Orthomyxoviridae

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Orthomyxovirus
Virus classification e
(unranked): Virus
Phylum: Negarnaviricota
Class: Insthoviricetes
Order: Articulavirales
Family: Orthomyxoviridae
Genera

The Orthomyxoviruses (ὀρθός, orthós, Greek for "straight"; μύξα, mýxa, Greek for "mucus")[1] are a family of RNA viruses that includes seven genera: Influenza virus A, Influenza virus B, Influenza virus C, Influenza virus D, Isavirus, Thogotovirus, and Quaranjavirus. The first four genera contain viruses that cause influenza in vertebrates, including birds (see also avian influenza), humans, and other mammals. Isaviruses infect salmon; the thogotoviruses are arboviruses, infecting vertebrates and invertebrates, such as ticks and mosquitoes.[2][3][4]

The four genera of Influenza virus, which are identified by antigenic differences in their nucleoprotein and matrix protein, infect vertebrates as follows:

Classification[edit]

Influenza Virus.

In a phylogenetic-based taxonomy, the category "RNA virus" includes the category "negative-sense ssRNA virus", which includes the Order "Mononegavirales", and the Family "Orthomyxovirus" (among others). The genera-associated species and serotypes of Orthomyxovirus are shown in the following table.

Orthomyxovirus Genera, Species, and Serotypes
Genus Species (* indicates type species) Serotypes or Subtypes Hosts
Influenza virus A Influenza A virus* H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H7N9, H9N2, H10N7 Human, pig, bird, horse, bat
Influenza virus B Influenza B virus* Victoria, Yamagata[5] Human, seal
Influenza virus C Influenza C virus* Human, pig, dog
Influenza virus D Influenza D virus* Pig, cattle
Isavirus Infectious salmon anemia virus* Atlantic salmon
Thogotovirus Thogotovirus* Tick, mosquito, mammal (including human)
Dhori virus Batken virus, Bourbon virus, Jos virus
Quaranjavirus[6]
Quaranfil virus,* Johnston Atoll virus

ICTV Taxonomy[edit]

Group: ssRNA(-)

[7]

Types[edit]

There are four genera of influenza virus, each containing only a single species, or type. Influenza A and C infect a variety of species, while influenza B almost exclusively infects humans, and influenza D infects cattle and pigs.[8][9][10]

Influenza A[edit]

Influenza A viruses are further classified, based on the viral surface proteins hemagglutinin (HA or H) and neuraminidase (NA or N). Sixteen H subtypes (or serotypes) and nine N subtypes of influenza A virus have been identified.

Diagram of influenza nomenclature

Further variation exists; thus, specific influenza strain isolates are identified by a standard nomenclature specifying virus type, geographical location where first isolated, sequential number of isolation, year of isolation, and HA and NA subtype.[11][12]

Examples of the nomenclature are:

  1. A/Brisbane/59/2007 (H1N1)
  2. A/Moscow/10/99 (H3N2).

The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:

Known flu pandemics[16][17][18]
Name of pandemic Date Deaths Case fatality rate Subtype involved Pandemic Severity Index
1889–1890 flu pandemic
(Asiatic or Russian Flu)[19]
1889–1890 1 million 0.15% possibly H3N8
or H2N2
NA
1918 flu pandemic
(Spanish flu)[20]
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 N/A H1N1 N/A
2009 flu pandemic[21][22] 2009–2010 105,700–395,600[23] 0.03% H1N1 NA

Influenza B[edit]

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.[24] This type of influenza mutates at a rate 2–3 times lower than type A[25] and consequently is less genetically diverse, with only one influenza B serotype.[8] 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.[26] 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.[27]

Influenza C[edit]

The influenza C virus infects humans and pigs, and can cause severe illness and local epidemics.[28] However, influenza C is less common than the other types and usually seems to cause mild disease in children.[29][30]

Influenza D[edit]

This is a genus that was classified in 2016, the members of which were first isolated in 2011.[31] This genus appears to be most closely related to Influenza C, from which it diverged several hundred years ago.[32] There are at least two strains of this genus in extant.[33] The main hosts appear to be cattle, but this virus has seen to infect pigs as well.

Morphology[edit]

Structure of the influenza virion. The hemagglutinin (HA) and neuraminidase (NA) proteins are shown on the surface of the particle. The viral RNAs that make up the genome are shown as red coils inside the particle and bound to Ribonuclear Proteins (RNPs).

The virion is pleomorphic; the envelope can occur in spherical and filamentous forms. In general, the virus's morphology is ellipsoidal with particles 80 to 120 nm in diameter, or filamentous virions 80-120 nm in diameter and up to 20 µm long.[34] There are some 500 distinct spike-like surface projections of the envelope each projecting 10 to 14 nm from the surface with varying surface densities.

The major glycoprotein (HA) is interposed irregularly by clusters of neuraminidase (NA), with a ratio of HA to NA of about 4–5 to 1.

Cholesterol-laden membranes with protruding glycoproteins enclose the nucleocapsids; 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 to 130 nm long and 9 to 15 nm in diameter. They have a helical symmetry.

Genome[edit]

Viruses of this family contain 6 to 8 segments of linear negative-sense single stranded RNA.[35]

The total genome length is 12000–15000 nucleotides (nt). The size of each segment is as follows:

segment protein size (nt) protein size (aa)
PB1 polymerase 2300–2500 757+87 (F2)
PB2 polymerase 2300–2500 759
PA polymerase 2200–2300 716
HA Hemagglutinin 1700–1800 550
NP nucleoprotein 1500–1600 498
NA Neuraminidase 1400–1500 454
M Membrane protein(s) 1000–1100 252+97
NS non-structural protein(s) 800–900 230+121

The Genome sequence has terminal repeated sequences; repeated at both ends. Terminal repeats at the 5'-end 12–13 nucleotides long. Nucleotide sequences of 3'-terminus identical; the same in genera of same family; most on RNA (segments), or on all RNA species. Terminal repeats at the 3'-end 9–11 nucleotides long. Encapsidated nucleic acid is solely genomic. Each virion may contain defective interfering copies. In Influenza A (H1N1) PB1-F2 is produced from an alternative reading frame in PB1. The M and NS genes produce 2 different genes via alternative splicing.Bouvier NM, Palese P (September 2008). "The biology of influenza viruses". Vaccine. 26 Suppl 4: D49–53. doi:10.1016/j.vaccine.2008.07.039. PMC 3074182. PMID 19230160.

Structure[edit]

The following applies for Influenza A viruses, although other influenza strains are very similar in structure:[36]

The influenza A virus particle or virion is 80–120 nm in diameter, usually producing both ellipsoidal, baciliform, and filamentous particles.[37][38][39] Unusually for a virus, the influenza A genome is not a single piece of nucleic acid; instead, it contains eight pieces of segmented negative-sense RNA (13.5 kilobases total), which encode 11 proteins (HA, NA, NP, M1, M2, NS1, NEP, PA, PB1, PB1-F2, PB2).[40] The best-characterised of these viral proteins are hemagglutinin and neuraminidase, two large glycoproteins found on the outside of the viral particles. Neuraminidase is an enzyme involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles. By contrast, hemagglutinin is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell.[41] The hemagglutinin (H) and neuraminidase (N) proteins are targets for antiviral drugs.[42] These proteins are also recognised by antibodies, i.e. they are antigens.[16] The responses of antibodies to these proteins are used to classify the different serotypes of influenza A viruses, hence the H and N in H5N1.

Replication cycle[edit]

Invasion and replication of the influenza virus. The steps in this process are discussed in the text.

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. Out 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 lakes in northeast Siberia). They can be inactivated easily by disinfectants and detergents.[43][44][45]

The viruses bind to a cell through interactions between its hemagglutinin glycoprotein and sialic acid sugars on the surfaces of epithelial cells in the lung and throat (Stage 1 in infection figure).[46] The cell imports the virus by endocytosis. In the acidic endosome, part of the haemagglutinin 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 cytoplasm (Stage 2).[47] These proteins and vRNA form a complex that is transported into the cell nucleus, where the RNA-dependent RNA polymerase begins transcribing complementary positive-sense cRNA (Steps 3a and b).[48] The cRNA is either exported into the cytoplasm and translated (step 4), or remains in the nucleus. Newly synthesised viral proteins are either secreted through the Golgi apparatus onto the cell surface (in the case of neuraminidase and hemagglutinin, step 5b) or transported back into the nucleus to 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 the released nucleotides for vRNA synthesis and also inhibiting translation of host-cell mRNAs.[49]

Negative-sense vRNAs that form the genomes of future viruses, RNA-dependent RNA transcriptase, and other viral proteins are assembled into a virion. Hemagglutinin and neuraminidase molecules cluster into a bulge in the 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 cell in a sphere of host phospholipid membrane, acquiring hemagglutinin and neuraminidase with this membrane coat (step 7).[50] As before, the viruses adhere to the cell through hemagglutinin; the mature viruses detach once their neuraminidase has cleaved sialic acid residues from the host cell.[46] After the release of new influenza virus, the host cell dies.

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.[51] 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.Dias A, Bouvier D, Crépin T, McCarthy AA, Hart DJ, Baudin F, Cusack S, Ruigrok RW (April 2009). "The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit". Nature. 458 (7240): 914–8. Bibcode:2009Natur.458..914D. doi:10.1038/nature07745. PMID 19194459. 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.[52] 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).[16]

Viability and disinfection[edit]

Mammalian influenza viruses tend to be labile, but can survive several hours in mucus.[53] Avian influenza virus can survive for 100 days in distilled water at room temperature, and 200 days at 17 °C (63 °F). The avian virus is inactivated more quickly in manure, but can survive for up to 2 weeks in feces on cages. Avian influenza viruses can survive indefinitely when frozen.[53] Influenza viruses are susceptible to bleach, 70% ethanol, aldehydes, oxidizing agents, and quaternary ammonium compounds. They are inactivated by heat of 133 °F (56 °C) for minimum of 60 minutes, as well as by low pH <2.[53]

Vaccination and prophylaxis[edit]

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. However, when the antigenicities of the seed strains and wild viruses do not match, vaccines fail to protect the vaccinees. In addition, even when they do match, escape mutants are often generated. Drugs available for the treatment of influenza include Amantadine and Rimantadine, which inhibit the uncoating of virions by interfering with M2, 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.[54]

See also[edit]

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