Influenza A virus
Influenza A virus, or IAV is a pathogen with strains that cause seasonal flu in humans; it can also infect birds and some mammals. Strains of IAV circulate constantly in bats, pigs, horses, and dogs, while other mammals may be infected occasionally. It has also been the cause of a number of pandemics, most notably the Spanish Flu pandemic from 1918–1920.
Subtypes of IAV are defined by the combination of the molecules on the surface of the virus which provoke an immune response; for example, "H1N1" denotes a subtype that has a type-1 hemagglutinin protein and a type-1 neuraminidase protein. Variations within subtypes affect how easily the virus spreads, the severity of illness, and its ability to infect different hosts. The virus changes through mutation and genetic reassortment, allowing it to evade immunity and sometimes jump between species.
Symptoms of human seasonal flu usually include fever, cough, sore throat, muscle aches and, in severe cases, breathing problems and pneumonia that may be fatal. 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. Bird-adapted strains of the virus can be asymptomatic in some aquatic birds but lethal if they spread to other species, such as chickens.
IAV disease in poultry can be prevented by vaccination; however, biosecurity control measures such as quarantine, segregation, and good hygiene are preferred. In humans, seasonal influenza can be prevented by vaccination, or treated in its early stages with antiviral medicines. The Global Influenza Surveillance and Response System monitors the spread of influenza worldwide and informs development of both seasonal and pandemic vaccines. 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 influenza viruses which could potentially infect humans. IAV vaccines need to be reformulated regularly in order to keep up with changes in the virus.
Virology
Taxonomy
Influenza A virus, or IAV, is the only species of the genus Alphainfluenzavirus of the virus family Orthomyxoviridae.Classification
There are two methods of classification, one based on the antigenic surface proteins, and the other based on its behavior, mainly the host animal.''''Subtypes
There are two antigenic proteins on the surface of the viral envelope, hemagglutinin and neuraminidase. Based on their serotype, there are 18 known types of hemagglutinin and 11 types of neuraminidase. 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 protein and a type-1 neuraminidase protein.By definition, the subtyping scheme only takes into account the two outer proteins, not the additional eight or more proteins which are coded by the genome. Almost all possible combinations of H and N have been isolated from wild birds. H17 and H18 have only been discovered in bats. Further variation exists within viral subtypes which may lead to significant differences in behavior.
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, which describes, among other things, the subtype, year, and place of collection. Some examples include:- .
- * The starting indicates that the virus is an influenza A virus.
- * indicates the place of collection. is a laboratory sequence number. indicates that the sample was collected in 2021. No species is mentioned so by default, the sample was collected from a human.
- * indicates the subtype of the virus.
- .
- * This example shows an additional field before the place:. It indicates that the sample was collected from a pig.
- .
- * This example carries an unusual designation in the last part: instead of a usual, it uses. This was in order to distinguish the Pandemic H1N1/09 virus lineage from older H1N1 viruses.
Structure and genetics
Structure
The influenza A virus has a negative-sense, single-stranded, segmented RNA genome, enclosed in a lipid envelope. The virus particle is 80–120 nanometers in diameter, such that the smallest virions adopt an elliptical shape; larger virions have a filamentous shape.Core – The central core of the virion contains the viral RNA genome, which is made of eight separate segments. The nucleoprotein coats the viral RNA to form a ribonucleoprotein that assumes a helical configuration. Three large proteins, which are responsible for RNA transcription and replication, are bound to each segment of viral RNP.
Capsid – The matrix protein M1 forms a layer between the nucleoprotein and the envelope, called the capsid.
Envelope – The viral envelope consists of a lipid bilayer derived from the host cell. Two viral proteins; hemagglutinin and neuraminidase, are inserted into the envelope and are exposed as spikes on the surface of the virion. Both proteins are antigenic; a host's immune system can react to them and produce antibodies in response. The M2 protein forms an ion channel in the envelope and is responsible for uncoating the virion once it has bound to a host cell.
Genome
The table below presents a concise summary of the influenza genome and the principal functions of the proteins which are encoded. Segments are conventionally numbered from 1 to 8 in descending order of length.| RNA segment | Length | Protein | Function |
| 1- PB2 | 2341 | PB2 | A component of the viral RNA polymerase. PB2 also inhibits JAK1/STAT signaling to inhibit host innate immune response |
| 2- PB1 | 2341 | PB1 | A component of the viral RNA polymerase. It also degrades the host cell's mitochondrial antiviral signaling protein |
| 2- PB1 | 2341 | PB1-F2 | An accessory protein of most IAVs. Not needed for virus replication and growth, it interferes with the host immune response. |
| 3- PA | 2233 | PA | A component of the viral RNA polymerase |
| PA-X | Arises from a ribosomal frameshift in the PA segment. Inhibits innate host immune responses, such as cytokine and interferon production. | ||
| 4- HA | 1775 | HA | Part of the viral envelope, a protein that binds the virion to host cells, enabling the virus's RNA genetic material to invade it |
| 5- NP | 1565 | NP | The nucleoprotein associates with the viral RNA to form a ribonucleoprotein. At the early stage of infection, the RNP binds to the host cell's importin-α which transports it into the host cell nucleus, where the viral RNA is transcribed and replicated. At a later stage of infection, newly manufactured viral RNA segments assemble with the NP protein and polymerase to form the core of a progeny virion |
| 6- NA | 1409 | NA | Part of the viral envelope. NA enables the newly assembled virions to escape the host cell and go on to propagate the infection. NA also facilitates the movement of infective virus particles through mucus, enabling them to reach host epithelial cells. |
| 7- M | 1027 | M1 | Forms the capsid, which coats the viral nucleoproteins and supports the structure of the viral envelope. M1 also assists with the function of the NEP protein. |
| 7- M | 1027 | M2 | Forms a proton channel in the viral envelope, which is activated once a virion has bound to a host cell. This uncoats the virus, exposing its infective contents to the cytoplasm of the host cell |
| 8- NS | 890 | NS1 | Counteracts the host's natural immune response and inhibits interferon production. |
| 8- NS | 890 | NEP | Cooperates with the M1 protein to mediate the export of viral RNA copies from nucleus into cytoplasm in the late stage of viral replication |
Three viral proteins - PB1, PB2, and PA – associate to form the RNA-dependent RNA polymerase which functions to transcribe and replicate the viral RNA.
Viral messenger RNA transcription – The RdRp complex transcribes viral mRNAs by using a mechanism called cap-snatching. It consists in the hijacking and cleavage of host capped pre-mRNAs. Host cell mRNA is cleaved near the cap to yield a primer for the transcription of positive-sense viral mRNA using the negative-sense viral RNA as a template. The host cell then transports the viral mRNA into the cytoplasm where ribosomes manufacture the viral proteins.
Replication of the viral RNA – The replication of the influenza virus, unlike most other RNA viruses, takes place in the nucleus and involves two steps. The RdRp first of all transcribes the negative-sense viral genome into a positive-sense complimentary RNA, then the cRNAs are used as templates to transcribe new negative-sense vRNA copies. These are exported from the nucleus and assemble near the cell membrane to form the core of new virions.
Epidemiology
Evolution and history
The predominant natural reservoir of influenza viruses is thought to be wild waterfowl. A 2023 study involving total RNA sequencing and transcriptome mining found that Influenzaviruses and the broader Articulavirales order likely had an aquatic origin, with fish being some of the earliest hosts, and the earliest viruses in the order evolving from Crustaceans over 600 million years ago. 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.Outbreaks of influenza-like disease can be found throughout recorded history. The first probable record is by Hippocrates in 412 BCE. The historian Fujikawa listed 46 epidemics of flu-like illness in Japan between 862 and 1868. In Europe and the Americas, a number of epidemics were recorded through the Middle Ages and up to the end of the 19th century.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. 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. The 1968 pandemic 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.
In the 21st century, a strain of H1N1 flu 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".
Influenza A virus continues to circulate and evolve in birds and pigs. Almost all possible combinations of H and N have been isolated from wild birds. 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.