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Influenza A virus
Structure of influenza A virus
Transmission electron micrograph of influenza A viruses (light objects on a dark background).
TEM micrograph of influenza A viruses
Virus classification Edit this classification
(unranked): Virus
Realm: Riboviria
Kingdom: Orthornavirae
Phylum: Negarnaviricota
Class: Insthoviricetes
Order: Articulavirales
Family: Orthomyxoviridae
Genus: Alphainfluenzavirus
Species:
Influenza A virus

Influenza A virus (IAV) is a pathogen with strains that infect birds and some mammals, as well as causing seasonal flu in humans.[1] Mammals in which different strains of IAV circulate with sustained transmission are bats, pigs, horses and dogs; other mammals can occasionally become infected.[2][3]

IAV is an enveloped negative-sense RNA virus, with a segmented genome.[3] Through a combination of mutation and genetic reassortment the virus can evolve to acquire new characteristics, enabling it to evade host immunity and occasionally to jump from one species of host to another.[4][5]

Subtypes of IAV are defined by the combination of the antigenic H and N proteins in the viral envelope; for example, "H1N1" designates an IAV subtype that has a type-1 hemagglutinin (H) protein and a type-1 neuraminidase (N) protein.[6] Almost all possible combinations of H (1 thru 16) and N (1 thru 11) have been isolated from wild birds.[7] Further variations exist within the subtypes and can lead to very significant differences in the virus's ability to infect and cause disease, as well as to the severity of symptoms.[8][9]

Symptoms of human seasonal flu usually include fever, cough, sore throat, muscle aches, conjunctivitis and, in severe cases, breathing problems and pneumonia that may be fatal.[10][11] Humans can rarely become infected with strains of avian or swine influenza, usually as a result of close contact with infected animals; symptoms range from mild to severe including death.[12][13] Bird-adapted strains of the virus can be asymptomatic in some aquatic birds but lethal if they spread to other species, such as chickens.[14]

IAV disease in poultry can be can be prevented by vaccination, however biosecurity control measures are preferred.[15][16] In humans, seasonal influenza can be treated in its early stages with antiviral medicines.[17] A global network, the Global Influenza Surveillance and Response System (GISRS) monitors the spread of influenza with the aim to inform development of both seasonal and pandemic vaccines.[18] Several millions of specimens are tested by the GISRS network annually through a network of laboratories in 127 countries. As well as human viruses, GISRS monitors avian, swine, and other potentially zoonotic influenza viruses. IAV vaccines need to be reformulated regularly in order to keep up with changes in the virus.[19]

Virology

Classification

Influenza A virus is the only species of the genus Alphainfluenzavirus of the virus family Orthomyxoviridae.[20] There are two methods of classification, one based on surface proteins (originally serotypes),[21] and the other based on its behavior, mainly the host animal.

Subtypes

Diagram of influenza nomenclature

There are two antigenic proteins on the surface of the viral envelope, hemagglutinin and neuraminidase[22] Different influenza virus genomes encode different hemagglutinin and neuraminidase proteins. Based on their serotype, there are 18 known types of hemagglutinin and 11 types of neuraminidase.[23][24] Subtypes of IAV are classified by their combination of H and N proteins. For example, "H5N1" designates an influenza A subtype that has a type-5 hemagglutinin (H) protein and a type-1 neuraminidase (N) protein.[23] Further variations exist within the subtypes and can lead to very significant differences in the virus's behavior.[25]

By definition, the subtyping scheme only takes into account the two outer proteins, not the at least 8 proteins internal to the virus.[26] Almost all possible combinations of H (1 thru 16) and N (1 thru 11) have been isolated from wild birds.[27] H17 and H18 have only been discovered in bats.[28]

Influenza virus nomenclature

Due to the high variability of the virus, subtyping is not sufficient to uniquely identify a strain of influenza A virus. To unambiguously describe a specific isolate of virus, researchers use the Influenza virus nomenclature,[29] which describes, among other things, the subtype, year, and place of collection. Some examples include:[30]

  • A/Rio de Janeiro/62434/2021 (H3N2).[30]
    • The starting A indicates that the virus is an influenza A virus.
    • Rio de Janeiro indicates the place of collection. 62434 is a laboratory sequence number. 2021 (or just 21) indicates that the sample was collected in 2021. No species is mentioned so by default, the sample was collected from a human.
    • (H3N2) indicates the subtype of the virus.
  • A/swine/South Dakota/152B/2009 (H1N2)[30]
    • This example shows an additional field before the place: swine. It indicates that the sample was collected from a pig.
  • A/California/04/2009 A(H1N1)pdm09.[30]
    • This example carries an unusual designation in the last part: instead of a usual (H1N1), it uses A(H1N1)pdm09. This was in order to distinguish the Pandemic H1N1/09 virus lineage from older H1N1 viruses.[30]

Structure and genetics

See also: H5N1 genetic structure
Influenza A virus structure

The influenza A virus has a negative-sense, single-stranded, segmented RNA genome, enclosed in a protein envelope. The virus particle (also called the virion) is 80–120 nanometers in diameter such that the smallest virions adopt an elliptical shape; larger virions have a filamentous shape.[31] The viral envelope comprises two main proteins; hemagglutinin (HA) and neuraminidase (NA). HA is a protein that binds the virion to host cells, enabling the RNA genetic material to invade it. Once the host cell has started manufacturing the components of new virions, NA enables the newly assembled virions to escape the host cell and go on to propagate the infection. Both proteins are antigenic; a host's immune system can react to them and produce antibodies in response.[32]

The central core of the virion contains the genetic material and the viral proteins that package and protect it. Unlike the genomes of most organisms (including humans, animals, plants, and bacteria) which are made up of double-stranded DNA, many viral genomes are made up of a different, single-stranded nucleic acid called RNA. Unusually for a virus, though, the influenza type A virus genome is not a single piece of RNA; instead, it consists of 8 segments of RNA, each piece containing either one or two genes which code for a gene product (protein).[33] The segmented nature of the genome allows for the exchange of entire genes between different viral strains.[33][34][32]

Epidemiology

Evolution and history

Genetic evolution of human and swine influenza viruses, 1918–2009
See also: Timeline of influenza

The predominant natural reservoir of influenza viruses is thought to be wild waterfowl.[35] The subtypes of influenza A virus are estimated to have diverged 2,000 years ago. Influenza viruses A and B are estimated to have diverged from a single ancestor around 4,000 years ago, while the ancestor of influenza viruses A and B and the ancestor of influenza virus C are estimated to have diverged from a common ancestor around 8,000 years ago.[36]

Outbreaks of influenza-like disease can be found throughout recorded history. The first probable record is by Hippocrates in 142 BCE.[37] The historian Fujikawa listed 46 epidemics of flu-like illness in Japan between 862 and 1868.[38] In Europe and the Americas, a number of epidemics were recorded through the Middle Ages and up to the end of the 19th century.[37]

Timeline of flu pandemics and epidemics caused by influenza A virus

In 1918-1919 came the first flu pandemic of the 20th century, known generally as the "Spanish flu", which caused an estimated 20 to 50 million deaths worldwide. It is now known that this was caused by an immunologically novel H1N1 subtype of influenza A.[39] The next pandemic took place in 1957, the "Asian flu", which was caused by a H2N2 subtype of the virus in which the genome segments coding for HA and NA appeared to have derived from avian influenza strains by reassortment, while the remainder of the genome was descended from the 1918 virus.[40] The 1968 pandemic ("Hong Kong flu") was caused by a H3N2 subtype in which the NA segment was derived from the 1957 virus, while the HA segment had been reassorted from an avian strain of influenza.[40]

In the 21st century, a strain of H1N1 flu (since titled H1N1pdm09) which was antigenically very different from previous H1N1 strains, leading to a pandemic in 2009. Because of its close resemblance to some strains circulating in pigs, this became known as "Swine flu"[41]

Influenza A virus continues to circulate and evolve in birds and pigs. Almost all possible combinations of H (1 thru 16) and N (1 thru 11) have been isolated from wild birds.[27] As of June 2024, two particularly virulent IAV strains - H5N1 and H7N9 - are predominant in wild bird populations. These frequently cause outbreaks in domestic poultry, with occasional spillover infections in humans who are in close contact with poultry.[42][43]

Pandemic potential

Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses.[44] The segmentation of the influenza A virus genome facilitates genetic recombination by segment reassortment in hosts who become infected with two different strains of influenza viruses at the same time.[45][46] With reassortment between strains, an avian strain which does not affect humans may acquire characteristics from a different strain which enable it to infect and pass between humans - a zoonotic event.[47] It is thought that all influenza A viruses causing outbreaks or pandemics among humans since the 1900s originated from strains circulating in wild aquatic birds through reassortment with other influenza strains.[48][49] It is possible (though not certain) that pigs may act as an intermediate host for reassortment.[50]

Surveillance

The Global Influenza Surveillance and Response System (GISRS) is a global network of laboratories that monitor the spread of influenza with the aim to provide the World Health Organization with influenza control information and to inform vaccine development.[51] Several millions of specimens are tested by the GISRS network annually through a network of laboratories in 127 countries.[52] As well as human viruses, GISRS monitors avian, swine, and other potentially zoonotic influenza viruses.

Seasonal flu

Main article: Flu season
Seasonal variation in deaths due to influenza or pneumonia in 122 U.S. cities, as a proportion of all causes.[53]

Flu season is an annually recurring time period characterized by the prevalence of an outbreak of influenza, caused either by Influenza A or by Influenza B. The season occurs during the cold half of the year in temperate regions; November through February in the northern hemisphere and May to October in the southern hemisphere. Flu seasons also exist in the tropics and subtropics, with variability from region to region.[54] Annually, about 3 to 5 million cases of severe illness and 290,000 to 650,000 deaths from seasonal flu occur worldwide.[55]

There are several possible reasons for the winter peak in temperate regions:

  • During the winter, people spend more time indoors with the windows sealed, so they are more likely to breathe the same air as someone who has the flu and thus contract the virus. [56]
  • Days are shorter during the winter, and lack of sunlight leads to  low levels of vitamin D and melatonin, both of which require sunlight for their generation. This compromises our immune systems, which in turn decreases ability to fight the virus[56]
  • The influenza virus may survive better in colder, drier climates, and therefore be able to infect more people [56]
  • Cold air reduces the ability of the nasal membranes to resist infection.[57]

Zoonotic infections

A zoonosis a disease in a human caused by a pathogen (such as a bacterium, or virus) that has jumped from a non-human to a human.[58][59] Avian and pig influenza viruses can, on rare occasions, transmit to humans and cause zoonotic influenza virus infections; these infections are usually confined to people who have been in close contact with infected animals or material such as infected feces and meat, they do not spread to other humans. Symptoms of these infections in humans vary greatly; some are in asymptomatic or mild while others can cause severe disease, leading to severe pneumonia and death.[60] A wide range of Influenza A virus subtypes have been found to cause zoonotic disease.[60][61]

Zoonotic infections can be prevented by good hygiene, by preventing farmed animals from coming into contact with wild animals, and by using appropriate personal protective equipment.[59]

As of June 2024, there is concern about two subtypes of avian influenza which are circulating in wild bird populations worldwide, H5N1 and H7N9. Both of these have potential to devastate poultry stocks, and both have jumped to humans with relatively high case fatality rates.[61] H5N1 in particularly has infected a wide range of mammals and may be adapting to mammalian hosts.[62]

Prevention and treatment

Vaccine

Main article: Influenza vaccine

As of June 2024, the influenza viruses which circulate widely in humans are IAV subtypes H1N1 and H2N3, together with Influenza B.[63] Annual vaccination is the primary and most effective way to prevent influenza and influenza-associated complications, especially for high-risk groups.[64] Vaccines against the flu are trivalent or quadrivalent, providing protection against the dominant strains of IAV(H1N1) and IAV(H3N2), and one or two influenza B virus strains; the formulation is continually reviewed in order to match the predominant strains in circulation.[65][66]

Poultry and other animals - it is possible to vaccinate poultry and pigs against specific strains of influenza. Vaccination should be combined with other control measures such as infection monitoring, early detection and biosecurity.[67][68][69]

Treatment

Main article: Influenza treatment

The main treatment for mild influenza is supportive; rest, fluids, and over-the-counter medicines to alleviate symptoms while the body's own immune system works to recover from infection. Antiviral drugs are recommended for those with severe symptoms, or for those who are at risk of developing complications such as pneumonia.[70][71]

Human influenza virus

"Human influenza virus" usually refers to those subtypes that spread widely among humans. H1N1, and H3N2 are the principal influenza A virus subtypes circulating among humans.[8]

Human flu symptoms usually include fever, cough, sore throat, muscle aches, conjunctivitis and, in severe cases, breathing problems and pneumonia that may be fatal. The severity of the infection will depend in large part on the state of the infected person's immune system and if the victim has been exposed to the strain before, and is therefore partially immune.[citation needed] Follow-up studies on the impact of statins on influenza virus replication show that pre-treatment of cells with atorvastatin suppresses virus growth in culture.[72]

Other animals

See H5N1 for the epizootic (an epidemic in nonhumans) and panzootic (a disease affecting animals of many species especially over a wide area) of H5N1 influenza

Avian influenza

Main article: Avian influenza

Fowl act as natural asymptomatic carriers of influenza A viruses. Prior to the H5N1 epizootic, strains of influenza A virus had been demonstrated to be transmitted from wildfowl to only birds, pigs, horses, seals, whales and humans; and only between humans and pigs and between humans and domestic fowl; and not other pathways such as domestic fowl to horse.[73]

Wild aquatic birds are the natural hosts for a large variety of influenza A viruses. Occasionally, viruses are transmitted from these birds to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics.[74][75]

H5N1 has been shown to be transmitted to tigers, leopards, and domestic cats that were fed uncooked domestic fowl (chickens) with the virus. H3N8 viruses from horses have crossed over and caused outbreaks in dogs. Laboratory mice have been infected successfully with a variety of avian flu genotypes.[76].

Swine flu

Main article: Swine influenza

Swine influenza (or "pig influenza") refers to a subset of Orthomyxoviridae that create influenza and are endemic in pigs. The species of Orthomyxoviridae that can cause flu in pigs are influenza A virus and influenza C virus, but not all genotypes of these two species infect pigs. The known subtypes of influenza A virus that create influenza and are endemic in pigs are H1N1, H1N2, H3N1 and H3N2. In 1997, H3N2 viruses from humans entered the pig population, causing widespread disease among pigs.[77][failed verification]

Horse flu

Main article: Equine influenza

Horse flu (or "equine influenza") refers to varieties of influenza A virus that affect horses. Horse flu viruses were only isolated in 1956. The two main types of virus are called equine-1 (H7N7), which commonly affects horse heart muscle, and equine-2 (H3N8), which is usually more severe. H3N8 viruses from horses have infected dogs.[77][failed verification]

Dog flu

Main article: Canine influenza

Dog flu (or "canine influenza") refers to varieties of influenza A virus that affect dogs.

Bat flu

Main article: Bat influenza

Bat flu (or "Bat influenza") refers to the H17N10 and H18N11 influenza A virus strains that were discovered in Central and South American fruit bats as well as a H9N2 virus isolated from the Egyptian fruit bat.[78] Until now it is unclear whether these bat-derived viruses are circulating in any non-bat species and whether they pose a zoonotic threat. Initial characterization of the H18N11 subtype, however, suggests that this bat influenza virus is not well adapted to any other species than bats.[79]

Research

FI6, an antibody that targets the hemagglutinin protein, was discovered in 2011. FI6 is the only known antibody effective against all 16 subtypes of the influenza A virus.[80][81][82]

See also

Notes

References

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Further reading

Official sources
Further information: H5N1
General information
Further information: Flu