the equatorial and subequatorial zones.

The humid subtropical belt is also referred to the natural habitat of malaria: for example, in the Sochi region, malaria at the beginning of the 20th century was a big problem before measures were taken to drain wetlands, oil reservoirs and other measures that eventually led to the destruction of the breeding grounds of anopheles mosquitoes in the resort zone.

In Russia and the USSR, until the early 1950s, the incidence of malaria was massive, and not only in the Caucasus, Transcaucasia and Central Asia, but also in the middle zone of the European part (the Volga region and other regions).The peak in the absolute number of cases occurred in 1934-1935, when more than 9 million cases of malaria were registered.

Etiology

The causative agents of malaria are the protozoa of the genus Plasmodium (plasmodia). For humans, four species of this genus are pathogenic: P.vivax (English), P.ovale (English), P.malariae (English) and P.falciparum. In recent years, it has been established that a fifth species, Plasmodium knowlesi, also causes malaria in humans in Southeast Asia. A person becomes infected with them at the time of inoculation (injection) by a female malaria mosquito of one of the stages of the life cycle of the pathogen (so-called sporozoites) into the blood or lymphatic system, which occurs during bloodsucking.

The erythrocyte or clinical stage of malaria begins with the attachment of merozoites that have entered the bloodstream to specific receptors on the surface of the erythrocyte membrane. These receptors, which serve as targets for infection, appear to be different for different species of malaria plasmodia.

Plasmodia, falling into prey, stimulate the release of substances that are attractive to mosquitoes. This is the conclusion the researchers came to when they conducted a series of experiments on mice. Malaria parasites altered the body odor of mice, and this odor became especially “attractive” during the period of their (parasites’) full maturation.

Symptoms and Diagnosis

Symptoms of malaria are usually: fever, chills, arthralgia (joint pain), vomiting, anemia due to hemolysis, hemoglobinuria (excretion of hemoglobin in the urine), and convulsions. A tingling sensation in the skin is also possible, especially in the case of P. falciparum malaria. Splenomegaly (enlarged spleen), unbearable headache, and cerebral ischemia may also occur. Malaria infection is deadly. Children and pregnant women are especially vulnerable.

Diagnosis is by detection of parasites in blood smears. Traditionally, two types of strokes are used – thin and thick (or the so-called “thick drop”). A thin smear allows you to more reliably determine the type of malaria plasmodium, since the appearance of the parasite (the shape of its cells) is better preserved with this type of study. A thick smear allows the microscopist to view a larger volume of blood, therefore this method is more sensitive, but the appearance of the Plasmodium changes, which makes it difficult to distinguish between Plasmodium species.It is often difficult to make a diagnosis based on microscopic examination, since immature trophozoites of different types of Plasmodium malaria are poorly distinguishable, and usually several Plasmodia, which are at different stages of maturation, are needed for reliable differential diagnosis.

Rapid diagnostic tests (RDT, Rapid Diagnostic Tests) using immunochemical kits (more expensive, but giving a result after 5-15 minutes and not requiring the use of a microscope) and PCR tests (the most expensive, but most reliable )

Types (forms) of malaria

Symptoms, course and prognosis of the disease partly depend on the type of plasmodium, which is the causative agent of this form of the disease.

  • The causative agent of tropical malaria is P. falciparum. Causes the most dangerous form, often with complications and a high mortality rate. This same form is the most widespread (91% of all malaria cases in 2006).
  • The causative agent of four-day malaria is Plasmodium malariae. Attacks usually occur after 72 hours.
  • The causative agents of three-day malaria and similar oval malaria are Plasmodium vivax and Plasmodium ovale, respectively.Attacks occur every 40 to 48 hours.

These forms of malaria also differ in the length of the incubation period, the duration of different stages of the life cycle of plasmodia, symptoms and course.

Antimalarial immunity

The immune response against malaria infection develops slowly. It is characterized by low efficiency and practically does not protect against re-infection. Acquired immunity develops after several malaria cases over several years.This immunity is specific to the stage of the disease, to the species, and even to a specific strain of Plasmodium malaria. But clinical manifestations and symptoms decrease with the development of specific antimalarial immunity.

Possible explanations for such a weak immune response include the presence of malaria plasmodium in cells throughout most of its life cycle, general suppression of the immune system, the presence of antigens that are not recognized by T cells, suppression of B cell proliferation, significant polymorphism of malaria plasmodium and rapid change potential antigens on its surface.

Treatment

Quinine is still the most commonly used drug for treating malaria. For some time it was replaced by chloroquine, but now it has gained popularity again. The reason for this was the appearance in Asia and then spread across Africa and other parts of the world of Plasmodium falciparum with a mutation of resistance to chloroquine.

There are also several other substances that are used to treat and sometimes prevent malaria. Many of them can be used for both purposes.Their use depends mainly on the resistance of parasites to them in the area where this or that drug is used.

Currently, the most effective drugs for treatment are drugs combined with artemesinin. WHO resolution WHA60.18 (May 2007) insists on the use of these drugs, but they are still not registered or used in the Russian Federation.

Essential Antimalarial Drugs
Specimen Eng.name Prevention Treatment Notes
Artemether-Lumefantrine Artemether-lumefantrine + commercial name Coartem
Artesunate-amodiaquine Artesunate-amodiaquine +
Atovacuon-proguanil Atovaquone-proguanil + + commercial name Malarone
Quinine Quinine +
Chloroquine Chloroquine + + after the emergence of resistance, the use is limited to the commercial name Delagil
Cotrifazide Cotrifazid + +
Doxycycline Doxycycline + +
Mefloquine Mefloquine + + commercial name Lariam
Proguanil Proguanil +
Primaquine Primaquine +
Sulfadoxine-pyrimethamine Sulfadoxine-pyrimethamine + + commercial name Fansidar

Extracts of the Artemisia annua (Wormwood) plant, which contain the substance artemisinin and its synthetic analogs, are highly effective, but their production is expensive.Currently (2006), the clinical effects and the possibility of producing new drugs based on artemisinin are being studied. Another work by a team of French and South African researchers has developed a group of new drugs known as G25 and TE3, which have been successfully tested in primates.

Although antimalarial drugs are on the market, the disease poses a threat to people who live in endemic areas where there is no adequate access to effective drugs. According to Médecins Sans Frontières, the average cost of treating a person with malaria in some African countries is as low as $ 0.25-2.40.

Prevention

Methods used to prevent the spread of disease or to protect in areas where malaria is endemic include prophylactic drugs, mosquito control, and mosquito bites. There is currently no vaccine against malaria, but active research is underway to create one.

Vaccine development

Malaria vaccines are under development and clinical trials are underway.

In March 2013, after a series of failed experiments, US scientists successfully tested a fast-acting anti-malaria drug in mice, and a new drug is being prepared for human trials.

Malaria has always been and remains one of the most dangerous human diseases. Famous people who died of malaria include: Alexander the Great, Alaric (King of the Visigoths), Genghis Khan, Saint Augustine, at least 5 popes, Italian poet Dante, Holy Roman Emperor Charles V, Christopher Columbus, Oliver Cromwell, Michelangelo Merisi Caravaggio, Lord Byron and many others.

Current Malaria Record:

  • Malaria areas are home to 2.4 billion people, or 34% of the world’s population.
  • Every year, 300-500 million people are infected with malaria, and, according to WHO, this number is increasing annually by 16%. 90% of cases are registered in Africa, of the rest – 70% of cases occur in India, Brazil, Sri Lanka, Vietnam, Colombia and the Solomon Islands.
  • Every year, 1.5-3 million people die from malaria (15 times more than from HIV / AIDS).
  • Over the past decade, from the third place in the number of deaths per year (after pneumonia and tuberculosis), malaria came to the first among infectious diseases.
  • Every year about 30,000 people who visit hazardous areas contract malaria, 1% of whom die.

90,000 In Switzerland, developed a method for diagnosing malaria by the smell of the patient’s skin – Science

GENEVA, May 25. / TASS /. Experts from the Federal Polytechnic School of Zurich (ETH Zurich) have developed a diagnostic method that detects malaria infection by the smell of human skin.If the body is attacked by parasites, the smell will change and the instruments will notice the change. In their opinion, this discovery has good prospects for use in the field in the fight against malaria in developing countries due to the fact that it is not associated with high costs.

As reported by ETH Zurich on its website, the scientists conducted research in Kenya. They studied the skin odor of 400 sick and healthy schoolchildren and collected volatile substances exuded by the skin. Using gas spectrometers and chromatographs, the characteristics of these substances were then determined in sick and healthy people.

“At first, we were not sure what chemical constituents we were looking for,” said one of the authors of the scientific work, Professor Consuelo de Moraes. After all, the human body, he explained, exudes different smells – depending on the food intake, metabolism and illness. “The specific” signature “[of malaria] is not created by the presence or absence of specific components, but by a change in the concentration of components that healthy people also have,” he stated. “The challenge was to filter out the correct signals from the extensive background noise.”

In this way, biomarkers have been identified for recognizing malaria. Methods that allow detecting a pathogen by DNA at an early stage have existed before, notes ETH Zurich, but they are relatively expensive and require laboratory conditions for diagnosis. This makes it difficult to use them in the countries of the southern hemisphere of the planet.

“The discovered volatile biomarkers represent an important first step in research,” said study co-author Professor Mark Mescher.Scientific work will be continued. Scientists hope a similar method can be developed for other insect-borne diseases.

Malaria is an acute infectious disease. The first symptoms – fever, headache, vomiting – appear 7-15 days after being bitten by a mosquito (genus anopheles) infected with one of the plasmodium parasites, the most common of which are plasmodium vivax and plasmodium falciparum (the most deadly species). According to the latest data from the World Health Organization (WHO), published last November, there were 216 million cases of malaria in 91 countries in 2016, which is 5 million more than a year earlier.About 445 thousand people died from this disease.

90,000 Healthy lifestyle

The main import of malaria to Russia comes from the countries of the near and far abroad and the CIS countries that are unfavorable for malaria, causing local

diseases and local outbreaks of three-day malaria (in the Kemerovo region there is a real possibility of contracting three-day malaria from

90,162 imported mosquito-borne malaria cases. in 2016, a relapse of three days of malaria was registered in a patient who had malaria in 2015

.This type of malaria is the most dangerous for residents of the Kemerovo region due to the adaptability of the pathogen to local species of mosquitoes and the ability of

survive in temperate climates). Over the past 10 years, 4000 cases of imported malaria have been registered in Russia.

Who is the source of infection in malaria and how is it transmitted?

The source of infection is a patient with malaria or a parasite carrier.

From person to person, the infection is transmitted through the bites of mosquitoes of the Anopheles genus.They are the only carriers of human malaria.

Mosquitoes live in two environments: eggs, larvae and pupae develop in water, adult winged mosquitoes live in the air. Mostly

breeding of mosquitoes are reservoirs overgrown with algae, swamps, rice paddies, etc. Winged mosquitoes emerged from reservoirs live in

residential and non-residential premises.

There are such mosquitoes in the Tomsk region. The natural susceptibility of the population to malaria infection through a mosquito bite is almost

is ubiquitous.

When a mosquito bites a sick person, parasites of malaria enter the body of a mosquito and go through a complex development cycle, at the end of which

mosquito becomes contagious. During the next bloodsucking from the saliva of a mosquito, pathogens enter the human blood.

Infection through plasmodium-infected blood is also possible through blood transfusion or the use of infected needles and syringes, and

infection of the fetus from a sick mother (in utero or during childbirth) can also occur.

How is the development of the parasite in the human body?

Once in human blood, plasmodia penetrate and multiply first in liver cells. Then the liver cells are destroyed, and many parasites

enters the bloodstream. Further development of parasites takes place inside red blood cells – red blood cells. Affected red blood cells are destroyed,

and young parasites re-invade healthy red blood cells. Each release of parasites into the blood is manifested by a malarial attack.

Plasmodium malaria development cycle:

1 – Zygote, 2 – Formation of cysts in the salivary glands of a mosquito, 3 – Exit of plasmodia into the salivary glands, 4 – Liver cell, 5 – Exit of plasmodia from

cells, 6 – RBCs, 7 – Rupture of RBCs, 8 – Female gametes, 9 – Male gametes

How quickly do symptoms appear after exposure and are there any characteristic signs of malaria?

The incubation period (from the moment of infection until the onset of clinical symptoms) can last from 9-21 days to 8-12 months, depending on

forms of malaria.

The main characteristic symptom of the clinic is a malarial attack, in which three consecutive periods are distinguished: chills, fever, profuse

sweating. In typical cases, the attack begins with a shaking chill, headache, aches throughout the body. The patient is pale, lips are bluish.

There is an increase in heart rate and respiration. Then comes a period of heat. Body temperature quickly rises to 40-41C, headache increases

pain, thirst, there may be vomiting, convulsions, impaired consciousness.The patient’s face turns red, the skin becomes dry, hot, the heartbeat becomes more frequent. After

Profuse sweat appears at 6-8 o’clock. Body temperature drops sharply to normal levels and below. The patient is weak and often falls asleep. Total

seizure duration usually lasts 8-12 hours.

How does the patient feel during the interictal period and how often do the attacks recur?

During the interictal period, the patient feels satisfactory.With the first attacks, a herpetic rash often appears on the face. By the end of

the first week of the disease, the liver and spleen enlarge, anemia develops.

These attacks are repeated in a day or two, depending on the form of malaria. In tropical malaria, attacks can occur every day.

Are there any complications in malaria and what is the reason?

The disease can cause serious complications. The most serious complication is malarial coma in tropical malaria, which without

urgent intensive specific therapy is fatal.

Unfortunately, often the reasons for the severe course of the disease and complications are the wrong actions of the patients themselves. Malaria patients not

always seek medical help in a timely manner, self-medicate, hide the facts of leaving for malaria-affected areas

areas, before leaving for hot countries do not consult a doctor or parasitologist.

For timely treatment, prevention of clinical complications, as well as prevention of the spread of infection, large

the early appeal of the patient for medical help is important.With timely access to medical care, malaria completely

is healed.

What should be done to prevent infection and disease?

Staying in a malaria-poor country, especially in rural areas, for even a very short time leads to infection

malaria.

To prevent the disease, it is necessary to carry out chemoprophylaxis , that is, take antimalarial drugs.

Chemoprophylaxis (for all travelers to endemic countries) is carried out with chloroquine, as well as chloroquine in combination with proguanil or

mefloquine, depending on the intensity of transmission of the disease in the given focus, drug sensitivity of malaria parasites and others

factors. During your stay in a malaria-endemic territory, you should take the antimalarial drug used and active

for malaria pathogens in this particular area.

Chemoprophylaxis with should be started a few days before arriving in an area where malaria is possible. Do not finish

earlier than 2 weeks after leaving the malaria area. Irregular chemoprophylaxis cannot prevent

malaria disease. Moreover, the disease in such cases is atypical, which makes it difficult to make a correct diagnosis and does not allow

to start treatment in a timely manner.

It is also necessary to apply mosquito bite protection measures . They attack a person, as a rule, in the evening and at night. During this period

It is advisable to wear clothing that covers most of the body, and lubricate the exposed parts of the body with repellents – mosquito-repellent substances.

Windows and doors must be counted. Sleep under a mesh canopy, the edges of which are carefully tucked under the mattress.

A person who has suffered from malaria must have a certificate indicating the time of the disease, the type of parasite detected and the medication that was administered

treatment.Dispensary observation of the state of health is established within 2 years after returning from an endemic country.

90,000 MALARIA. CLINIC, DIAGNOSTICS AND PREVENTION

Malaria – infectious and parasitic pathology, manifested by fever, hepatomegaly and splenomegaly. This acute protozoan disease is caused by plasmodia, which enter the human body when bitten by Anopheles mosquitoes. The disease is characterized by paroxysmal and recurrent course.If the pathology is not treated, serious complications will arise.

Malaria is a disease of the African continent, South America and Southeast Asia. Most of the infections occur in young children living in West and Central Africa. In these countries, malaria leads among all infectious diseases and is the main cause of disability and death of the population.

Etiology

Plasmodia are parasitic unicellular organisms that cause malaria. Microbes enter the human body through bloodsucking, during which they are injected by a female mosquito into the blood or lymph. Plasmodia stay in the blood for a short time and penetrate into liver cells, affecting them. The hepatic stage of the disease lasts quite a long time, periodically causing relapses due to the release of protozoa into the bloodstream. They attach to the membranes of erythrocytes, which leads to the transition of the hepatic stage to the erythrocyte stage.

Malaria mosquitoes are ubiquitous.They breed in stagnant, well-heated water bodies, where favorable conditions remain – high humidity and high air temperatures. This is why malaria was formerly called “swamp fever.” Malaria mosquitoes differ in appearance from other mosquitoes: they are slightly larger, have a darker color and have transverse white stripes on their legs. Their bites also differ from ordinary mosquitoes: malaria mosquitoes bite more painfully, the bitten area swells and itches.

Pathogenesis

In the development of plasmodium, 2 phases are distinguished: sporogony in the body of a mosquito and schizogony in the human body.

Tissue schizogony lasts 1-2 weeks. It occurs in hepatocytes and ends with the release of microbes into the bloodstream. Tissue schizogony corresponds to the incubation period and proceeds without obvious clinical signs.

Erythrocytic schizogony develops after the breakdown of red blood cells and the penetration of parasite toxins into the blood plasma. This phase is associated with the appearance of the main symptoms of malaria. Massive breakdown of red blood cells can result in the development of hemolytic anemia, microcirculation disorder, shock.

Epidemiology

The source of infection is sick or carriers. Persons with a recurrent course of the disease are of particular importance in the spread of infection, since their blood contains the maximum number of parasites. Carriage of malaria plasmodia is formed as a result of inadequate treatment or resistance of microbes to drugs.

The infection spreads most often in a transmissible way with the help of a carrier – a female mosquito of the genus Anopheles.Mosquitoes become infected by sucking blood from carriers of the malaria parasite or from people with malaria.

In more rare cases, it occurs:

1. Transplacental pathway – from a sick mother to a child,

2. Blood transfusion route – with blood transfusion,

3. Infection through contaminated medical instruments.

The infection is highly susceptible. The inhabitants of the equatorial and subequatorial zones are most susceptible to malaria.
Malaria is the leading cause of death in young children living in endemic regions.

Regions where malaria is spread

The incidence is usually recorded in the autumn-summer period, and in hot countries – during the year. This is anthroponosis: only people are sick with malaria.

Immunity after infection is unstable, type-specific.

Clinic

Malaria has an acute onset and presents with fever, chills, malaise, weakness and headache. The body temperature rises suddenly, the patient is shaking. In the future, dyspeptic and pain syndromes join, which are manifested by pain in muscles and joints, nausea, vomiting, diarrhea, hepatosplenomegaly, convulsions.

Types of malaria

Three-day malaria is characterized by a paroxysmal course. The attack lasts 10-12 hours and is conventionally divided into 3 stages: chills, fever and apyrexia.

Manifestations of malaria

In the first stage the patient shivers, his skin turns pale, the limbs turn cold and turn blue, acrocyanosis develops. The pulse becomes fast, breathing is shallow. The chill stage lasts 2 hours, during which the body temperature gradually rises and eventually reaches 40-41 degrees.

The second stage lasts from 5-8 hours to a day. At this time, the state of health of patients worsens: the face becomes red, the sclera are injected, the mucous membranes are dry, the tongue is coated. Tachycardia, hypotension, shortness of breath, agitation, vomiting develop, diarrhea is possible.

An attack of fever ends in with a sharp drop in body temperature, profuse sweating and an improvement in the patient’s condition. The third stage lasts from 2 to 5 hours and ends with deep sleep.

In the interictal period, the body temperature normalizes, patients experience fatigue, weakness, weakness. The spleen and liver are hardened, the skin and sclera become subicterous. In a general blood test, erythropenia, anemia, leukopenia, thrombocytopenia are found. Against the background of attacks of malaria, all body systems suffer: reproductive, excretory, hematopoietic.

The disease is characterized by a prolonged benign course, the attacks are repeated every other day.

In four-day malaria, the pathogen remains in the human body for a long time. Fever attacks recur every 48 hours. The symptomatology of the pathology is in many ways similar to that of three-day malaria. The clinical symptoms of malaria are due to low levels of parasitemia. In patients, the liver and spleen enlarge slowly, anemia develops gradually.

Diagnostics

With periodic bouts of chills and fever for no apparent reason, malaria can always be suspected, especially if the patient has been visiting foci of malaria over the past year or two years.Typical in the diagnosis of malaria is the detection of the parasite in the smear and thick droplet. It is necessary to identify the type of pathogen, since treatment and prognosis depend on this. Blood smears are repeated after 4-6 hours if the first smear was negative.

To diagnose P. falciparum, test strips with monoclonal antibodies to histidine-rich protein-2, which has an accuracy comparable to a blood drop, and requires less effort than microscopy, can be used directly at the patient’s bedside.PCR and other probes are informative, but they are not widely used. Serologic tests may reflect previous infection, but do not diagnose an acute process.

How is malaria treated?

All patients with malaria are hospitalized in an infectious diseases hospital. In addition to etiotropic therapy, symptomatic and pathogenetic treatment is carried out, including detoxification measures, restoration of microcirculation, decongestant therapy, and the fight against hypoxia.

Prevention

Prevention of malaria requires taking special pills. They should start taking them 2 weeks before the intended departure to the risk zone. An infectious disease doctor can prescribe them. It is worth continuing to take the prescribed pills after arrival (within 1-2 weeks).

In addition, to prevent the spread of infection in countries where the disease is not uncommon, measures are being taken to destroy malaria mosquitoes.Building windows are protected with special nets. If you are going to go to such a dangerous area, you should get special protective clothing and do not forget about taking prophylactic pills.

Such preventive measures almost completely exclude infection with this dangerous disease. In the event that at least a few of the symptoms described above are observed, you should immediately contact an infectious disease specialist. Timely started treatment will allow you to almost completely get rid of the disease and prevent the development of complications.

Malaria: Symptoms, Diagnosis, Symptoms | doc.ua

In general, malaria includes several forms, depending on the caused pathogens. This means that it can be three-day – the causative agent of Plasmodium vivax malaria, four-day – Plasmodium malariae, tropical – Plasmodium falciparum, ovale-malaria – Plasmodium ovale.

The viability of malaria parasites includes two stages: sexual, occurring in the body of a female of the genus Anopheles, and asexual, formed in the human body.

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Malaria parasites can develop in the human body sequentially – in several phases: tissue schizogony and erythrocytic schizogony, which occurs in erythrocytes.

Tissue schizogony

At this stage, infection is carried out by the bite of an infectious female mosquito. Mosquito saliva forms sporozoites in the human body, which are spindle-shaped organisms 14–15 µm long and about 1–1.5 µm wide. Infection occurs literally in half an hour, since sporozoites instantly penetrate into the blood and lymph, and, thus, are spread throughout the body.The sporozoite is divided into tens of thousands of small formations that develop in erythrocytes.

The duration of schizogony during 3-day malaria is about 6 days, with tropical – 8 days, with four days – 14-15 days, with oval-malaria – 9 days. Plasmodium malaria may be asymptomatic in humans, depending on the incubation period.

Erythrocytic schizogony

When tissue merozoites penetrate into erythrocytes, they turn into asexual forms (trophozoites).Directly in the erythrocytes themselves, these dividing cells form erythrocytic merozoites, the number of which depends on the type of pathogen. This leads to erythrocyte death and general decay. Merozoites can invade new erythrocyte bodies and schizogony repeats its cycle.

The duration of interaction of such a cycle of schizogony in malaria of the four-day type can be about 72 hours, with three-day, tropical and oval malaria – about 48 hours.

The process of erythrocytic schizogony is characterized by the formation of germ cells called gamonts or gametocytes, male or female division.There are no special symptoms in the presence of gametes in the body, but a person can be a source of infection for malaria mosquitoes.

Sporogony

Anopheles females can become infected from a sick person through blood, which causes various malaria plasmodia to enter the insect’s stomach. Immature gamont and asexual forms are processed in the stomach of the mosquito. But mature gametocytes in the stomach of an insect develop their own cycle – sporogony.

Symptoms

In most countries, malaria is an anthroponosis because the source is actually a person.In some tropical areas, there is also an exchange of malaria parasites from monkeys.

So, a person carrying malaria in the body is a parasite carrier, since there are gametocytes in his blood. The spread of malaria is also associated with seasonality.

Human susceptibility to this contaminant is almost the same. Only newborns, due to passive immunity, can easily tolerate the disease, that is, their infection usually proceeds easily.

In the case of malaria, attacks of fever are observed, which are associated with the fact that foreign organisms – carriers of foreign protein – were transported into the blood.There is also an increase in temperature, chills, fever, or an allergic effect. Anemia may also occur.

Parasites disrupt the normal functioning of the brain, kidneys, liver, intestines and other organs in the body. That is, malaria, in addition to allergic reactions, can also be accompanied by nephritis, necrosis of internal organs, malarial purpura and other malignant manifestations.

The latency period lasts from one to three months, after which an early development of the disease is observed.

Characteristics of forms of the disease

Several forms of the disease are known: three-day malaria, oval malaria, four-day malaria and tropical malaria, and mixed malaria (combines several types). From the intensity of development, mild, moderate and severe forms can occur.

The disease can develop over several periods:

  • primary malaria is accompanied by a series of primary attacks;
  • early relapses – observed in all forms of malaria and are detected within two or three months.Further, the multiplication of parasites is observed due to the revival of erythrocytic schizogony;
  • the interictal period has a duration of 7-11 months with oval-malaria or three days. It occurs sequentially after early relapses and is characterized by the presence of dormant parasites in the body and an asymptomatic course of the disease;
  • Late relapses are characterized by activation of hypnozoites.

Tropical malaria has an incubation period of 7–16 days, three days from 10 to 20 days, or up to 14 months – long incubation.Oval malaria has a latency period of 11-16 days, and four-day malaria – 25-42 days. The incubation period can be extended due to inadequate chemoprophylaxis.

The first manifestations can last for about several months and are characterized by malaise, headache.

If malaria is contracted, the most common symptom over time is fever, which can be intermittent or persistent. The initial fever is present only with a fresh manifestation of malaria, since after a while the attacks of fever have a characteristic alternation with an increase and normalization of body temperature.

A malarial attack is characterized by several stages: chills, lsat, sweat. Initially, the attack begins with a chill of varying strength, maybe even such when “tooth to tooth” does not fall, while the skin becomes “goose bumps”. Chills can last in different ways, ranging from half an hour to four hours. Further, it is replaced by a fever, in which the patient turns red, rushes about in bed, he is tormented by thirst. This stage lasts up to 12 hours.

This is followed by torrential sweat and a drop in temperature, usually up to 35 degrees.The condition temporarily improves and the patient calms down.

Malarial attacks can sometimes last more than a day. They manifest themselves more typically in the morning, and a high rise in temperature is observed in the morning. The attacks usually recur at the same hours.

In four-day malaria, attacks generally occur after two days. And with oval malaria, tropical, three days – every other day. Naturally, on those days when there are no seizures, the patient feels satisfactory, the appetite increases, and working capacity is possible.But if the number of attacks severely depletes the body, then the condition remains severe – this can be the case with daily attacks, often observed in tropical malaria.

An enlargement of the spleen and liver and their soreness can also be a sign of malaria. And lingering malaria can lead to functional impairment and bone marrow depression.

Still, it can be said that three-day and four-day malaria can usually proceed favorably.

Tropical malaria

Tropical malaria can be accompanied by symptoms of intoxication: headache, vomiting, joint pain, insomnia, etc.The total duration of this form of malaria is about a year, and when infected with other strains – and more than a year. In addition, tropical malaria can be accompanied by damage to the cardiovascular system, vascular insufficiency, liver damage, renal edema and others.

Complications

The effects of malaria can manifest as damage to the nervous system, resulting in a coma. But a true coma occurs only in the tropical form. That is, despite other types of malaria, it is tropical malaria that is the most dangerous.

In general, there are three periods of malarial coma: somnolence (drowsiness and a state of deafness), stupor or hibernation (consciousness periodically returns), complete coma. In such conditions, if there is no fight against malaria and appropriate treatment, the patient may die in 3-5 days.

Malarial algid can also be observed in the tropical form, which is accompanied by the presence of consciousness, but the patient is indifferent, his features are sharpened, the temperature is lowered, the pulse is threadlike, there may be diarrhea.The prognosis in this state is not so favorable, since it is not entirely easy to get out of this state.

The most severe complication of tropical malaria is hemoglobinuric fever, which is manifested by acute hemolysis of erythrocytes and excretion of hemoglobin in the urine. Often, hemorrhages in the retina of the eyes, profuse bleeding, renal failure can also be observed – due to which a lethal outcome is possible.

Diagnostics

Usually, the presence of the disease can be established using the general clinical picture and the detection of the parasites themselves in the blood.Alternating febrile seizures, enlarged liver or spleen, and hypochromic anemia may be due to the disease, although the signs of malaria vary. It is necessary to clarify how the infection could have occurred – to determine the source of malaria. If the suspicions are confirmed, then they take blood for examination. At the same time, at the first attacks of fever, it is difficult to detect parasites, therefore, a microscopic examination should be carried out after a few days.

Treatment

Treatment should be initiated after a specific diagnosis has been made with a blood test.Do not forget that not only hours, but also minutes can be important for saving the patient’s life.

Antimalarial drugs can be schizotropic, gamotropic (primaquine, quinocid), hematoschizotropic (rezoquine, chloroquine, bigumal, acriquine, quinine), histochizotropic (quinocid, chloridine, primaquine) action.

Three-day malaria may be associated with chloroquine phosphate and primaquine phosphate. Tropical malaria is also treated with chloroquine phosphate, quinine, clindamycin.If malarial coma develops, then a certain dose of quinine is required.

In some cases, steroid hormones, glucose or dextrose solutions, diphenhydramine, suprastin, chlorpromazine and others may be prescribed.

Prevention

In general, it is important to take preventive measures on time. Today, the fight against malaria mosquitoes is multilaterally carried out: they exterminate larvae and pupae in the area of ​​water bodies, eliminate the breeding places of mosquitoes, exterminate winged mosquitoes.All this is not in vain, since even a vaccination against malaria cannot always help with infection. Therefore, it is important to carry out one’s own chemoprophylaxis, which may be based on taking drugs from the group of aminoquinolines. It is especially rational to use them when cases of malaria are known in the immediate area. It is necessary to start taking medications in advance, especially if you are going to go to places where infection is possible. Remember that timely chemoprophylaxis does not guarantee or exclude the possibility of infection.

Scientists have developed an effective way to kill anopheles mosquitoes

  • James Gallagher
  • BBC Science Observer

Photo Credit, Getty Images

Genetically modified mushroom poison , similar to spider toxins, can kill large numbers of malaria mosquitoes in a short time.

Scientists in Burkina Faso conducted tests to confirm these findings.In the course of the experiment, the mosquito population decreased by 99% in 45 days.

Scientists explain that they do not pursue the goal of completely eradicating bloodsucking, but are looking for ways to stop the spread of malaria.

This disease, carried by female mosquitoes, claims more than 400,000 lives annually. Given that every year around the world fall ill about 219 million people.

In the process of research, scientists from the University of Maryland (USA), together with colleagues from Burkina Faso, first identified the fungus Metarhizium pingshaense, which naturally infects malaria mosquitoes.

The next step was to give it new characteristics. “This fungus is very malleable and can be easily modified through genetic engineering,” Professor Raymond Liger of the University of Maryland told the BBC.

Photo author, Getty Images

Photo caption,

The genetic code of the fungus Metarhizium pingshaense was given the command to start producing the spider toxin

For this, scientists used the venom of Australian funnel spiders. Through gene manipulation, the genetic code of the fungus Metarhizium pingshaense was instructed to begin producing a spider toxin when an anopheles mosquito enters the body.

“The spider bites through the skin of other insects with the help of chalicerae (a type of teeth) and injects poison, and in our country the fungus plays this role,” explains Professor Liger.

Laboratory tests have shown that the modified fungus kills faster and requires fewer fungal spores to achieve results.

Next, scientists had to test the action of the fungus in conditions as close as possible to natural.

For this purpose, an entire artificial village with an area of ​​more than 600 square meters was built in Burkina Faso.meters, with real vegetation, huts, water sources and mosquito hosts. The artificial settlement was surrounded by a double layer of mosquito netting to prevent mosquitoes from flying away.

Photo author, Etienne Bilgo

Caption,

A “mosquito sphere” was built in Burkina Faso for testing in Burkina Faso, creating the most natural conditions without the threat of infected mosquitoes flying to human habitats

Spores of a poisonous fungus were mixed with sesame oil and spread the mixture over black cotton sheets.To be exposed to the poison, the mosquitoes had to sit on a sheet. The trials involved 1,500 mosquitoes.

The research results are published in the popular scientific journal Science. It follows from them that the mosquito population began to grow rapidly when they were left alone for a while.

But when black sheets were placed in the “mosquito sphere”, only 13 insects survived for 45 days.

Photo Credit, Oliver Zida

Caption,

Mosquito Breeding Pool in Test Area

“The transgenic fungus quickly wiped out the population in just two generations of mosquitoes,” says Dr. Brian Lovett of the University of Maryland.

It is also important that the fungus infects only malaria mosquitoes and is not dangerous for other species of insects, for example, for bees.

“Our new technology is not aimed at completely eradicating mosquitoes, but at stopping the spread of malaria in a particular area,” adds Dr. Lovett.

The need to develop new methods of malaria control is urgent as mosquitoes become more and more resistant to insecticides.The World Health Organization (WHO) warns that the incidence of malaria is on the rise in the 10 countries most affected by malaria mosquitoes in Africa.