ORTHOMYXOVIRIDAE

''Influenzavirus A''

''Influenzavirus B''

''Influenzavirus C''

''Isavirus''

''Thogotovirus
The '''Orthomyxoviridae''' are a family of RNA viruses that includes viruses which cause influenza in vertebrates. It also includes viruses that in addition to infecting vertebrates can also infect invertebrates (''Thogotovirus'' can infect ticks^[1], and ''Isavirus'' can possibly infect (but definitely is carried and transmitted by) sea lice^[2]).
There are three genera of influenza virus, identified by antigenic differences in their nucleoprotein and matrix protein:^[3]

★ Influenzavirus A are the cause of all flu pandemics and are known to infect humans, other mammals and birds (see also avian influenza),

★ Influenzavirus B are known to infect humans and seals,

★ Influenzavirus C are known to infect humans and pigs.

Latest flu pandemics Realities and enigmas of human viral influenza: pathogenesis, epidemiology and control., Hilleman M, , , Vaccine, 2002

Name of pandemic	Date	Deaths	Subtype involved
Asiatic (Russian) Flu	1889-90	1 million	possibly H2N2
Spanish Flu	1918-20	40 million	H1N1
Asian Flu	1957-58	1 to 1.5 million	H2N2
Hong Kong Flu	1968-69	0.75 to 1 million	H3N2

Contents

Morphology

Nucleic Acid

Types of influenza virus

Structure and properties

Infection and replication

Terminology

Virus versus disease

Genera versus species

Categorization

Sources

Morphology

The virions have envelopes and occur in pleomorphic and filamentous forms. In general the virus's morphology is spherical with particles 50 to 120 nm in diameter, or filamentous virions 20 nm in diameter and 200 to 300 (-3000) nm long. There are some 500 distinct spike-like surface projections of the envelope each projecting 10 to 14 nm from the surface with some types (i.e. hemagglutininesterase (HEF)) densely dispersed over the surface, and with others (i.e. hemagglutinin (HA)) spaced widely apart.
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.
Lipoprotein membranes enclose the nucleocapsids; nucleoproteins of different size classes with a loop at each end; the arrangement within the virion is uncertain. The nucleocapsids 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.

Nucleic Acid

Viruses of this family contain 7 to 8 segments of linear negative-sense single stranded RNA.
The total genome length is 12000-15000 nucleotides (nt). The largest segment 2300-2500 nt; of second largest 2300-2500 nt; of third 2200-2300 nt; of fourth 1700-1800 nt; of fifth 1500-1600 nt; of sixth 1400-1500 nt; of seventh 1000-1100 nt; of eighth 800-900 nt. 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.

Types of influenza virus

There are three types of influenza virus: Influenzavirus A, Influenzavirus B or Influenzavirus C. Influenza A and C infect multiple species, while influenza B almost exclusively infects humans. The evolution of human influenza viruses., Hay A, Gregory V, Douglas A, Lin Y, , , Philos Trans R Soc Lond B Biol Sci, 2001
The type A viruses are the most virulent human pathogens among the three influenza types and causes the most severe disease. The Influenza A virus can be subdivided into different serotypes based on the antibody response to these viruses. The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:

★ H1N1 caused "Spanish Flu".

★ H2N2 caused "Asian Flu".

★ H3N2 caused "Hong Kong Flu".

★ H5N1 is a pandemic threat in 2006-7 flu season.

★ H7N7 has unusual zoonotic potential.^[4]

★ H1N2 is endemic in humans and pigs.

★ H9N2, H7N2, H7N3, H10N7.
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.^[5] This type of influenza mutates at a rate 2-3 times lower than type A^[6] and consequently is less genetically diverse, with only one influenza B serotype. 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. Evolution and ecology of influenza A viruses., Webster R, Bean W, Gorman O, Chambers T, Kawaoka Y, , , Microbiol Rev, 1992 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. Epidemiology and pathogenesis of influenza., Zambon M, , , J Antimicrob Chemother, 1999
The influenza C virus infects humans and pigs, and can cause severe illness and local epidemics.^[7] However, influenza C is less common than the other types and usually seems to cause mild disease in children.^[8][9]

Structure and properties

The following applies for Influenza A viruses, although other influenza strains are very similar in structure^[10]:
The influenza A virus particle or ''virion'' is 80-120 nm in diameter and usually roughly spherical, although filamentous forms can occur.^[11] 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). Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution., Ghedin E, Sengamalay N, Shumway M, Zaborsky J, Feldblyum T, Subbu V, Spiro D, Sitz J, Koo H, Bolotov P, Dernovoy D, Tatusova T, Bao Y, St George K, Taylor J, Lipman D, Fraser C, Taubenberger J, Salzberg S, , , Nature, 2005 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.^[12] The hemagglutinin (H) and neuraminidase (N) proteins are targets for antiviral drugs.^[13] These proteins are also recognised by antibodies, i.e. they are antigens. 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''.

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

Infection and replication

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. 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.^[14][15] Flu viruses 'can live for decades' on ice, NZ Herald, November 30, 2006.
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). Functional balance between haemagglutinin and neuraminidase in influenza virus infections., Wagner R, Matrosovich M, Klenk H, , , Rev Med Virol, 2002 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 transcriptase into the cytoplasm (Stage 2).^[16] These proteins and vRNA form a complex that is transported into the cell nucleus, where the RNA-dependent RNA transcriptase begins transcribing complementary positive-sense vRNA (Steps 3a and b).^[17] The vRNA 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.^[18]
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).^[19] 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. After the release of new influenza virus, the host cell dies.
Because of the absence of RNA proofreading enzymes, 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 mutation in its genome.^[20] The separation of the genome into eight separate segments of vRNA allows mixing or ''reassortment'' of the genes if more than one variety of influenza virus has infected the same cell. The resulting alteration in the genome segments packaged in to 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).^[21]

Terminology

Virus versus disease

Avian influenza is not a genus of Orthomyxoviridae.. The term "avian influenza" denotes a disease, not a virus. The orthomyxovirus family consists of 5 genera: Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus, and Thogotovirus. Influenzavirus A is not the same as "avian influenza": the former is a genus of viruses, the latter is an illness.

Genera versus species

Orthomyxoviridae include the following genera and species:

★ Genus ''Influenzavirus A''; type species: ''Influenza A virus''

★ Genus ''Influenzavirus B''; type species: ''Influenza B virus''

★ Genus ''Influenzavirus C''; type species: ''Influenza C virus''

★ Genus ''Isavirus''; type species: ''Infectious salmon anemia virus''

★ Genus ''Thogotovirus''; type species: ''Thogoto virus''

Categorization

In a phylogenetic-based taxonomy the "RNA viruses" includes the "negative-sense ssRNA viruses" which includes the Order "''Mononegavirales''", and the Family "''Orthomyxoviridae''" (among others), which includes the Genus "''Influenzavirus A''" which includes the Type Species "Influenza A virus".
The category "influenza virus" is the subset of orthomyxoviruses that cause influenza. This is not a phylogenetically based taxonomic category.
Influenza A viruses can be further classified, based on the viral surface proteins hemagglutinin (HA or H) and neuraminidase (NA or N) that are essential to the virus' life cycle. Sixteen H subtypes and nine N subtypes have been identified for influenza A virus. Only one H subtype and one N subtype have been identified for influenza B virus. At present, the most common antigenic variants of influenza A virus are H1N1 and H3N2 ^[22].

Diagram of influenza nomenclature.

Yet 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^{[23] [24]}.
Examples of the nomenclature are:
#A/Moscow/10/99 (H3N2)
#B/Hong Kong/330/2001
The term 'superflu' is used to refer to a strain of flu that spreads unusually quickly, is unusually virulent, or for which the host is uncommonly unresponsive to treatment — the kinds of strains which cause epidemics or pandemics. There is no exact scientific definition of a superflu.

Sources

1.
★ International Committee on Taxonomy of Viruses - 46.0.3.0.001 Thogoto virus

★ Non-viraemic transmission of Thogoto virus: influence of time and distance says "Previous studies have demonstrated that Thogoto virus is transmitted from infected to uninfected ticks when co-feeding on uninfected guinea-pigs, even though the guinea-pigs do not develop detectable viraemia. The dynamics of this 'non-viraemic transmission' were investigated. The percentage of nymphs (recipients) that acquired virus increased from zero, when co-feeding with infected adults (donors) for 3 d, to 80% for a co-feeding period of 5 d. No statistically significant difference was detected when infected donors and uninfected recipients were separated physically up to a maximum distance of approximately 160 mm. These results indicate that the temporal, but not the spatial, relationship affects the number of recipient ticks that become infected."

★ Molecular Biology of Orthomyxoviruses

2.
★ Ely, B. Infectious Salmon Anaemia. Mill Hill Essays, National Institute for Medical Research says "More recently the sea-louse, a small marine crustacean that attacks the protective mucous, scales and skin of the salmon has been shown to transmit Infectious Salmon Anaemia virus. Sea lice have often been called the greatest enemy of farmed salmon and farmers have constantly to work against lice infestations of their fish. It is not known whether the Infectious Salmon Anaemia virus can reproduce itself in the sea louse in the way that viruses seem to do within the ticks that carry other diseases."

★ Raynard RS, Murray AG, Gregory A (2001) Infectious salmon anaemia virus in wild fish from Scotland, Diseases of Aquatic Organisms, Vol. 46: 93-100
3. FAO article in English with non-English title ''Epidemiología de la influenza aviar''
4. Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome., Fouchier R, Schneeberger P, Rozendaal F, Broekman J, Kemink S, Munster V, Kuiken T, Rimmelzwaan G, Schutten M, Van Doornum G, Koch G, Bosman A, Koopmans M, Osterhaus A, , , Proc Natl Acad Sci U S A, 2004
5. Influenza B virus in seals., Osterhaus A, Rimmelzwaan G, Martina B, Bestebroer T, Fouchier R, , , Science, 2000
6. Comparison of the mutation rates of human influenza A and B viruses., Nobusawa E, Sato K, , , J Virol, 2006
7. Antigenic and genetic characterization of influenza C viruses which caused two outbreaks in Yamagata City, Japan, in 1996 and 1998., Matsuzaki Y, Sugawara K, Mizuta K, Tsuchiya E, Muraki Y, Hongo S, Suzuki H, Nakamura K, , , J Clin Microbiol, 2002
8. Clinical features of influenza C virus infection in children., Matsuzaki Y, Katsushima N, Nagai Y, Shoji M, Itagaki T, Sakamoto M, Kitaoka S, Mizuta K, Nishimura H, , , J Infect Dis, 2006
9. An outbreak of type C influenza in a children's home., Katagiri S, Ohizumi A, Homma M, , , J Infect Dis, 1983
10. International Committee on Taxonomy of Viruses descriptions of: Orthomyxoviridae Influenzavirus B Influenzavirus C
11. The Universal Virus Database, version 4: Influenza A International Committee on Taxonomy of Viruses
12. Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses., Suzuki Y, , , Biol Pharm Bull, 2005
13. Recent strategies in the search for new anti-influenza therapies., Wilson J, von Itzstein M, , , Curr Drug Targets, 2003
14. The effect of various disinfectants on detection of avian influenza virus by real time RT-PCR, , D, Suarez, Avian Dis, 2003
15. Avian Influenza (Bird Flu): Implications for Human Disease. Physical characteristics of influenza A viruses. UMN CIDRAP.
16. Visualizing infection of individual influenza viruses., Lakadamyali M, Rust M, Babcock H, Zhuang X, , , Proc Natl Acad Sci U S A, 2003
17. Trafficking of viral genomic RNA into and out of the nucleus: influenza, Thogoto and Borna disease viruses., Cros J, Palese P, , , Virus Res, 2003
18. Hijacking of the host-cell response and translational control during influenza virus infection., Kash J, Goodman A, Korth M, Katze M, , , Virus Res, 2006
19. Assembly and budding of influenza virus., Nayak D, Hui E, Barman S, , , Virus Res, 2004
20. Rates of spontaneous mutation among RNA viruses., Drake J, , , Proc Natl Acad Sci U S A, 1993
21. http://www.bestonlinedictionary.com/medical-terms-dictionary/medical-dictionary-a/an/Antigenic%20shift.htm
22. (Yohannes et al., 2004)
23. http://www.cdc.gov/nip/publications/pink/flu.pdf Epidemiology & Prevention of Vaccine-Preventable Diseases,"The Pink Book", 9th Edition. 2006. National Immunization Program, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services
24. http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/biofacts/avflu_human.html
Avian Influenza (Bird Flu): Implications for Human Disease (CIDRAP) - see 8th main bullet point from top


★ International Committee on Taxonomy of Viruses - 00.046. Orthomyxoviridae

★ ICTV approved Virus Orders, Families and Genera