Influenza A virus is a pathogen that causes the flu in birds and some mammals, including humans.[1] It is an RNA virus whose subtypes have been isolated from wild birds. Occasionally, it is transmitted from wild to domestic birds, and this may cause severe disease, outbreaks, or human influenza pandemics.[2][3][4]
Each virus subtype includes a wide variety of strains with differing pathogenic profiles; some may cause disease only in one species but others to multiple ones. Because the viral genome is segmented, subtypes are neither strains nor lineages, as the subtype designation refers to proteins encoded by only two of the eight genome segments.
A filtered and purified influenza A vaccine for humans has been developed and many countries have stockpiled it to allow a quick administration to the population in the event of an avian influenzapandemic. In 2011, researchers reported the discovery of an antibody effective against all types of the influenza A virus.[5]
Influenza A virus is the only species of the genusAlphainfluenzavirus of the virus family Orthomyxoviridae.[6] There are two methods of classification, one based on surface proteins (originally serotypes),[7] and the other based on its behavior, mainly the host animal.
There are two proteins on the surface of the viral envelope:[8]
Different influenza virus genomes encode different hemagglutinin and neuraminidase proteins. Based on how the different H and N proteins react to antisera, scientists defined 18 types of hemaglutinin and 11 types of neuraminidase.[9][10] In modern days, determination of serotype is more commonly done by polymerase chain reaction.[11] For example, "H5N1" designates an influenza A subtype that has a type-5 hemagglutinin (H) protein and a type-1 neuraminidase (N) protein.[9] Further variations exist within the subtypes and can lead to very significant differences in the virus's behavior.[a]
By definition, the subtyping scheme only takes into account the two outer proteins, not the at least 8 proteins internal to the virus.[15]
Using subtyping and host range is not sufficient to uniquely identify an influenza A virus (or a lineage of them sharing a common ancestor). To unambiguously describe a specific isolate of virus, researchers use the Influenza virus nomenclature,[16] which describes, among other things, the serotype, time, and place of collection. Some examples include:[17]
This example carries an unusual designation in the last part: instead of a usual (H1N1), it uses A(H1N1)pdm09. This is because the CDC found it necessary to distinguish the Pandemic H1N1/09 virus lineage from older H1N1 viruses.
The annual flu (also called "seasonal flu" or "human flu") in the US "results in approximately 36,000 deaths and more than 200,000 hospitalizations each year. In addition to this human toll, influenza is annually responsible for a total cost of over $10 billion in the U.S."[18] Globally the toll of influenza virus is estimated at 290,000–645,000 deaths annually, exceeding previous estimates.[19]
The annually updated, trivalent influenza vaccine consists of hemagglutinin (HA) surface glycoprotein components from influenza H3N2, H1N1, and B influenza viruses.[20] For example, the World Health Organization recommends flu shots for the 2023-2024 flu season in northern hemisphere to use the A/Darwin/9/2021 (H3N2)-like virus.
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.[22][23][24]
Influenza A viruses are negative-sense, single-stranded, segmented RNA virus. The several subtypes are labeled according to an H number (for the type of hemagglutinin) and an N number (for the type of neuraminidase). There are 18 different known H antigens (H1 to H18) and 11 different known N antigens (N1 to N11).[9][10] H17N10 was isolated from fruit bats in 2012.[25][26] H18N11 was discovered in a Peruvian bat in 2013.[10]
A transmission electron micrograph (TEM) of the reconstructed 1918 pandemic influenza virus. The bottom structure represents membrane debris from the cells used to amplify the virus.[27] Pictured are the 'elliptical' particles representing the smallest particles produced by influenza virus. Purification techniques often deform the particles without proper fixation protocols, leading to 'spherical' appearance.[28] Filamentous or intermediate sized particles simply extend along the long axis on the opposite side of the genome segments.
Influenza type A viruses are very similar in structure to influenza viruses types B, C, and D.[29] The virus particle (also called the virion) is 80–120 nanometers in diameter such that the smallest virions adopt an elliptical shape.[30][28] The length of each particle varies considerably, owing to the fact that influenza is pleomorphic, and can be in excess of many tens of micrometers, producing filamentous virions.[31] Confusion about the nature of influenza virus pleomorphy stems from the observation that lab adapted strains typically lose the ability to form filaments[32] and that these lab adapted strains were the first to be visualized by electron microscopy.[33] Despite these varied shapes, the virions of all influenza type A viruses are similar in composition. They are all made up of a viral envelope containing two main types of proteins, wrapped around a central core.[34]
The two large proteins found on the outside of viral particles are hemagglutinin (HA) and neuraminidase (NA). HA is a protein that mediates binding of the virion to target cells and entry of the viral genome into the target cell. NA is involved in release from the abundant non-productive attachment sites present in mucus[35] as well as the release of progeny virions from infected cells.[36] These proteins are usually the targets for antiviral drugs.[37] Furthermore, they are also the antigen proteins to which a host's antibodies can bind and trigger an immune response. Influenza type A viruses are categorized into subtypes based on the type of these two proteins on the surface of the viral envelope. There are 16 subtypes of HA and 9 subtypes of NA known, but only H 1, 2 and 3, and N 1 and 2 are commonly found in humans.[38]
The central core of a virion contains the viral genome and other viral proteins that package and protect the genetic material. 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 segmented pieces of negative-sense RNA, each piece containing either one or two genes which code for a gene product (protein).[34] The term negative-sense RNA just implies that the RNA genome cannot be translated into protein directly; it must first be transcribed to positive-sense RNA before it can be translated into protein products. The segmented nature of the genome allows for the exchange of entire genes between different viral strains.[34]
Influenza A virus structure
The entire Influenza A virus genome is 13,588 bases long and is contained on eight RNA segments that code for at least 10 but up to 14 proteins, depending on the strain. The relevance or presence of alternate gene products can vary:[15]
Segment 1 encodes RNA polymerase subunit (PB2).
Segment 2 encodes RNA polymerase subunit (PB1) and the PB1-F2 protein, which induces cell death, by using different reading frames from the same RNA segment.
Segment 3 encodes RNA polymerase subunit (PA) and the PA-X protein, which has a role in host transcription shutoff.[39]
Segment 4 encodes for HA (hemagglutinin). About 500 molecules of hemagglutinin are needed to make one virion. HA determines the extent and severity of a viral infection in a host organism.
Segment 5 encodes NP, which is a nucleoprotein.
Segment 6 encodes NA (neuraminidase). About 100 molecules of neuraminidase are needed to make one virion.
Segment 7 encodes two matrix proteins (M1 and M2) by using different reading frames from the same RNA segment. About 3,000 matrix protein molecules are needed to make one virion.
Segment 8 encodes two distinct non-structural proteins (NS1 and NEP) by using different reading frames from the same RNA segment.
Influenza A virus replication cycle
The RNA segments of the viral genome have complementary base sequences at the terminal ends, allowing them to bond to each other with hydrogen bonds.[36] Transcription of the viral (-) sense genome (vRNA) can only proceed after the PB2 protein binds to host capped RNAs, allowing for the PA subunit to cleave several nucleotides after the cap. This host-derived cap and accompanied nucleotides serve as the primer for viral transcription initiation. Transcription proceeds along the vRNA until a stretch of several uracil bases is reached, initiating a 'stuttering' whereby the nascent viral mRNA is poly-adenylated, producing a mature transcript for nuclear export and translation by host machinery.[40]
The RNA synthesis takes place in the cell nucleus, while the synthesis of proteins takes place in the cytoplasm. Once the viral proteins are assembled into virions, the assembled virions leave the nucleus and migrate towards the cell membrane.[41] The host cell membrane has patches of viral transmembrane proteins (HA, NA, and M2) and an underlying layer of the M1 protein which assist the assembled virions to budding through the membrane, releasing finished enveloped viruses into the extracellular fluid.[41]
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.[42]
Influenza virus is able to undergo multiplicity reactivation after inactivation by UV radiation,[43][44] or by ionizing radiation.[45]
Upon infection, influenza virus induces a host response involving increased production of reactive oxygen species, and this can damage the virus genome.[46] If, under natural conditions, virus survival is ordinarily vulnerable to the challenge of oxidative damage, then multiplicity reactivation is likely selectively advantageous as a kind of genomic repair process. It has been suggested that multiplicity reactivation involving segmented RNA genomes may be similar to the earliest evolved form of sexual interaction in the RNA world that likely preceded the DNA world.[47]
Timeline of flu pandemics and epidemics caused by influenza A virus
"Human influenza virus" usually refers to those subtypes that spread widely among humans. H1N1, H1N2, and H3N2 are the only known influenza A virus subtypes circulating among humans.[48]
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. 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.[49]
Highly pathogenic H5N1 avian influenza in a human is far worse, killing 50% of humans who catch it. In one case, a boy with H5N1 experienced diarrhea followed rapidly by a coma without developing respiratory or flu-like symptoms.[50]
The influenza A virus subtypes that have been confirmed in humans are:
Human cases and fatalities caused by different influenza A virus subtypesH1N1 was responsible for the 2009 pandemic in both human and pig populations. A variant of H1N1 was responsible for the Spanish flu pandemic that killed some 50 million to 100 million people worldwide over about a year in 1918 and 1919.[55] Another variant was named a pandemic threat in the 2009 flu pandemic. Controversy arose in October 2005, after the H1N1 genome was published because of fears that this information could be used for bioterrorism.[56]
H3N2 is endemic in both human and pig populations. It evolved from H2N2 by antigenic shift and caused the Hong Kong flu pandemic of 1968, and 1969, that killed up to 750,000.[58] A severe form of the H3N2 virus killed several children in the United States in late 2003.[59]
The dominant strain of annual flu in January 2006 was H3N2. Measured resistance to the standard antiviral drugs amantadine and rimantadine in H3N2 increased from 1% in 1994 to 12% in 2003 to 91% in 2005.[60][61] Human H3N2 influenza viruses are now[when?] endemic in pigs in southern China, where they circulate together with avian H5N1 viruses.[62]
Japan's Health Ministry said January 2006 that poultry farm workers in Ibaraki prefecture may have been exposed to H5N2 in 2005.[63] The H5N2 antibody titers of paired sera of 13 subjects increased fourfold or more.[64]
In February 2021, Russia reported the first known cases of H5N8 in humans. Seven people were confirmed to have been infected in December 2020 and have since recovered.[65] There was no indication of human-to-human transmission.[66]
In North America, the presence of avian influenza strain H7N3 was confirmed at several poultry farms in British Columbia in February 2004. As of April 2004, 18 farms had been quarantined to halt the spread of the virus. Two cases of humans with avian influenza have been confirmed in that region. "Symptoms included conjunctivitis and mild influenza-like illness."[68]
On 2 April 2013, the Centre for Health Protection (CHP) of the Department of Health of Hong Kong confirmed four more cases in Jiangsu province in addition to the three cases initially reported on 31 March 2013.[69] This virus also has the greatest potential for an influenza pandemic among all of the Influenza A subtypes.[70]
In 2004, in Egypt, H10N7 was reported for the first time in humans. It caused illness in two infants in Egypt. One child's father was a poultry merchant.[71]
All influenza A pandemics since [the Spanish flu pandemic], and indeed almost all cases of influenza A worldwide (excepting human infections from avian viruses such as H5N1 and H7N7), have been caused by descendants of the 1918 virus, including "drifted" H1N1 viruses and reassorted H2N2 and H3N2 viruses. The latter are composed of key genes from the 1918 virus, updated by subsequently incorporated avian influenza genes that code for novel surface proteins, making the 1918 virus indeed the "mother" of all pandemics.
Researchers from the National Institutes of Health used data from the Influenza Genome Sequencing Project and concluded that during the ten-year period examined, most of the time the hemagglutinin gene in H3N2 showed no significant excess of mutations in the antigenic regions while an increasing variety of strains accumulated. This resulted in one of the variants eventually achieving higher fitness, becoming dominant, and in a brief interval of rapid evolution, rapidly sweeping through the population and eliminating most other variants.[74]
In the short-term evolution of influenza A virus, a 2006 study found that stochastic, or random, processes are key factors.[75] Influenza A virus HA antigenic evolution appears to be characterized more by punctuated, sporadic jumps as opposed to a constant rate of antigenic change.[76]
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
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.[77]
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.[3][4]
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.[78]
Known outbreaks of highly pathogenic flu in poultry 1959–2003[79]
*Outbreaks with significant spread to numerous farms, resulting in great economic losses. Most other outbreaks involved little or no spread from the initially infected farms.
More than 400 harbor seal deaths were recorded in New England between December 1979 and October 1980, from acute pneumonia caused by the influenza virus, A/Seal/Mass/1/180 (H7N7).[80]
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.[81][failed verification]
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.[81][failed verification]
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.[82] 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.[83]
Swapping the H gene in a HPAI-H5N8 with the H gene in a LPAI-H5N8 generates a H5N8 virus with low virulence.[12]
The human immune system does not very effectively recognize new types of H3N2 viruses despite having seen another H3N2 before. As a result, each year's flu vaccine is reformulated according to a list of likely strains from the World Health Organization (WHO).[13] The same occurs in chickens: H5 vaccines that target non-2.3.4.4b H5 genes do not effectively protect against the 2.3.4.4b branch of H5.[14]
^Havers FP, Campbell AJ (2020). "285. Influenza viruses". In Kliegman RM, St Geme III JW (eds.). Nelson Textbook of Pediatrics (21st ed.). Philadelphia: Elsevier. pp. 1727–1739. ISBN978-0-323-56890-6.
^Daum LT, Shaw MW, Klimov AI, Canas LC, Macias EA, Niemeyer D, et al. (August 2005). "Influenza A (H3N2) outbreak, Nepal". Emerging Infectious Diseases. 11 (8): 1186–91. doi:10.3201/eid1108.050302. PMC3320503. PMID16102305. "The 2003–2004 influenza season was severe in terms of its impact on illness because of widespread circulation of antigenically distinct influenza A (H3N2) Fujian-like viruses. These viruses first appeared late during the 2002–2003 influenza season and continued to persist as the dominant circulating strain throughout the subsequent 2003–2004 influenza season, replacing the A/Panama/2007/99-like H3N2 viruses (1). Of the 172 H3N2 viruses genetically characterized by the Department of Defense in 2003–2004, only one isolate (from Thailand) belonged to the A/Panama-like lineage. In February 2003, the World Health Organization (WHO) changed the H3N2 component for the 2004–2005 influenza vaccine to afford protection against the widespread emergence of Fujian-like viruses (2). The annually updated trivalent vaccine consists of hemagglutinin (HA) surface glycoprotein components from influenza H3N2, H1N1, and B viruses."
^Wilson JC, von Itzstein M (July 2003). "Recent strategies in the search for new anti-influenza therapies". Current Drug Targets. 4 (5): 389–408. doi:10.2174/1389450033491019. PMID12816348.
^Lynch JP, Walsh EE (April 2007). "Influenza: evolving strategies in treatment and prevention". Seminars in Respiratory and Critical Care Medicine. 28 (2): 144–58. doi:10.1055/s-2007-976487. PMID17458769. S2CID260316848.
^Detailed chart of its evolution hereArchived 9 May 2009 at the Wayback Machine at PDF called Ecology and Evolution of the Flu
^Mahmoud 2005, p. 115 "There is particular pressure to recognize and heed the lessons of past influenza pandemics in the shadow of the worrisome 2003–2004 flu season. An early-onset, severe form of influenza A H3N2 made headlines when it claimed the lives of several children in the United States in late 2003. As a result, stronger than usual demand for annual flu inactivated vaccine outstripped the vaccine supply, of which 10 to 20 percent typically goes unused. Because statistics on pediatric flu deaths had not been collected previously, it is unknown if the 2003–2004 season witnessed a significant change in mortality patterns."
^Mahmoud 2005, p. 126 "H5N1 virus is now endemic in poultry in Asia (Table 2-1) and has gained an entrenched ecological niche from which to present a long-term pandemic threat to humans. At present, these viruses are poorly transmitted from poultry to humans, and there is no conclusive evidence of human-to-human transmission. However, continued, extensive exposure of the human population to H5N1 viruses increases the likelihood that the viruses will acquire the necessary characteristics for efficient human-to-human transmission through genetic mutation or reassortment with a prevailing human influenza A virus. Furthermore, contemporary human H3N2 influenza viruses are now endemic in pigs in southern China (Peiris et al., 2001) and can reassort with avian H5N1 viruses in this 'intermediate host.' Therefore, it is imperative that outbreaks of H5N1 disease in poultry in Asia are rapidly and sustainably controlled. The seasonality of the disease in poultry, together with the control measures already implemented, are likely to reduce temporarily the frequency of H5N1 influenza outbreaks and the probability of human infection."
^CBS News article Dozens in Japan May Have Mild Bird Flu January 2006.
^Mahmoud 2005, p. 82 "Interestingly, recombinant influenza viruses containing the 1918 HA and NA and up to three additional genes derived from the 1918 virus (the other genes being derived from the A/WSN/33 virus) were all highly virulent in mice (Tumpey et al., 2004). Furthermore, expression microarray analysis performed on whole lung tissue of mice infected with the 1918 HA/ NA recombinant showed increased upregulation of genes involved in apoptosis, tissue injury, and oxidative damage (Kash et al., 2004). These findings were unusual because the viruses with the 1918 genes had not been adapted to mice. The completion of the sequence of the entire genome of the 1918 virus and the reconstruction and characterization of viruses with 1918 genes under appropriate biosafety conditions will shed more light on these findings and should allow a definitive examination of this explanation. Antigenic analysis of recombinant viruses possessing the 1918 HA and NA by hemagglutination inhibition tests using ferret and chicken antisera suggested a close relationship with the A/swine/Iowa/30 virus and H1N1 viruses isolated in the 1930s (Tumpey et al., 2004), further supporting data of Shope from the 1930s (Shope, 1936). Interestingly, when mice were immunized with different H1N1 virus strains, challenge studies using the 1918-like viruses revealed partial protection by this treatment, suggesting that vaccination strategies are adequate against a 1918-like virus (Tumpey et al., 2004)."
^Geraci JR, St Aubin DJ, Barker IK, Webster RG, Hinshaw VS, Bean WJ, et al. (February 1982). "Mass mortality of harbor seals: pneumonia associated with influenza A virus". Science. 215 (4536): 1129–31. Bibcode:1982Sci...215.1129G. doi:10.1126/science.7063847. PMID7063847. More than 400 harbor seals, most of them immature, died along the New England coast between December 1979 and October 1980 of acute pneumonia associated with influenza virus, A/Seal/Mass/1/180 (H7N7). The virus has avian characteristics, replicates principally in mammals, and causes mild respiratory disease in experimentally infected seals. Concurrent infection with a previously undescribed mycoplasma or adverse environmental conditions may have triggered the epizootic. The similarities between this epizootic and other seal mortalities in the past suggest that these events may be linked by common biological and environmental factors.
^ abCDC Centers for Disease Control and Prevention – Transmission of Influenza A Viruses Between Animals and People
Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, et al. (September 2005). "Avian influenza A (H5N1) infection in humans". The New England Journal of Medicine. 353 (13): 1374–85. CiteSeerX10.1.1.730.7890. doi:10.1056/NEJMra052211. PMID16192482.
Mahmoud (2005). Stacey L. Knobler, Alison Mack, Mahmoud A, Stanley M. Lemon (eds.). The threat of pandemic influenza : are we ready? : workshop summary / prepared for Forum on Microbial Threats, Board on Global Health. The National Academies Press. p. 285. ISBN0-309-09504-2. Highly pathogenic avian influenza virus is on every top ten list available for potential agricultural bioweapon agents
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