Influenza A virus | |
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Structure of influenza A virus | |
TEM micrograph of influenza A viruses | |
Virus classification | |
(unranked): | Virus |
Realm: | Riboviria |
Kingdom: | Orthornavirae |
Phylum: | Negarnaviricota |
Class: | Insthoviricetes |
Order: | Articulavirales |
Family: | Orthomyxoviridae |
Genus: | Alphainfluenzavirus |
Species: | Influenza A virus |
Subtypes | |
Influenza A virus (IAV) 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 influenza pandemic. 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 genus Alphainfluenzavirus 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]
The hemagglutinin is central to the virus's recognizing and binding to target cells, and also to its then infecting the cell with its RNA. The neuraminidase, on the other hand, is critical for the subsequent release of the daughter virus particles created within the infected cell so they can spread to other cells.[ citation needed ]
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. [lower-alpha 1]
By definition, the subtyping scheme only takes into account the two outer proteins, not the at least 8 proteins internal to the virus. [15]
Variants are sometimes named according to the species (host) in which the strain is endemic or to which it is adapted. The main variants named using this convention are:[ citation needed ]
Variants have also sometimes been named according to their deadliness in poultry, especially chickens:[ citation needed ]
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 collection of viruses, researchers use the Influenza virus nomenclature, which describes, among other things, the serotype, time, and place of collection. Some examples include: [16]
Some variants [lower-alpha 2] are informally identified and named according to the isolate they resemble, thus are presumed to share lineage (example Fujian flu virus-like); according to their typical host (example human flu virus); according to their subtype (example H3N2); and according to their deadliness (example LP, low pathogenic). So a flu from a virus similar to the isolate A/Fujian/411/2002 (H3N2) is called Fujian flu, human flu, and H3N2 flu.[ citation needed ]
Most known strains are extinct strains. For example, the annual flu subtype H3N2 no longer contains the strain that caused the Hong Kong flu, A/Hong Kong/1/1968 (H3N2). 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. [17]
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]
Measured resistance to the standard antiviral drugs amantadine and rimantadine in H3N2 has increased from 1% in 1994 to 12% in 2003 to 91% in 2005.[ citation needed ]
"Contemporary human H3N2 influenza viruses are now endemic in pigs in southern China and can reassort with avian H5N1 viruses in this intermediate host." [21]
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]
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]
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]
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] If any of the eight RNA strands that make up the genome contains damage that prevents replication or expression of an essential gene, the virus is not viable when it alone infects a cell (a single infection). However, when two or more damaged viruses infect the same cell (multiple infection), viable progeny viruses can be produced provided each of the eight genomic segments is present in at least one undamaged copy. That is, multiplicity reactivation can occur.[ citation needed ]
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]
"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 currently circulating among humans. [48]
Genetic factors in distinguishing between "human flu viruses" and "avian influenza viruses" include:
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, ordered by the number of known human pandemic deaths, are:
H10N3
In May 2021, in Zhenjiang, China H10N3 was reported for the first time in humans. One person was infected. [72]
According to Jeffery Taubenberger: [73]
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] Using phylogenetic analysis of 413 complete genomes of human influenza A viruses that were collected throughout the state of New York, the authors of Nelson et al. 2006 were able to show that genetic diversity, and not antigenic drift, shaped the short-term evolution of influenza A via random migration and reassortment. The evolution of these viruses is dominated more by the random importation of genetically different viral strains from other geographic locations and less by natural selection. Within a given season, adaptive evolution is infrequent and had an overall weak effect as evidenced from the data gathered from the 413 genomes. Phylogenetic analysis revealed the different strains were derived from newly imported genetic material as opposed to isolates that had been circulating in New York in previous seasons. Therefore, the gene flow in and out of this population, and not natural selection, was more important in the short term.[ citation needed ]
Fowl act as natural asymptomatic carriers of influenza A viruses. Prior to the current[ when? ] 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]
Influenza A viruses spread in the air and in manure, and survives longer in cold weather. They can also be transmitted by contaminated feed, water, equipment, and clothing; however, there is no evidence the virus can survive in well-cooked meat. Symptoms in animals vary, but virulent strains can cause death within a few days. Avian influenza viruses that the World Organisation for Animal Health and others test for to control poultry disease include H5N1, H7N2, H1N7, H7N3, H13N6, H5N9, H11N6, H3N8, H9N2, H5N2, H4N8, H10N7, H2N2, H8N4, H14N5, H6N5, and H12N5.[ citation needed ]
Year | Area | Affected | Subtype |
---|---|---|---|
1959 | Scotland | Chicken | H5N1 |
1963 | England | Turkey | H7N3 |
1966 | Ontario (Canada) | Turkey | H5N9 |
1976 | Victoria (Australia) | Chicken | H7N7 |
1979 | Germany | Chicken | H7N7 |
1979 | England | Turkey | H7N7 |
1983 | Pennsylvania (US)* | Chicken, turkey | H5N2 |
1983 | Ireland | Turkey | H5N8 |
1985 | Victoria (Australia) | Chicken | H7N7 |
1991 | England | Turkey | H5N1 |
1992 | Victoria (Australia) | Chicken | H7N3 |
1994 | Queensland (Australia) | Chicken | H7N3 |
1994 | Mexico* | Chicken | H5N2 |
1994 | Pakistan* | Chicken | H7N3 |
1997 | New South Wales (Australia) | Chicken | H7N4 |
1997 | Hong Kong (China)* | Chicken | H5N1 |
1997 | Italy | Chicken | H5N2 |
1999 | Italy* | Turkey | H7N1 |
2002 | Hong Kong (China) | Chicken | H5N1 |
2002 | Chile | Chicken | H7N3 |
2003 | Netherlands* | Chicken | H7N7 |
*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]
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]
Dog flu (or "canine influenza") refers to varieties of influenza A virus that affect dogs. The equine influenza virus H3N8 was found to infect and kill – with respiratory illness – greyhound race dogs at a Florida racetrack in January 2004.
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]
H3N8 is now endemic in birds, horses and dogs.
Influenza A virus has the following subtypes:[ citation needed ]
Antigenic shift is the process by which two or more different strains of a virus, or strains of two or more different viruses, combine to form a new subtype having a mixture of the surface antigens of the two or more original strains. The term is often applied specifically to influenza, as that is the best-known example, but the process is also known to occur with other viruses, such as visna virus in sheep. Antigenic shift is a specific case of reassortment or viral shift that confers a phenotypic change.
Influenza hemagglutinin (HA) or haemagglutinin[p] is a homotrimeric glycoprotein found on the surface of influenza viruses and is integral to its infectivity.
Orthomyxoviridae is a family of negative-sense RNA viruses. It includes seven genera: Alphainfluenzavirus, Betainfluenzavirus, Gammainfluenzavirus, Deltainfluenzavirus, Isavirus, Thogotovirus, and Quaranjavirus. The first four genera contain viruses that cause influenza in birds and mammals, including humans. Isaviruses infect salmon; the thogotoviruses are arboviruses, infecting vertebrates and invertebrates. The Quaranjaviruses are also arboviruses, infecting vertebrates (birds) and invertebrates (arthropods).
Antigenic drift is a kind of genetic variation in viruses, arising from the accumulation of mutations in the virus genes that code for virus-surface proteins that host antibodies recognize. This results in a new strain of virus particles that is not effectively inhibited by the antibodies that prevented infection by previous strains. This makes it easier for the changed virus to spread throughout a partially immune population. Antigenic drift occurs in both influenza A and influenza B viruses.
Influenza A virus subtype H5N1 (A/H5N1) is a subtype of the influenza A virus which can cause illness in humans and many other species. A bird-adapted strain of H5N1, called HPAI A(H5N1) for highly pathogenic avian influenza virus of type A of subtype H5N1, is the highly pathogenic causative agent of H5N1 flu, commonly known as avian influenza. It is enzootic in many bird populations, especially in Southeast Asia. One strain of HPAI A(H5N1) is spreading globally after first appearing in Asia. It is epizootic and panzootic, killing tens of millions of birds and spurring the culling of hundreds of millions of others to stem its spread. Many references to "bird flu" and H5N1 in the popular media refer to this strain.
Swine influenza is an infection caused by any of several types of swine influenza viruses. Swine influenza virus (SIV) or swine-origin influenza virus (S-OIV) refers to any strain of the influenza family of viruses that is endemic in pigs. As of 2009, identified SIV strains include influenza C and the subtypes of influenza A known as H1N1, H1N2, H2N1, H3N1, H3N2, and H2N3.
An influenza pandemic is an epidemic of an influenza virus that spreads across a large region and infects a large proportion of the population. There have been six major influenza epidemics in the last 140 years, with the 1918 flu pandemic being the most severe; this is estimated to have been responsible for the deaths of 50–100 million people. The 2009 swine flu pandemic resulted in under 300,000 deaths and is considered relatively mild. These pandemics occur irregularly.
Influenza A virus subtype H2N2 (A/H2N2) is a subtype of Influenza A virus. H2N2 has mutated into various strains including the "Asian flu" strain, H3N2, and various strains found in birds. It is also suspected of causing a human pandemic in 1889. The geographic spreading of the 1889 Russian flu has been studied and published.
Influenza A virus subtype H3N2 (A/H3N2) is a subtype of viruses that causes influenza (flu). H3N2 viruses can infect birds and mammals. In birds, humans, and pigs, the virus has mutated into many strains. In years in which H3N2 is the predominant strain, there are more hospitalizations.
Influenza B virus is the only species in the genus Betainfluenzavirus in the virus family Orthomyxoviridae.
Influenza A virus subtype H1N2 (A/H1N2) is a subtype of the species Influenza A virus. It is currently endemic in pig populations and is occasionally seen in humans.
H5N1 genetic structure is the molecular structure of the H5N1 virus's RNA.
Spanish flu research concerns studies regarding the causes and characteristics of the Spanish flu, a variety of influenza that in 1918 was responsible for the worst influenza pandemic in modern history. Many theories about the origins and progress of the Spanish flu persisted in the literature, but it was not until 2005, when various samples of lung tissue were recovered from American World War I soldiers and from an Inupiat woman buried in permafrost in a mass grave in Brevig Mission, Alaska, that significant genetic research was made possible.
Fujian flu refers to flu caused by either a Fujian human flu strain of the H3N2 subtype of the Influenza A virus or a Fujian bird flu strain of the H5N1 subtype of the Influenza A virus. These strains are named after Fujian, a coastal province in Southeast China.
Influenza, commonly known as "the flu" or just "flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms begin from one to four days after exposure to the virus and last for about 2–8 days. Diarrhea and vomiting can occur, particularly in children. Influenza may progress to pneumonia, which can be caused by the virus or by a subsequent bacterial infection. Other complications of infection include acute respiratory distress syndrome, meningitis, encephalitis, and worsening of pre-existing health problems such as asthma and cardiovascular disease.
Viral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell. Neuraminidases are enzymes that cleave sialic acid groups from glycoproteins. Viral neuraminidase was discovered by Alfred Gottschalk at the Walter and Eliza Hall Institute in 1957. Neuraminidase inhibitors are antiviral agents that inhibit influenza viral neuraminidase activity and are of major importance in the control of influenza.
The FluChip is a low-density DNA microarray for the identification of influenza viruses, originally developed at the University of Colorado at Boulder in the laboratory of Professor Kathy Rowlen in collaboration with the Centers for Disease Control and Prevention (CDC) in Atlanta.
A H5N1 vaccine is an influenza vaccine intended to provide immunization to influenza A virus subtype H5N1.
A universal flu vaccine is a flu vaccine that is effective against all influenza strains regardless of the virus sub type, antigenic drift or antigenic shift. Hence it should not require modification from year to year. As of 2021 no universal flu vaccine had been approved for general use, several were in development, and one was in clinical trial.
Type A influenza vaccine is for the prevention of infection of influenza A virus and also the influenza-related complications. Different monovalent type A influenza vaccines have been developed for different subtypes of influenza A virus including H1N1 and H5N1. Both intramuscular injection or intranasal spray are available on market. Unlike the seasonal influenza vaccines which are used annually, they are usually used during the outbreak of certain strand of subtypes of influenza A. Common adverse effects includes injection site reaction and local tenderness. Incidences of headache and myalgia were also reported with H1N1 whereas cases of fever has also been demonstrated with H5N1 vaccines. It is stated that immunosuppressant therapies would reduce the therapeutic effects of vaccines and that people with egg allergy should go for the egg-free preparations.
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: CS1 maint: multiple names: authors list (link)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.
Highly pathogenic avian influenza virus is on every top ten list available for potential agricultural bioweapon agents