| Orthomyxoviridae | |
|---|---|
 | |
| Influenza A andinfluenza B viruses genome, mRNA, and virion diagram | |
Virus classification | |
| (unranked): | Virus |
| Realm: | Riboviria |
| Kingdom: | Orthornavirae |
| Phylum: | Negarnaviricota |
| Class: | Insthoviricetes |
| Order: | Articulavirales |
| Family: | Orthomyxoviridae |
| Genera | |
Orthomyxoviridae (from Ancient Greek ὀρθός (orthós) 'straight' and μύξα (mýxa) 'mucus')[1] is a family ofnegative-senseRNA viruses. It includes ninegenera:Alphainfluenzavirus,Betainfluenzavirus,Gammainfluenzavirus,Deltainfluenzavirus,Isavirus,Mykissvirus,Quaranjavirus,Sardinovirus, andThogotovirus. The first four genera contain viruses that causeinfluenza inbirds (see alsoavian influenza) andmammals, including humans. Isaviruses infectsalmon; the thogotoviruses arearboviruses, infectingvertebrates andinvertebrates (such asticks andmosquitoes).[2][3][4] The Quaranjaviruses are alsoarboviruses, infecting vertebrates (birds) and invertebrates (arthropods).
The four genera of Influenza virus that infect vertebrates, which are identified by antigenic differences in theirnucleoprotein andmatrix protein, are as follows:
The influenzavirusvirion ispleomorphic; theviral envelope can occur in spherical and filamentous forms. In general, the virus's morphology is ellipsoidal with particles 100–120 nm in diameter, or filamentous with particles 80–100 nm in diameter and up to 20 μm long.[5] There are approximately 500 distinct spike-like surface projections in the envelope each projecting 10–14 nm from the surface with varying surface densities. The majorglycoprotein (HA) spike is interposed irregularly by clusters ofneuraminidase (NA) spikes, with a ratio of HA to NA of about 10 to 1.[6]
The viral envelope composed of alipid bilayer membrane in which the glycoprotein spikes are anchored encloses thenucleocapsids; nucleoproteins of different size classes with a loop at each end; the arrangement within the virion is uncertain. The ribonuclear proteins are filamentous and fall in the range of 50–130 nm long and 9–15 nm in diameter with helical symmetry.[citation needed]
Viruses of the familyOrthomyxoviridae contain six to eight segments of linearnegative-sense single stranded RNA. They have a total genome length that is 10,000–14,600nucleotides (nt).[7] The influenza Agenome, for instance, has eight pieces of segmented negative-senseRNA (13.5 kilobases total).[8]
The best-characterised of the influenzavirus proteins arehemagglutinin andneuraminidase, two largeglycoproteins found on the outside of the viral particles. Hemagglutinin is alectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell.[9] In contrast, neuraminidase is anenzyme involved in the release ofprogeny virus from infected cells, by cleaving sugars that bind the mature viral particles. The hemagglutinin (H) and neuraminidase (N)proteins are key targets for antibodies and antiviral drugs,[10][11] and they are used to classify the differentserotypes of influenza A viruses, hence theH andN inH5N1.
The genome sequence has terminal repeated sequences, and these are repeated at both ends (i.e., at both the 5’ end and the 3’ end). These terminal repeats at the 5′-end are 12–13 nucleotides long. Nucleotide sequences at the 3′-terminus are identical, are the same in genera of the same family, most on RNA (segments), or on all RNA species. Terminal repeats at the 3′-end are 9–11 nucleotides long. Encapsidated nucleic acid is solely genomic. Each virion may contain defective interfering copies. In Influenza A (specifically, in H1N1) PB1-F2 is produced from an alternative reading frame in PB1. The M and NS genes produce two genes each (4 genes total) viaalternative splicing.[12]
Typically, influenza is transmitted from infected mammals through the air by coughs or sneezes, creatingaerosols containing the virus, and from infected birds through theirdroppings. Influenza can also be transmitted bysaliva,nasal secretions,feces andblood. Infections occur through contact with these bodily fluids or with contaminated surfaces. On certain surfaces (i.e, outside of a host), flu viruses can remain infectious for about one week at human body temperature, over 30 days at 0 °C (32 °F), and indefinitely at very low temperatures (such as in lakes in northeastSiberia). They can be inactivated easily bydisinfectants anddetergents.[13][14][15]
The viruses interacts between its surfacehemagglutinin glycoprotein to bind to the host’s surfacesialic acid sugars, specifically on the surfaces ofepithelial cells in the lung and throat (Stage 1 in infection figure).[16] The cell imports the virus byendocytosis. In the acidic pH environment of theendosome, part of the hemagglutinin protein fuses the viral envelope with the vacuole's membrane, releasing: the viral RNA (vRNA) molecules, accessory proteins andRNA-dependent RNA polymerase into the host cell’scytoplasm (Stage 2).[17] These proteins and vRNA form a complex that is transported into the hostcell nucleus, where the host’s own RNA-dependent RNA polymerase begins transcribing complementary positive-sense cRNA (Steps 3a and b).[18] The cRNA is either exported into the cytoplasm and translated (step 4), or remains in the host nucleus. Newly synthesised viral proteins are either secreted through theGolgi apparatus onto the host cell surface (in the case of neuraminidase and hemagglutinin, step 5b) or transported back into the host nucleus, where they bind vRNA and form new viral genome particles (step 5a). Other viral proteins have multiple actions in the host cell, including degrading cellularmRNA and using those consequently-releasednucleotides for vRNA synthesis, while also inhibiting translation of the host cell’s mRNAs.[19]
A virion assembles from negative-sense vRNAs (that form thegenomes of newly created viruses), RNA-dependent RNA transcriptase and other viral proteins. Hemagglutinin and neuraminidase molecules cluster into a bulge in the host cell membrane. The vRNA andviral core proteins leave the nucleus and enter this membrane protrusion (step 6). The mature virus buds off from the host cell in a sphere of host phospholipid membrane, acquiring hemagglutinin and neuraminidase with this membrane coat (step 7).[20] As before, the viruses then adhere to the same host cell capsule through hemagglutinin; the mature viruses detach once theirneuraminidase has cleaved sialic acid residues from the host cell.[16] After the release of new influenza virus, the host cell dies, and infection repeats in other host cells.
Orthomyxoviridae viruses are one of two RNA viruses that replicate in the nucleus (the other beingretroviridae). This is because the machinery of orthomyxo viruses cannot make their own mRNAs. They use cellular RNAs as primers for initiating the viral mRNA synthesis in a process known ascap snatching.[21] Once in the nucleus, the RNA Polymerase Protein PB2 finds a cellular pre-mRNA and binds to its 5′ capped end. Then RNA Polymerase PA cleaves off the cellular mRNA near the 5′ end and uses this capped fragment as a primer for transcribing the rest of the viral RNA genome in viral mRNA.[22] This is due to the need of mRNA to have a 5′ cap in order to be recognized by the cell'sribosome for translation.
Since RNAproofreading enzymes are absent, the RNA-dependent RNA transcriptase makes a single nucleotide insertion error roughly every 10 thousand nucleotides, which is the approximate length of the influenza vRNA. Hence, nearly every newly manufactured influenza virus will contain a mutation in its genome.[23] The separation of the genome into eight separate segments of vRNA allows mixing (reassortment) of the genes if more than one variety of influenza virus has infected the same cell (superinfection). The resulting alteration in the genome segments packaged into viral progeny confers new behavior, sometimes the ability to infect new host species or to overcome protective immunity of host populations to its old genome (in which case it is called anantigenic shift).[10]
In aphylogenetic-basedtaxonomy,RNA viruses include the subcategorynegative-sense ssRNA virus, which includes the orderArticulavirales, and the familyOrthomyxoviridae. The family contains the following genera:[24]
There are four genera of influenza virus, each containing only a single species, or type. Influenza A and C infect a variety of species (including humans), while influenza B almost exclusively infects humans, and influenza D infects cattle and pigs.[25][26][27]
Influenza A viruses are further classified, based on the viral surface proteinshemagglutinin (HA or H) andneuraminidase (NA or N). 18 HA subtypes (or serotypes) and 11 NA subtypes of influenza A virus have been isolated in nature. Among these, the HA subtype 1-16 and NA subtype 1-9 are found in wild waterfowl and shorebirds and the HA subtypes 17-18 and NA subtypes 10-11 have only been isolated from bats.[28][29]
Further variation exists; thus, specific influenza strainisolates are identified by theInfluenza virus nomenclature,[30] specifying virus type, host species (if not human), geographical location where first isolated, laboratory reference, year of isolation, and HA and NA subtype.[31][32]
Examples of the nomenclature are:
The type A influenza viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. It is thought that all influenza A viruses causing outbreaks or pandemics originate from wild aquatic birds.[33] All influenza A virus pandemics since the 1900s were caused byAvian influenza, throughReassortment with other influenza strains, either those that affect humans (seasonal flu) or those affecting other animals (see2009 swine flu pandemic).[34] The serotypes that have been confirmed inhumans, ordered by the number of confirmed human deaths, are:
| Name of pandemic | Date | Deaths | Case fatality rate | Subtype involved | Pandemic Severity Index |
|---|---|---|---|---|---|
| 1889–1890 flu pandemic (Asiatic or Russian Flu)[41] | 1889–1890 | 1 million | 0.15% | PossiblyH3N8 orH2N2 | — |
| 1918 flu pandemic (Spanish flu)[42] | 1918–1920 | 20 to 100 million | 2% | H1N1 | 5 |
| Asian Flu | 1957–1958 | 1 to 1.5 million | 0.13% | H2N2 | 2 |
| Hong Kong Flu | 1968–1969 | 0.75 to 1 million | <0.1% | H3N2 | 2 |
| Russian flu | 1977–1978 | No accurate count | — | H1N1 | — |
| 2009 flu pandemic[43][44] | 2009–2010 | 105,700–395,600[45] | 0.03% | H1N1 | N/A |
Influenza B virus is almost exclusively a human pathogen, and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is theseal.[46] This type of influenza mutates at a rate 2–3 times lower than type A[47] and consequently is less genetically diverse, with only one influenza B serotype.[25] As a result of this lack ofantigenic diversity, a degree of immunity to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible.[48] This reduced rate of antigenic change, combined with its limited host range (inhibiting cross speciesantigenic shift), ensures that pandemics of influenza B do not occur.[49]
The influenza C virus infectshumans andpigs, and can cause severe illness and localepidemics.[50] However, influenza C is less common than the other types and usually causes mild disease in children.[51][52]
This is a genus that was classified in 2016, the members of which were first isolated in 2011.[53] This genus appears to be most closely related to Influenza C, from which it diverged several hundred years ago.[54] There are at least two extant strains of this genus.[55] The main hosts appear to be cattle, but the virus has been known to infect pigs as well.
Mammalian influenza viruses tend to be labile, but they can survive several hours in a host’s mucus.[56] Avian influenza virus can survive for 100 days in distilled water at room temperature and for 200 days at 17 °C (63 °F). The avian virus is inactivated more quickly in manure but can survive for up to two weeks in feces on cages. Avian influenza viruses can survive indefinitely when frozen.[56] Influenza viruses are susceptible to bleach, 70% ethanol, aldehydes, oxidizing agents and quaternary ammonium compounds. They are inactivated by heat at 133 °F (56 °C) for minimum of 60 minutes, as well as by low pH <2.[56]
Vaccines and drugs are available for the prophylaxis and treatment of influenza virus infections. Vaccines are composed of either inactivated or live attenuated virions of the H1N1 and H3N2 human influenza A viruses, as well as those of influenza B viruses. Because the antigenicities of the wild viruses evolve, vaccines are reformulated annually by updating the seed strains.[57]
More specifically, flu vaccines are made using the reassortment method, and this has been used for over 50 years. In this method, scientists inject eggs with both one noninfectious flu strain and also one infectious strain. The inert strain must be one that multiples very well in chicken eggs. Scientists pick an infectious strain that carries the desired HA and N receptors that the final product should prevent from infection. They choose these strains by picking the surface HA and NA versions circulating the most in the public, and the ones thought most likely to be prevalent in the upcoming flu season. The two strains—pathogenic and non pathogenic—then multiply and exchange DNA until an inert strain carries eight copies of the infectious strain’s two glycoprotein targets. Finally, of the newly created viruses, scientists pick six versions that multiplied the best in chicken eggs which also carry the necessary HA and NA genes. Ultimately, millions of eggs are injected with those noninfectious strains—which carry the desired proteins—so that the genes can be harvested and used for the vaccine product.[57]
Another method of making the vaccine is by splicing genes from infectious strains and then creating copies in a lab, without the need for the tedious process of chicken egg culture. This method relies on using virus plasmids to excerpt the target genes.[57]
When the antigenicities of the seed strains and wild viruses do not match, vaccines fail to protect the vaccines.[57]
Drugs available for the treatment of influenza includeAmantadine andRimantadine, which inhibit the uncoating of virions by interfering withM2 proton channel, andOseltamivir (marketed under the brand nameTamiflu),Zanamivir, andPeramivir, which inhibit the release of virions from infected cells by interfering with NA. However, escape mutants are often generated for the former drug and less frequently for the latter drug.[58]
This Memorandum was drafted by the signatories listed on page 590 on the occasion of a meeting held in Geneva in February 1980.
| Components |  | |
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| Viral life cycle | ||
| Genetics | ||
| By host | ||
| Other | ||
