H1N1 transmission to humans: The request could not be satisfied

08.03.197215.08.2021 by alexxlab

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Swine Influenza – an overview

Viruses That Cause Diseases Represent a Small Fraction of the Viral Community

Diseases such as smallpox, rabies, AIDS, bird flu, swine flu, herpes, hepatitis, Japanese encephalitis, cassava mosaic disease as well as some of the more common, chickenpox, and the ever prolific common cold have helped perpetuate the bias toward viewing viruses as major challenges to humans, either directly through affecting our health or through affecting the health of livestock and crops. Indeed, much of the historical and current research resolved around determining the causative agent of virus diseases that often negatively affect their hosts, whether by causing disease in humans, plants, or animals or by killing their microbial hosts. Not only can virus diseases take a large toll on human life, some infections are seen as development concerns affecting education, income, productivity, and economic growth. Economic losses due to viruses derive from the treatment of the diseases they cause, their prevention, control of their vectors, as well as a myriad of varying consequences of social, economic and political impact, and the research aimed at developing control strategies—including vaccines and their administration. In agriculture viruses can lead to a complete crop loss due to reductions in plant growth and vigor, decreases in product quality (and hence, market value), investments in the development of prevention and control strategies, the implementation of quarantine programs, development of detection protocols, and more.

Although some virus diseases, such as smallpox and poliomyelitis, have been eradicated or almost wiped out, many diseases persist with limited little success at management and containment. In addition, new infectious diseases are emerging and old ones are reappearing after a significant decline in incidence. The term emerging disease refers to the appearance of an as yet unrecognized infection, or a previously recognized infection that has expanded into a new ecological niche or geographical zone. Emerging or re-emerging diseases are typically zoonotic, i.e., the infection can be spread between animals and humans and is often accompanied by some change in pathogenicity. HIV/AIDS is an example. HIV crossed into humans from chimpanzees in the 1920s presumably because of the bush meat trade—the hunting and killing of chimpanzees and other animals for human consumption. Severe acute respiratory syndrome (SARS), avian influenza, and Zika are more recent emerging zoonotic diseases. Zoonoses have been known since early historical times, but their incidence has quadrupled in the last half-century, mainly because of increasing human encroachment into wildlife habitats, air travel, and wildlife trafficking.

As this book will present diseases of viral etiology no further details will be provided in this section. Suffice to say that viruses can inflict damage in ways not caused by other pathogens mainly because virus infections are not always easy to control or prevent. However, it now appears that viruses with bad intent represent only a small fraction of a massive viral community and that a large number of viruses are unknown to science. Technologies of DNA and RNA deep sequencing, as well as genomics and metagenomics, are rapidly uncovering new species of viruses from seemingly healthy hosts. A diverse, abundant, and underappreciated viral community exists on and within us, even within our own genomes. Unlike the influenza- and Ebola-like viruses, these viruses establish a balanced coexistence by regulating their gene expression (possibly involving the use of noncoding RNAs such as microRNAs) thus allowing them to exist for the host’s entire lifetime under the radar of the host’s defense systems.

Health Alert: h2N1 Info | Health Services

h2N1 INFLUENZA

h2N1 influenza is a unique combination of genes from swine, bird, and human h2N1 influenza A virus that has demonstrated transmission from animal to humans. In light of recent outbreaks in Mexico, U.S., Canada, and other global areas, there is evidence that h2N1 influenza now has greater ease of human-to-human transmission.

On June 11, 2009, the World Health Organization declared a worldwide pandemic based upon distribution and prevalence of the disease. It is anticipated that the United States will experience a “second spike” in h2N1 cases this fall and winter as we move into cold and flu season. Symptoms of flu-like illness are: fever of > 100.0F, cough, and sore throat. In addition, the h2N1 influenza may also produce chills, body aches, headache, nausea, vomiting, and diarrhea. Incubation period is one to three days and duration of the illness averages approximately one week. All students and employees who experience flu-like symptoms are strongly encouraged to remain home until they are fever free for 24 hours without the use of fever-reducing medication.

Transmission

h2N1 influenza is not spread by food, or by eating pork or pork products. It is transmitted through large respiratory droplets that are generated when an infected person coughs or sneezes. The large droplets can be inhaled by susceptible people within six feet of the droplet source. Transmission also can occur through direct and indirect contact with infectious respiratory secretions.

Prevention

It is very important to engage in good respiratory hygiene to prevent the spread of any type of respiratory-borne illness. Here are a few simple measures:

Wash your hands often, especially after coughing or sneezing!! Make sure to use soap and water or hand sanitizers. Hand sanitizers are available on campus in the residence halls, dining halls, and other public places.
Dispose of used tissues in the trash. Do not leave used tissues on surfaces in common areas or on surfaces where others may come in contact.
Avoid touching your eyes, nose, and mouth as these become portals for the spread of germs.
Use proper coughing technique. If a tissue is not available, cough into the crook of your arm or sleeve.
Get a seasonal flu vaccine early! Even though the seasonal flu vaccine does not offer protection from h2N1 influenza, it does help boost your immune system.

Diagnosis

Diagnosis of h2N1 influenza is made with viral cultures taken from a nasal swab of a symptomatic person. There are no commercially available rapid influenza kits that can detect h2N1 influenza.

Treatment

Treatment of h2N1 influenza is largely symptomatic. Use acetaminophen and ibuprofen to help reduce fever and ease symptoms of body aches, chills, and headache. Avoid aspirin and aspirin containing products such as Pepto-Bismol as these products have been associated with Reyes syndrome in children. Maintain bed rest and drink plenty of fluids to avoid becoming dehydrated. If you are using a communal bathroom, use a respiratory mask to avoid spreading germs.

The CDC has recommended the use of antiviral medications for persons who are at high risk for influenza complications. These include pregnant women, people age 65 years or older, and persons with underlying medical conditions. Persons who meet this criteria should consult their private healthcare provider or contact the Monmouth University Health Services.

Signs and Symptoms

Influenza presents as a rapid onset of symptoms. Seek medical assistance if you develop sudden onset of the following symptoms:

For further update information go to http://www.nj.gov/highereducation/More_HE_Resources/h2N1_Resources.htm.

h2N1 Influenza – Causes, Symptoms, Treatment, Diagnosis

The Facts

h2N1 influenza is a contagious respiratory disease that causes symptoms of seasonal influenza in people.

The name “swine flu” was initially used to describe this type of influenza because laboratory tests showed that this strain of flu virus was made up of genes that were very similar to the ones that caused influenza among pigs (swine). Just like humans, pigs can get the flu. However, we now know that the h2N1 flu virus is made up of genes from several different flu viruses that normally circulate among pigs, birds, and humans. This strain was the most common cause of influenza in 2009, when it caused disease worldwide (“pandemic”).

Causes

h2N1 flu is caused by an influenza A virus. The letters H and N in the subtype name stand for proteins found on the surface of the virus, which are used to distinguish between different influenza A subtypes.

Influenza viruses are constantly changing their genes, a process called mutation. When a swine flu virus is found in humans, it is said to have “jumped the species barrier.” This means that the virus has mutated in a way that allows it to cause the condition in humans. Because humans have no natural protection or immunity to the virus, they are likely to become ill. The h2N1 flu virus is made up of genes from flu viruses that normally cause influenza in pigs, birds, and humans.

h2N1 flu virus is contagious. Person-to-person transmission of h2N1 flu virus occurs, and the virus is easily spread among people. It is believed that it is spread the same way as regular seasonal influenza. A person infected with h2N1 flu virus can infect others starting 1 day before symptoms develop and up to 7 or more days after becoming ill.

Influenza is spread from person to person when the virus enters the body through the eyes, nose, and/or mouth. Coughing and sneezing release the germs into the air, where they can be breathed in by others. The virus can also rest on hard surfaces like doorknobs, ATM buttons, and counters. A person who touches these surfaces with their hands and then touches their eyes, mouth, or nose can become infected with the virus. Influenza is generally not spread by eating food or drinking water.

Symptoms and Complications

The various strains of influenza A virus infection produce identical symptoms. People may experience:

body aches
chills
cough
fatigue
fever
headache
loss of appetite
sore throat

Some people with h2N1 flu virus have also reported vomiting and diarrhea.

The severity of symptoms can vary from mild to severe and sometimes require hospitalization. In some cases, severe complications such as pneumonia and respiratory failure can cause death. Like the seasonal flu, h2N1 flu may worsen existing chronic medical conditions.

Making the Diagnosis

Your doctor will diagnose based on signs,symptoms and a physical exam. A swab sample from your nose or throat can be used to help identify the flu virus.

Treatment and Prevention

There is a vaccine against h2N1 flu that is available to all Canadians who want to be vaccinated.Protection against h2N1 flu is now incorporated as part of the seasonal influenza vaccine each year.

People diagnosed with h2N1 flu generally recover fully without medical attention and without antiviral medications. However, treatment with antivirals (e.g., oseltamivir*, zanamivir) may be recommended for people who have moderate-to-severe symptoms and for people who are at risk for complications of influenza (e. g., people with underlying medical conditions).

For people who are sick, help yourself get better and prevent the spread of the virus by doing the following:

Stay at home if you are sick. Do not go to work or school.
Stay at least 1 metre away from other people.
Rest and drink plenty of fluids.
Cover your mouth and nose with a tissue when coughing or sneezing. Throw your used tissue in the garbage. If you do not have tissue available, cover your sneezes with your sleeve or hands. Wash your hands thoroughly afterwards.
Wash your hands regularly with soap and water. Make sure to wash your hands with soap for at least 15 seconds. Use an alcohol-based hand sanitizer if you don’t have access to soap and water.

There are ways to protect yourself from catching the h2N1 flu virus. By far, the most effective preventative measure is to get the influenza vaccine just before the annual flu season (generally November through April in North America). Here are some tips to prevent flu:

Avoid close contact with people who are sick and who have symptoms of h2N1 flu (e.g., fever, cough).
Wash your hands with soap and water frequently and thoroughly. To ensure proper sanitization, you should wash your hands with soap for at least 15 seconds. Use alcohol-based sanitizers if handwashing is not convenient.

All material copyright MediResource Inc. 1996 – 2021. Terms and conditions of use. The contents herein are for informational purposes only. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Source: www.medbroadcast.com/condition/getcondition/h2N1-Influenza

Swine Flu (h2N1): Overview and More

Swine flu is the name for the influenza type A virus that affects pigs (swine). Although swine flu doesn’t typically affect humans, there was a global outbreak (pandemic) in 2009 to 2010—the first flu pandemic in more than 40 years. It was caused by a then-new flu virus known as h2N1, an influenza virus that’s a combination of swine, avian (bird), and human genes that mixed together in pigs and spread to humans. h2N1 is now considered a normal type of seasonal flu and is included in the flu vaccine.

Verywell / Lara Antal

History

h2N1 was first detected in April 2009 in a 10-year-old girl in California. It was declared a global pandemic in June 2009 by the World Health Organization (WHO) and was finally over in August 2010.

The Centers for Disease Control and Prevention (CDC) estimates that swine flu infected nearly 61 million people in the United States and caused 12,469 deaths. Worldwide, up to 575,400 people died from pandemic swine flu.

The 1918 influenza pandemic was also caused by an h2N1 virus. Known as the Spanish flu, its genes show that it may have developed from a swine flu virus or from an avian (bird) flu virus. The pandemic killed an estimated 50 million people worldwide and was notable in that it had a high death rate among healthy adults.

Swine Flu Symptoms

h2N1 causes respiratory illness and is very contagious. Symptoms of h2N1 are similar to those of the seasonal flu and may include:

Fever
Body aches
Loss of appetite
Cough
Sore throat
Headache
Fatigue
Runny nose
Irritated eyes
Vomiting, nausea
Diarrhea

Causes

Type A influenza viruses have the ability to mix with other strains, creating a new strain, which is what happened to cause the pandemic of 2009 to 2010.

Pigs are able to contract all three types of influenza (human, swine, and avian), make them perfect vessels in which the virus can mix and change. The h2N1 virus is made of swine, human, and avian genes that metamorphosed in pigs, probably several years before the pandemic (hence the name “swine flu.”)

Influenza circulates among pigs throughout the year but is most common during the late fall and winter, similar to the human flu season. Sometimes pigs can pass the flu to the humans who work. This is what happened during the 2009 to 2010 pandemic, only, in this case, the new h2N1 strain spread quickly because humans had no immunity to it.

When people get the h2N1 virus, it’s in the same way they can get any type of flu— by contact with another person who is sick, from either droplets in the air that contain the live virus or by touching a surface that has been contaminated and then touching your eyes, nose, or mouth.

You can’t get influenza from eating pork, though you should always make sure that it’s cooked thoroughly and handled carefully.

Diagnosis

If you develop signs of the flu and are otherwise in good health, you likely don’t need to see a doctor. However, if you’re pregnant, your immune system is compromised, or you have a chronic illness such as asthma, diabetes, emphysema, or a heart condition, you should see your doctor right away.

Your doctor will be able to diagnose you with the flu by taking a swab from your nose and/or throat within the first four to five days of your sickness. There are rapid influenza diagnostic tests that can tell if you have the flu or not, as well as which type (A or B), though they are not as accurate as other tests.

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There are also rapid molecular assays, which are more accurate and can also give a rapid result. Since there is more than one strain of influenza A virus strain, a positive influenza A test doesn’t necessarily mean you have the h2N1 virus. To definitively diagnose and classify the strain of influenza you have, such as h2N1, your doctor may send your specimen to a specialized hospital or state lab for analysis.

Treatment

h2N1 flu is a virus just like any other strain of flu. The antiviral medications Tamiflu and Relenza do not cure the illness, but they may shorten the duration, make symptoms less severe, or help you avoid it altogether if you are exposed. They are usually reserved for people who are at a higher risk of complications, so the likelihood of the virus developing a resistance to them is lessened.

Otherwise, treatment for most people mainly consists of comfort measures and treating symptoms as they occur. If you have asthma or emphysema, for instance, your doctor might add a medication to help relieve your respiratory symptoms.

Annual flu shots now provide immunity against h2N1, meaning that swine flu has become preventable.

A Word From Verywell

As with any type of flu, you should respect the h2N1 virus, but there’s no reason to be afraid of it. Though complications can occur as a result of getting any type of flu, getting your annual flu vaccine (which protects against h2N1), washing your hands regularly and thoroughly, and staying away from infected people can help lessen your risk of picking up any strain of flu.

China reports first known human case of h20N3 bird flu

A man in China caught the first case of h20N3 bird flu ever reported in a human, China’s National Health Commission (NHC) announced Tuesday (June 1).

The h20N3 strain of avian influenza normally causes mild disease in birds, and until now, no cases of the viral infection had been reported in humans, according to a statement on the NHC website, as translated by Reuters. But on April 23, a 41-year-old man in the city of Zhenjiang developed a fever that progressed over the following days, and on April 28, he went to a local hospital for treatment.

(Although h20N3 only causes mild disease in its natural hosts, that may not hold true when the strain jumps to people.)

On May 28, the Chinese Center for Disease Control and Prevention (CCDC) performed a genetic analysis on specimens from the infected man and determined he was infected with h20N3, according to the statement. The CCDC then monitored the surrounding province of Jiangsu for additional cases of infection and specifically sought out the man’s close contacts, but they discovered no additional cases. The man is now in stable condition and ready for discharge from the hospital, the statement notes.

Related: 11 (sometimes) deadly diseases that hopped across species

Scientists will need to thoroughly examine the genetic material of the strain that infected the man to see how it differs from h20N3 samples collected in the past, Filip Claes, regional laboratory coordinator of the UN’s Emergency Centre for Transboundary Animal Diseases at the Regional Office for Asia and the Pacific, part of the agency’s Food and Agriculture Organization, told Reuters.

In general, h20N3 doesn’t crop up very often in its natural hosts, birds, Claes noted. From the late 1970s to 2018, scientists isolated about 160 samples of the viral strain from infected animals, mostly from wild birds and waterfowl, and the strain hadn’t been detected in chickens, he said.

The CCDC did not specify how or when the infected man may have picked up the virus from a bird, Reuters noted. But based on the CCDC’s assessments so far, there’s little risk of the virus spreading on a large scale, the agency said. When avian influenza viruses make the leap from birds to humans, they usually don’t spread between humans, and when they do, their transmission is typically “limited, inefficient and not sustained,” according to the U.S. Centers for Disease Control and Prevention.

However, in rare instances, avian flu can indeed spark major outbreaks among people, so monitoring for new cases of infection remains very important for public health, according to the CDC. For instance, the last bird flu to cause significant outbreaks among humans was H7N9, which killed more than 300 people in 2016 and 2017, Science magazine reported. That virus strain has a case-fatality rate of about 40%, according to a 2016 issue of the CDC journal Morbidity and Mortality Weekly Report.

And back in 1957, the avian influenza virus h3N2 swapped genes with human flu viruses and sparked a full-blown pandemic, Gizmodo reported. Evidence suggests that the flu strain that caused the 1918 pandemic, h2N1, also came from birds, refuting some older studies that suggested it originated from a mix of human and swine viruses, Nature reported in 2014.

Earlier this year, Russian authorities reported the first known cases of an avian influenza virus called H5N8 passing from poultry to humans, Live Science previously reported. Seven workers at a poultry plant caught this strain, but there was no evidence of human-to-human transmission, meaning the virus spread directly from birds to the workers and did not spread from the workers to other humans.

Originally published on Live Science.

Influenza Virus h2N1 Fact Sheet

The influenza type A virus, known as h2N1 is a respiratory infection that was popularly named “swine flu. ” The virus was first recognized in April 2009 and spread quickly to 74 countries worldwide. The World Health Organization (WHO) declared the virus a global pandemic. This was the first global pandemic in over 40 years and was listed as a global pandemic for more than a year. The name “swine flu” means influenza in pigs and occasionally the influenza virus can be transmitted to people who work with pigs. Very seldom does the person who works with pigs transmit the virus to others, but this was the case with h2N1. The virus does not spread by consuming pork.

So what does h2N1 mean?

Influenza viruses are split up into three broad groups known as influenza A, B and C. Influenza A is the most common type, and h2N1 is a type of influenza A. The designation “h2N1” indicates unique traits, which exhibit characteristics that identify the virus to the immune system and allows for attachment and replication of the virus. The “H” (hemagglutinin) and the “N” (neuraminidases) are both proteins that are found on the outer shell or envelope of the virus. Different viruses have different hemagglutinin and neuraminidase proteins. There are 16(h2 to h26) known types of hemagglutinin and 9(N1 to N9) known types of neuraminidase, which gives 144 different possible combinations of these proteins.

How does the influenza virus change?

Influenza viruses can change in two different ways: antigenic drift and antigenic shift. Antigenic drift occurs more commonly and refers to small, gradual changes that occur through mutations in the genetic material that cause small changes in the surface proteins hemagglutinin and neuraminidase. Antigenic drift produces new virus strains that may not be recognized by the immune system, even if it has been primed (by vaccination or prior infection) to recognize other influenza strains. A person infected with a particular influenza strain creates antibodies that recognize that strain of virus, but, if a new strain appears, the older antibodies will not recognize it, causing the person to become sick again. This is one reason a person may get the flu more than once during the flu season and why it is important to create vaccines against the viruses that are currently circulating the population. Every year the vaccine is updated to keep up with changes in the circulating influenza viruses so it is important to be immunized annually.

Antigenic shift refers to an abrupt, major change that produces a new influenza subtype in humans that was not previously transmitted between people. Antigenic shift occurs through animal to human transmission or through mixing of human influenza A and animal influenza A virus genes to create a new human influenza A subtype with new types of hemagglutinin, neuraminidase or both. When this happens, most people have little or no protection against the new influenza virus, as was the case in the h2N1 virus.

The 2009 h2N1 influenza virus had two genes from flu viruses that normally circulate in pigs in Europe and Asia, plus avian and human genes. This virus was originally referred to as “swine flu” because laboratory testing showed that its gene segments were similar to influenza viruses that were most recently identified in and known to circulate among pigs. The CDC believes that this virus resulted from antigenic shift, which as noted above is a process through which two or more influenza viruses can swap genetic information by infecting a single human or animal host. When antigenic shift occurs, the virus that emerges will have some gene segments from each of the infecting parent viruses and may have different characteristics than either of the parental viruses, just as children may exhibit unique characteristics that are like both of their parents. In this case, the shift most likely occurred between influenza viruses circulating in North American pig herds and among Eurasian pig herds. Influenza type A viruses can undergo both antigenic drift and shift, while the influenza type B viruses only change by antigenic drift.

Frontiers | Adaptation of Human Influenza Viruses to Swine

Introduction

Influenza is one of the most devastating respiratory pathogens of pigs and humans and continues to threat animal and public health with the continuing possibility of outbreaks or a pandemic. The intricacies of influenza A viruses (IAV) at the human-swine interface dates back to the 1918 pandemic. For several decades, it was hypothesized that pigs played a role in the origin of the 1918 h2N1 pandemic virus (1). Although there is evidence suggesting that the pandemic virus did not originate from pigs and that the classical swine h2N1 virus was in fact derived from the 1918 human virus (2), the bias perceiving swine as the source of IAV to humans still remains.

The ecology of IAV is complex and involves a broad range of avian and mammalian host species. IAVs are enveloped, segmented RNA viruses in the family Orthomyxoviridae (3). The virus genome is composed of eight negative-sense, single-stranded viral RNA (vRNA) segments that encode between 10 and 17 viral proteins depending on the strain (4–6). Each RNA segment forms the viral ribonucleoprotein complexes (vRNPs) with the nucleoprotein (NP) and the three polymerase proteins (PB2, PB1, and PA). Two major glycoproteins are projected on the virus envelope, hemagglutinin (HA), and neuraminidase (NA) (7). Based on the antigenic properties of the HA and NA, IAV are divided into 18 HA subtypes (h2–h28) and 11 NA subtypes (N1–N11) (7–9).

Influenza viruses have high mutation rates and are constantly changing, which enables the virus to quickly adapt to changes in the host environment, as is the case during interspecies transmission. The rapid evolution results from two mechanisms: reassortment and point mutations (10). Reassortment occurs when two different strains infect the same cell of a given host, allowing for exchange of intact gene segments. When reassortment involves either the HA or NA segments, it is termed antigenic shift. Point mutations occur due to an error prone polymerase devoid of a proof-reading and correction mechanism. When point mutations are fixed in the HA or NA segments, usually a result of escape from immune pressure, it is termed antigenic drift. Both of these mechanisms play pivotal roles in the emergence of novel influenza viruses that could jump the host barrier. Once the virus jumps into a new host, it must adapt and change to be able to spread and become established in the new population.

In this review, we describe the role of pigs in the interspecies transmission of influenza and how their susceptibility to different viruses can affect the overall epidemiology of swine influenza. We discuss the factors that have been implicated in the interspecies transmission of influenza with an emphasis on the human-swine interface. We then provide an overview of human-to-swine IAV spillover events that significantly affected the epidemiology of viruses circulating in swine and how these viruses can have a negative effect on the control of influenza in pigs.

Why Pigs Become Infected With Viruses From Other Species?

To result in a successful replicative cycle, influenza viruses must efficiently infect the host cell, replicate, and produce functional virus progeny that will be released and infect new cells. The first step for infection is the attachment of the HA protein to the cell receptor. The HA is a type I transmembrane glycoprotein, present as a homotrimer on the virus’ surface, each monomer carrying a transmembrane anchor and a small cytoplasmic tail. The proteolytic cleavage of the precursor HA0 produces two subunits, HA1 (globular head) and HA2 (stem). The receptor binding site (RBS) forms a shallow pocket at the distal tip of the HA1 head and consists of a base of four highly conserved amino acid residues (Y98, W153, h283, and Y195, numbering based on the h4 subtype) that are bordered by the 130-loop, the 190-helix and the 220-loop (11–13).

Through the RBS, influenza viruses bind to terminal sialic acid (SA, N-acetylneuraminic acid) moieties in glycoprotein or glycolipid receptors on the host cell surface. The SAs are usually bound to the penultimate galactose (Gal) in two major conformations: α2,3SA or α2,6SA (13). Differences in the type of SA linkage found in receptors expressed in different host species have a major impact on the host restriction of IAVs. Sialic acids with α2,3-linkage are predominantly expressed on epithelial cells in the intestinal and respiratory tracts of birds while the epithelial cells in the upper respiratory tract of humans contains predominantly α2,6-linked SA receptors (14–17) (Figure 1). Most avian influenza viruses preferentially bind to α2,3-SA, whereas human and other mammalian influenza viruses preferentially recognize α2,6- SA receptors (21–23).

Figure 1. Overall distribution of α2,6-linked sialic acid (SA; green long arrow) and α2,3-linked SA (blue short arrow) in the epithelium of the respiratory tract of pigs (18, 19) and humans (14, 15). Adapted from de Graaf and Fouchier (20).

Pigs have been historically believed to be intermediary hosts, or “mixing vessels,” of influenza viruses due to their susceptibility to infection with both human-origin and avian-origin IAV and their propensity for the generation of reassortant viruses (24–27). Pigs have a similar distribution to humans of α2,3-SA and α2,6- SA receptors in the respiratory tract (Figure 1). As in humans, α2,6-linked SA receptors predominate in the upper respiratory tract of pigs, but α2,3-SA receptors are present in low quantities in swine tracheas, and the frequency increases toward the lower respiratory tract (18, 19) (Figure 1). The presence of both types of SA receptors in swine airways supports the potential role of pigs as “mixing vessels.” However, such distribution of α2,3- and α2,6-SA receptors is similar in swine and humans (15, 18), and it must be noted that avian viruses do not usually transmit from pig-to-pig as is also the case in humans (28, 29). Humans can also become infected with avian-origin IAVs directly from avian sources and could potentially provide the environment for the adaptation of avian viruses (30–32). Hence, generation of reassortant viruses with pandemic potential may not require swine as intermediate hosts. However, as highlighted by the 2009 pandemic (33), while swine are not required, they may serve as intermediate hosts for generation of reassortant viruses with the ability to cause human pandemics. The 2009 pandemic has led to an increased concern about the transmission of swine viruses to humans. However, improved surveillance of swine IAV after the pandemic has shown that human viruses are transmitted to pigs, and have resulted in sustained onward transmission, far more frequently than swine viruses have infected humans (34). This lower host barrier observed for human viruses in pigs can be explained in part by the similar receptor distribution in both species and the shared preference for α2,6-linked SA receptors between human and swine viruses (22, 26).

What Are The Mechanisms For Adaptation of Human Influenza Viruses To Pigs?

Although IAV transmission events from humans to pigs are continually detected globally and despite the similarities of receptor preference and distribution between the two species, whole human IAV rarely become established in swine. Typically, these viruses reassort and emerge with only some of the human-origin viral gene segments persisting, often with marked genetic differences from the precursor strain (34–36). This implies that adaptation factors other than the receptor linkage-type specificity are required for human-origin viruses to be transmitted and subsequently become endemic in swine populations.

The adaptation of influenza viruses between humans and pigs is likely driven by selective pressures or bottlenecks imposed to the virus population during IAV host jump, as a result of the changes in the host environment (37, 38). Several factors may affect these selective pressures during interspecies transmission, either within the virus or the host. Receptor-binding specificity and affinity, balance between HA and NA content, temperature of the host, and host-specific immune factors may be some of these factors. However, the differences in the selective pressure between humans and swine and how they may differently affect virus adaptation are not entirely understood, and some of the currently know differences are discussed below.

Binding Determinants of Host Range

Specific amino acid residues at the influenza HA are required for binding to either α2,3-SA or α2,6-SA receptors and specific amino acid substitutions at the RBS of the HA can alter receptor-binding specificity and facilitate host jump (Figure 2A). In h2 subtype viruses, positions 190 and 225 were shown to have an impact in receptor specificity. The combination of E190/G225, E190/D225, or D190/G225 in the RBS of the HA, found in avian viruses and late stage 2009 pandemic h2N1 strains, results in dual receptor-binding specificity, whereas D190/D225 and D190/E225, combinations found in seasonal human viruses, results in human-type receptor specificity (40–42). As for h4 and H9 viruses, positions 226 and 228 in the HA are critical for receptor specificity. Avian-adapted viruses usually present Q226/G228 and show dual-binding or α2,3-SA preference, but amino acid substitutions Q226L/G228S leads to receptor specificity switch to human-type receptor preference and is, therefore, more commonly found in human viruses (22, 43). Analysis of h2, h4, and H9 virus sequences from swine using the Influenza Research Database (44) revealed that swine viruses have mostly D190/D225 in h2 viruses, a fairly equal distribution between Q226/G228 and L226/G228 in H9 viruses, and the unique combination of amino acids in h4 viruses V226/S228 (Figure 3).

Figure 2. Host range determinants of influenza A viruses (IAV). (A) Avian influenza virus HA protein recognize short α2,3-linked sialic acid (blue), whereas HA from human and swine IAV recognize long α2,6-linked sialic acid (green). (B) The balance between the HA binding affinity and the NA activity to cleave sialic acid receptors is important for replication and adaptation to a new species. If a virus has strong biding affinity but low cleavage activity replication may be reduced. (C) The PB2 polymerase has an impact in the optimal replication temperature of IAV and can restrict host range. K627 increases replication at the low temperature of human or swine upper airway. E627 decreases replication at low temperatures, unless in combination with A271 or N701. (D) The sensitivity of a virus to host-specific innate immune factors can restrict interspecies transmission of IAV. To be able to replicate and spread in a new host, IAV must become resistant to the antiviral activity of interferon-induced Mx protein or to the neutralizing activity of surfactant protein D (SP-D) from that particular host. Adapted from Cauldwell et al. (39).

Figure 3. Proportion of amino acids found in influenza A viruses circulating in pigs globally at the HA receptor-binding site positions previously shown to impact receptor-specificity for h2, h4, and H9. Analysis was performed using the Influenza Research Database Sequence Variation (SNP) tool (44). Sequences with 100% identity were removed resulting in a set of 8076 h2 HA, 2287 h4 HA, and 46 H9 HA swine IAV sequences. The amino acids previously shown to change receptor-binding specificity are displayed on the right.

Receptor-binding specificity of influenza HA is not only mediated by changes in the sialic acid linkage, the structural length and topology of the glycans can also determine the binding specificity and affinity of IAV. Avian viruses were shown to bind to α2,3-linked SA carrying a shorter carbohydrate chain whereas human viruses bind preferentially to long α2,6-linked SA (45, 46). Moreover, avian HA binds to narrow α2,3-SA in a “cone-like” topology and human HA binds to long α2,6-SA in an “umbrella-like” topology, which are predominantly expressed in the human upper respiratory tissues (47). In general, human and swine viruses have been shown to recognize similar glycan structures on glycan microarrays, mainly branched α2,6-SA (48, 49).

NA and M as Determinants of Host-Range

While the HA is involved with binding to SA receptors, the NA cleaves α2-3 and α2-6-linked SA residues from cellular surfaces and mucus through its sialidase enzymatic activity and mediates the release of newly synthesized viruses from the host cells (7). For an optimal viral replication, balanced activities between the HA binding affinity and the NA enzymatic function are expected. The ideal HA-NA balance seems to be an important factor in host adaptation (Figure 2B). The HA-NA balance was shown to be crucial for the adaptation of the 2009 pandemic h2N1 virus to humans, since balanced HA and NA activities were seen in the human strains but not in precursor swine viruses (50) and this balance resulted in increased replication and transmissibility in ferrets (51). Additionally, adaptation of H5 and H7 viruses from wild birds to chickens led to selective changes in both HA and NA, maintaining a balance between binding and cleavage that was important for replication and transmission in the new host (52). These chicken-adapted H5 and H7 viruses possess a shorter NA due to the deletion of several residues in the stalk domain that were shown to enhance replication and virulence in chickens but block respiratory transmission in ferrets (53, 54).

In addition to the NA, the matrix (M) gene segment has been shown to be a critical determinant of respiratory transmission efficiency of IAV in new hosts. The M segment was implicated with the increased transmissibility of the 2009 pandemic h2N1 virus in animal models (55, 56), suggesting it played an important role on the spread of the virus in humans. In pigs, the combination of the NA and M genes from the 2009 pandemic virus was essential to facilitate efficient replication and transmissibility (57). Interestingly, reassortant h2 and h4 swine-origin viruses containing the M gene of the 2009 pandemic virus have caused almost yearly zoonotic outbreaks in humans, more frequently than was observed prior to the pandemic, confirming that the M gene plays a role in adaptation and transmission of swine viruses in humans (58–60).

Temperature Determinants of Host-Range

The virus polymerase (comprised of viral proteins PB1, PB2, and PA) was also shown to be a major determinant for host range of influenza viruses (61) (Figure 2C). This host restriction has been attributed to a single residue in the PB2 gene, amino acid 627, and is largely associated with the optimal temperature of replication of IAVs (62, 63). While the human upper respiratory tract temperature is around 33°C, in the avian intestinal tract the temperature is closer to 41°C. Therefore, enhanced replication at lower temperature should correlate with enhanced replication in the upper airway of humans and consequently improve transmission. Lysine (K) at position 627 in PB2, present in the vast majority of human viral isolates (64), was correlated with increased polymerase activity, virus replication and transmission in mammals (65–67), including enhanced replication of an avian virus in pigs (68). Replication and polymerase activity of different avian viruses, which predominantly possess glutamic acid (E) at position 627, were reduced at low temperature in mammalian cells (65, 66, 69).

The temperature of the upper respiratory tract of pigs is approximately 37°C and higher (approximately 39°C) in the lower respiratory tract. Interestingly, most swine isolates that have a PB2 of avian-origin retain the avian signature E627, including the predominant North American triple reassortant internal gene (TRIG) constellation viruses, the predominant Eurasian avian-like viruses, and even the 2009 pandemic h2N1 viruses (70, 71). The presence of the avian-like E627 in swine viruses usually does not result in the temperature sensitivity observed for avian viruses in mammalian cells (69), suggesting that these viruses can replicate at temperatures of avian intestines and human airways. Other residues, such as A271 and N701, were shown to compensate for the absence of K627 in these swine or swine-origin viruses and contribute to virus growth and transmission in swine and other mammalian species, including humans (71–74).

Immune Determinants of Host-Range

Following influenza infection in respiratory epithelial cells, acute inflammation leads to activation of the innate immune response through pro-inflammatory cytokines or chemokines (75). Type-I interferons (IFN-α/β) are cytokines quickly secreted after IAV infection. Type-I IFN mediated responses to IAV results in the expression of several antiviral proteins (76, 77). The Mx proteins are a family of large GTPases that are central to the antiviral activity of IFN against IAV by blocking nuclear entry of the vRNPs (78, 79). Sensitivity to interferon-induced Mx varies among different IAV strains and represents a barrier against transmission of avian influenza viruses to mammals: avian isolates are more susceptible to the antiviral action of murine Mx and human MxA proteins than human viruses (80, 81). The Mx sensitivity was shown to be determined by a cluster of surface-exposed amino acids on the viral NP (81, 82). Interestingly, serial passage in mice of a virus that is sensitive to murine/human Mx activity leads to a single amino acid adaptive NP mutation that results in escape from the Mx activity, and the same mutation is also seen in human H7N9 isolates (83). Not surprisingly, some swine IAV strains with avian-origin NP tend to have a higher sensitivity to mouse Mx1 than human isolates (84). However, the 1918 pandemic h2N1 and the 2009 pandemic h2N1 viruses acquired resistance-associated substitutions on the NP protein that allow escape from human Mx (82). The functional Mx1 protein is expressed in the lungs of pigs experimentally infected with IAV (85). It seems that the precursor of the 2009 pandemic h2N1 virus acquired Mx-resistance mutations driven by the porcine Mx1 during its circulation in pigs prior to the pandemic, being able to partially resist the human MxA (82). The Eurasian avian-like viruses are similarly resistant to human MxA, however different mutations were attributed to this phenotype (86). It remains unknown whether human and swine viruses would have different sensitivities to the porcine Mx protein.

Surfactant protein D (SP-D) is a collectin of the innate immune system that also has early strong antiviral activity against IAVs. SP-D binds to carbohydrate moieties on the surface of influenza viruses (HA and/or NA), blocking attachment to epithelial cells and inducing phagocytic responses, resulting in non-specific virus neutralization and clearance (87). The susceptibility of different IAV to SP-D activity was shown to be dependent on the glycosylation pattern of the virus, particularly on the HA (88–90). Influenza strains of the h4 subtype tend to acquire and accumulate more glycosylations on the HA head as a mechanism to evade the antibody response in humans, but this in turn may make them more susceptible to the antiviral effect of SP-D. Interestingly, porcine SP-D has a higher affinity to bind IAV glycans than human or rat SP-D, resulting in stronger neutralization activity (91, 92). Therefore, differences in susceptibility to Mx or SP-D could be an important component in host restriction of influenza viruses that needs to be overcome, usually by changes in specific viral proteins, in order for a virus to adapt to a new species (Figure 2D).

The IAV NS1 protein plays an important role as an antagonist of the host IFN response by preventing the activation of retinoic acid-inducible gene 1 (RIG-I) or inhibiting processing of mRNA (93). Differences between the NS1 amino acid sequences may affect the functional IFN-antagonistic properties of the NS1 (94, 95). Consequently, NS1 and its ability to control IFN response could play a role in host range of IAV. Indeed, although the avian NS1 protein was able to control IFN-α/β response in human cells, the human type I IFN response appeared to limit the replication of the avian viruses, suggesting that the NS1 also contributes to the host specificity of IAV (96).

The adaptive immunity of an individual or population can also have a role in host range restriction of IAV. Even when a novel virus contains an ideal combination of factors that allow replication in the new host, as discussed above, previous cross-protective immunity might block even the initial infection. In some cases, the level of cross-protective immunity of the population may still allow infection but might block virus dissemination; however, naïve individuals will be at a higher risk for infection and may serve as sources of transmission. That was the case for the zoonotic infections with swine-origin viruses in recent years, in which the majority of affected individuals were children (58, 59). For these outbreaks, infection was observed in people with close contact with pigs, and transmission from human-to-human was rare, which was attributed to low levels of cross-protective immunity in the human population due to previous exposure to seasonal viruses (97). In pigs, however, there is a continuous introduction of naïve individuals and the majority of the population does not have previous immunity to viruses circulating in humans, increasing the chances of those viruses that have ability to infect pigs to become widespread.

How Do Human Viruses Relate To The Evolution Of Swine Influenza Viruses?

Human-origin viruses have been repeatedly transmitted to swine worldwide and have had a major role on the epidemiology of swine IAV (34) (Figure 4). The classical swine h2N1 virus that emerged around the 1918 pandemic remained relatively antigenically stable for eight decades without causing major problems to swine producers. A novel triple-reassortant virus with human seasonal h4N2 surface genes emerged in the late 1990’s in North America (27, 98) and led to reassortment with the classical viruses and subsequently gave rise to different antigenically distinct h4N2, h2N1, and h2N2 strains (99, 100). The triple-reassortant internal gene (TRIG) constellation, containing gene segments from a complex reassortment history among swine-, human- and avian-origin IAVs, became the predominant backbone of the viruses circulating in pigs in the U.S. (101, 102). Shortly after, two additional introductions of human-origin h2N1 resulted in the establishment of two new lineages of h2N1 and h2N2 viruses after reassortment with the TRIG strains, termed δ-lineages (103). After the spread in humans, the h2N1 pandemic 2009 virus (h2N1pdm) was quickly transmitted to swine in North America (104). And recently, a novel virus derived from 2010 to 2011 human seasonal h4 IAV led to establishment of a new h4-lineage that is genetically and antigenically distinct from previously circulating strains (105). The current scenario for the epidemiology of IAV circulating in North American swine consists of a highly diverse pool of viruses, with 14 phylogenetic clades of HA co-circulating (36, 101, 105, 106). It is clear how impactful the human-to-swine transmissions were to this current epidemiology: at least 10 of these phylogenetic clades have evolved from a human virus. If considering the hypothesis that the classical swine virus originated from the human 1918 pandemic virus, all of those clades should be considered of human-origin.

Figure 4. Different subtypes/lineages of human-origin influenza viruses circulating in swine in different continents. The map is colored according to pork production in 1,000 metric tons. Map created with mapchart.net.

In Europe, a human-origin h4N2 virus descendent from the 1968 pandemic virus was introduced in the 1980’s. This virus became widespread after reassorting with an avian-origin h2N1 virus that was introduced to European swine in 1979 and remains endemic to date (107, 108). Another human-origin virus, an h2N2, was detected in 1994, containing the h2 that evolved from a 1980 human seasonal h2N1 virus and a human-origin N2 that is distinct from the previously introduced h4N2 human-like virus. This virus acquired the internal gene constellation of the 1979 avian-like virus after reassortment and is now endemic in Europe (109, 110). As in the U.S., the h2N1pdm virus has been transmitted from humans to pigs in Europe establishing a new endemic lineage (108, 111). Recently, a triple-reassortant h4N2 virus with a human-origin HA from a 2004–2005 seasonal virus, N2 from endemic swine viruses, and the internal genes from h2N1pdm has spread in Denmark swine herds (112). In China and other countries in Asia, importation of live animals has resulted in the co-circulation of both European (or Eurasian) and North American TRIG virus lineages that contain human-origin genes (113–115). Additionally, reassortant genotypes between these lineages containing HA and/or NA genes from h2N1 and h4N2 human viruses have been detected in Asia since the 1960’s and have become established in pigs (34, 116, 117).

Human-origin IAVs have been reported circulating in pigs in other countries where surveillance is limited (34, 118–120), including countries with large swine populations like Brazil (121, 122), Vietnam (123), Mexico and Chile (124). But, even in some of these cases where human-origin viruses or viral genes were reported in swine, it is not possible to infer if they have become endemic or predominant. However, in several cases, such as in Latin America, the human-origin swine viruses were most closely related to human seasonal strains that circulated many years earlier and were separated by long phylogenetic branches, suggesting that these viruses have circulated undetected in pigs for years prior to their recent detection (34, 118, 121, 124). Considering the frequency of human-to-swine transmissions in highly surveilled areas, it is likely that additional human-origin viruses have gone undetected in countries with low surveillance efforts.

In addition to the recurrent seasonal virus spillover events into swine populations, the h2N1pdm has been repeatedly transmitted from humans to swine globally (125). The h2N1pdm virus originated in Mexico from the reassortment between Eurasian and North American swine viruses and this novel virus may have circulated undetected for approximately 10 years before it gained the ability to infect humans (33). Soon after the initial spread of the h2N1pdm in the human population, the h2N1pdm virus was detected in pigs and since then transmitted from human to pigs throughout the world (104, 126–131). The virus has now become endemic in humans and circulates as a seasonal strain, increasing the possibility of spillovers to swine populations during influenza season each year. Owing to its swine-origin and yearly circulation in humans, continuous and frequent detection of the h2N1pdm virus in pigs has been reported globally (125, 132). The constant circulation and re-introduction of h2N1pdm globally has led to reassortment with endemic swine viruses and changed the genotypic characteristics of swine IAV by contributing several genes, most commonly the internal genes. In the U.S., the surface genes of the h2N1pdm are not frequently maintained, however most genotypes of h2 and h4 viruses contain at least one internal gene of pandemic lineage (133, 134). In Europe, the h2N1pdm virus has reassorted with endemic European viruses and gave rise to genotypes containing the internal genes from pandemic origin and some genotypes have maintained one or both surface genes of pandemic lineage (135). Interestingly, there is recent evidence of the independent antigenic evolution of the swine h2N1pdm virus in European pigs (136). In China, although Eurasian and North American viruses circulated prior to the 2009 pandemic without substantial evidence of reassortment, the introduction of the h2N1pdm led to the establishment of reassortant genotypes containing several internal genes from pandemic lineage (117). The h2N1pdm has been reported throughout the world in swine with frequent reassortment (137–139), even in countries that were previously considered influenza free like Australia and Norway (128, 140).

How Do Human-Origin Viruses Affect Control Of Influenza In Swine?

The repeated transmission of human seasonal viruses to pigs has resulted in the establishment of several human-origin virus lineages globally, adding to the antigenic diversity of swine viruses. Global antigenic characterization has revealed that the antigenic diversity of h2 and h4 viruses circulating in pigs was largely a result of the frequent introductions of human-origin IAV into swine (35). These viruses then evolved antigenically, independent from human strains and often confined to their geographic areas, contributing to the overall global diversity, which consequently contributes to the challenges for effective vaccination programs in swine. Most vaccines used against influenza in swine are whole inactivated virus (WIV) vaccines combined with oil-in-water adjuvants typically given to sows to allow transfer of maternally derived antibodies to piglets (141). Recently, two novel platforms were licensed for use in pigs in the U.S. as alternatives to improve the efficacy of swine vaccines, a non-replicating alphavirus RNA vectored-vaccine and a live-attenuated influenza virus (LAIV) vaccine (142, 143).

Because most vaccines rely on the effective stimulation of the immune response against the surface HA glycoprotein, any changes that lead to antigenic drift, such as the incursion of novel human-origin viruses, can lead to vaccine mismatch. It was demonstrated that changes in only 6 amino acids in the HA account for major antigenic changes of swine h4 influenza viruses, and a single amino acid change can lead to significant antigenic drift (144, 145). Amino acids in similar positions at the HA were also associated with antigenic characteristics of h2 viruses (36). It is not surprising, therefore, that when novel human-origin viruses become established in pigs there are considerable antigenic differences from the circulating swine strains (105), and any vaccines available at the time are unlikely to provide immunity against these novel viruses. In addition to the lack of protection, vaccine mismatch can also have detrimental effects. When the vaccine stimulates a cross-reactive antibody response that fails to neutralize the virus, it can result in severe immune-mediated disease termed vaccine-associated enhanced respiratory disease (VAERD). Therefore, more effective vaccine technologies and vaccination strategies that improve the breadth of the immune response and avoid any negative effects are needed to increase protection against the antigenically diverse human-origin viruses that are continuously introduced in pigs.

Concluding Remarks

Since the 2009 pandemic, renewed attention has been given to the interspecies transmission of influenza viruses between pigs and humans, bringing back the attention to the theory that pigs can serve as “mixing-vessels” of influenza viruses. However, it is not entirely clear if swine are in fact more susceptible to infection with avian viruses than humans. There is compelling evidence, though, that human viruses are frequently transmitted to pigs, and have had a significant impact on the diversity of viruses that circulate in pigs globally. Additional surveillance is necessary to understand the diversity of IAVs circulating in different regions and the participation of human-origin strains in this overall diversity. Surveillance is also critical for antigenic characterization of the strains that are circulating in a particular area to allow an accurate selection of representative vaccine strains that will provide an optimal protection. Moreover, despite the increasing evidence of the important role that human seasonal viruses have played in driving the genetic and antigenic diversity of IAV in swine, vaccine and sick leave policies for swine industry workers are not consistently employed but should be considered. Furthermore, understanding the mechanisms involved with host-range specificity and the adaptation to swine allows assessment of the risks posed by the introduction of novel viruses into the swine population, which is crucial for preparedness and to improve biosecurity measures to reduce the IAV burden to the swine industry.

Author Contributions

DR, AV, and DP contributed to the conceptualization of the ideas, drafting and critical revision of the manuscript, and final approval. DR designed figures.

Funding

The authors were supported in part by the Center for Research on Influenza Pathogenesis (CRIP), a National Institute of Allergy and Infectious Diseases (NIAID) funded Center of Excellence for Influenza Research and Surveillance (CEIRS, HHSN272201400008C).

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

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