Orthomyxoviridae
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Orthomyxoviridae (Template:Etymology)<ref>International Committee on Taxonomy of Viruses Index of Viruses — Orthomyxovirus (2006). In: ICTVdB—The Universal Virus Database, version 4. Büchen-Osmond, C (Ed), Columbia University, New York.</ref> is a family of negative-sense RNA viruses. It includes nine genera: Alphainfluenzavirus, Betainfluenzavirus, Gammainfluenzavirus, Deltainfluenzavirus, Isavirus, Mykissvirus, Quaranjavirus, Sardinovirus, and Thogotovirus. The first four genera contain viruses that cause influenza in birds (see also avian influenza) and mammals, including humans. Isaviruses infect salmon; the thogotoviruses are arboviruses, infecting vertebrates and invertebrates (such as ticks and mosquitoes).<ref name="pmid2617637">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid11678233">Template:Cite journal</ref> The Quaranjaviruses are also arboviruses, infecting vertebrates (birds) and invertebrates (arthropods).
The four genera of Influenza virus that infect vertebrates, which are identified by antigenic differences in their nucleoprotein and matrix protein, are as follows:
- Alphainfluenzavirus infects humans, other mammals, and birds, and causes all flu pandemics
- Betainfluenzavirus infects humans and seals
- Gammainfluenzavirus infects humans and pigs
- Deltainfluenzavirus infects pigs and cattle.
Structure
The influenzavirus virion is pleomorphic; the viral 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.<ref>Template:Cite journal</ref> 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 major glycoprotein (HA) spike is interposed irregularly by clusters of neuraminidase (NA) spikes, with a ratio of HA to NA of about 10 to 1.<ref>Template:Cite journal</ref>
The viral envelope composed of a lipid bilayer membrane in which the glycoprotein spikes are anchored encloses the nucleocapsids; nucleoproteins of different sizes; the arrangement within the virion is uncertain. The ribonuclear proteins are filamentous and fall in the range of 50–150 nm long with helical symmetry.<ref name=ictvreport />
Genome
Viruses of the family Orthomyxoviridae contain six to eight segments of linear negative-sense single stranded RNA. They have a total genome length that is 10,000–14,600 nucleotides (nt).<ref name=ictvreport >{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The influenza A genome, for instance, has eight pieces of segmented negative-sense RNA (13.5 kilobases total).<ref name="Ghedin">Template:Cite journal</ref>
The best-characterised of the influenzavirus proteins are hemagglutinin and neuraminidase, two large glycoproteins found on the outside of the viral particles. Hemagglutinin is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell.<ref>Template:Cite journal</ref> In contrast, neuraminidase is an enzyme involved in the release of progeny 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,<ref name="Hilleman">Template:Cite journal</ref><ref>Template:Cite journal</ref> and they are used to classify the different serotypes of influenza A viruses, hence the H and N in H5N1.
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) via alternative splicing.<ref name="Bouvier2008">Template:Cite journal</ref>
Replication cycle
Typically, influenza is transmitted from infected mammals through the air by coughs or sneezes, creating aerosols containing the virus, and from infected birds through their droppings. Influenza can also be transmitted by saliva, nasal secretions, feces and blood. 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 Template:Convert, and indefinitely at very low temperatures (such as in lakes in northeast Siberia). They can be inactivated easily by disinfectants and detergents.<ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="NHZ2006-11-30">Template:Cite news</ref>
The viruses interacts between its surface hemagglutinin glycoprotein to bind to the host's surface sialic acid sugars, specifically on the surfaces of epithelial cells in the lung and throat (Stage 1 in infection figure).<ref name=Wagner>Template:Cite journal</ref> The cell imports the virus by endocytosis. In the acidic pH environment of the endosome, part of the hemagglutinin protein fuses the viral envelope with the vacuole's membrane, releasing: the viral RNA (vRNA) molecules, accessory proteins and RNA-dependent RNA polymerase into the host cell's cytoplasm (Stage 2).<ref>Template:Cite journal</ref> These proteins and vRNA form a complex that is transported into the host cell nucleus, where the host's own RNA-dependent RNA polymerase begins transcribing complementary positive-sense cRNA (Steps 3a and b).<ref>Template:Cite journal</ref> 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 the Golgi apparatus onto the host cell surface (in the case of neuraminidase and hemagglutinin, step 5b) or transported 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 cellular mRNA and using those consequently-released nucleotides for vRNA synthesis, while also inhibiting translation of the host cell's mRNAs.<ref>Template:Cite journal</ref>
A virion assembles from negative-sense vRNAs (that form the genomes 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 and viral 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).<ref>Template:Cite journal</ref> As before, the viruses then adhere to the same host cell capsule through hemagglutinin; the mature viruses detach once their neuraminidase has cleaved sialic acid residues from the host cell.<ref name=Wagner/> 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 being retroviridae). 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 as cap snatching.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name=Bouvier2009>Template:Cite journal</ref> This is due to the need of mRNA to have a 5′ cap in order to be recognized by the cell's ribosome for translation.
Since RNA proofreading 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.<ref>Template:Cite journal</ref> 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 an antigenic shift).<ref name=Hilleman/>
Classification
In a phylogenetic-based taxonomy, RNA viruses include the subcategory negative-sense ssRNA virus, which includes the order Articulavirales, and the family Orthomyxoviridae. The family contains the following genera:<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Template:Div col
- Alphainfluenzavirus
- Betainfluenzavirus
- Deltainfluenzavirus
- Gammainfluenzavirus
- Isavirus
- Mykissvirus
- Quaranjavirus
- Sardinovirus
- Thogotovirus
Influenza types
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.<ref name="hay">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>
Influenza A
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Influenza A viruses are further classified, based on the viral surface proteins hemagglutinin (HA or H) and neuraminidase (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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
Further variation exists; thus, specific influenza strain isolates are identified by the Influenza virus nomenclature,<ref>Template:Cite journal</ref> specifying virus type, host species (if not human), geographical location where first isolated, laboratory reference, year of isolation, and HA and NA subtype.<ref>Template:Cite book</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Examples of the nomenclature are:
- Template:Tt - isolated from a human
- Template:Tt - isolated from a pig
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.<ref>Template:Cite journal</ref> All influenza A virus pandemics since the 1900s were caused by Avian influenza, through Reassortment with other influenza strains, either those that affect humans (seasonal flu) or those affecting other animals (see 2009 swine flu pandemic).<ref>Template:Cite journal</ref> The serotypes that have been confirmed in humans, ordered by the number of confirmed human deaths, are:
- H1N1 caused "Spanish flu" in 1918 and "Swine flu" in 2009.<ref>Template:Cite journal</ref>
- H2N2 caused "Asian Flu".
- H3N2 caused "Hong Kong Flu".
- H5N1, "avian" or "bird flu".<ref>Template:Cite journal</ref>
- H7N7 has unusual zoonotic potential.<ref>Template:Cite journal</ref>
- H1N2 infects pigs and humans.<ref>Template:Cite journal</ref>
- H9N2, H7N2, H7N3, H10N7.
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Name of pandemic | Date | Deaths | Case fatality rate | Subtype involved | Pandemic Severity Index |
|---|---|---|---|---|---|---|
| 1889–1890 flu pandemic (Asiatic or Russian Flu)<ref>Template:Cite journal</ref> |
1889–1890 | 1 million | 0.15% | Possibly H3N8 or H2N2 |
Template:N/A | |
| 1918 flu pandemic (Spanish flu)<ref>Template:Cite journal</ref> |
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 | Template:N/a | Template:N/A | H1N1 | Template:N/A | |
| 2009 flu pandemic<ref>Template:Cite journal</ref><ref name="ecdc">{{#invoke:citation/CS1|citation | CitationClass=web
}}</ref> |
2009–2010 | 105,700–395,600<ref>Template:Cite journal</ref> | 0.03% | H1N1 | N/A |
Influenza B
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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 the seal.<ref>Template:Cite journal</ref> This type of influenza mutates at a rate 2–3 times lower than type A<ref>Template:Cite journal</ref> and consequently is less genetically diverse, with only one influenza B serotype.<ref name="hay" /> As a result of this lack of antigenic 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.<ref name="webster">Template:Cite journal</ref> This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of influenza B do not occur.<ref name="Zambon">Template:Cite journal</ref>
Influenza C
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The influenza C virus infects humans and pigs, and can cause severe illness and local epidemics.<ref>Template:Cite journal</ref> However, influenza C is less common than the other types and usually causes mild disease in children.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
Influenza D
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This is a genus that was classified in 2016, the members of which were first isolated in 2011.<ref name="Hause2013">Template:Cite journal</ref> This genus appears to be most closely related to Influenza C, from which it diverged several hundred years ago.<ref name="Sheng2014">Template:Cite journal</ref> There are at least two extant strains of this genus.<ref name="Collin2015">Template:Cite journal</ref> The main hosts appear to be cattle, but the virus has been known to infect pigs as well.
Viability and disinfection
Mammalian influenza viruses tend to be labile, but they can survive several hours in a host's mucus.<ref name="cfsph.iastate.edu">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Avian influenza virus can survive for 100 days in distilled water at room temperature and for 200 days at Template:Convert. 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.<ref name="cfsph.iastate.edu" /> Influenza viruses are susceptible to bleach, 70% ethanol, aldehydes, oxidizing agents and quaternary ammonium compounds. They are inactivated by heat at Template:Convert for minimum of 60 minutes, as well as by low pH <2.<ref name="cfsph.iastate.edu" />
Vaccination and prophylaxis
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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.<ref name="Hood">Template:Cite journal</ref>
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.<ref name="Hood" />
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.<ref name="Hood" />
When the antigenicities of the seed strains and wild viruses do not match, vaccines fail to protect the vaccines.<ref name="Hood" />
Drugs available for the treatment of influenza include Amantadine and Rimantadine, which inhibit the uncoating of virions by interfering with M2 proton channel, and Oseltamivir (marketed under the brand name Tamiflu), Zanamivir, and Peramivir, 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.<ref>Template:Cite journal</ref>
See also
References
Further reading
External links
Template:Sister project Template:Refbegin
- Health-EU Portal: EU work to prepare a global response to influenza.
- Influenza Research Database: Database of influenza genomic sequences and related information.
- European Commission—Public Health: EU coordination on Pandemic (H1N1) 2009
- 3D Influenza-virus-related structures from the EM Data Bank (EMDB)
- Viralzone: Orthomyxoviridae
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