Orthomyxoviridae

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Orthomyxoviridae
Virus classification
Group: Group V ((-)ssRNA)
Family: Orthomyxoviridae
Genera

Influenzavirus A
Influenzavirus B
Influenzavirus C
Isavirus
Thogotovirus
Flu

The Orthomyxoviridae are a family of RNA viruses which, so far as is known, infect mainly vertebrates (Thogotovirus in ticks, Isavirus in the sea louse). It includes those viruses which cause influenza.

There are three genera of influenza virus, identified by antigenic differences in their nucleoprotein and matrix protein:

Known flu pandemics [1]
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
Structure of the influenza viron. 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).
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Structure of the influenza viron. 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).

Contents

[edit] 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.

[edit] 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.

[edit] 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.[2]

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.[2] The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:

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.[4] This type of influenza mutates at a rate 2-3 times lower than type A[5] and consequently is less genetically diverse, with only one influenza B serotype.[2] 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.[6] 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.[7]

The influenza C virus infects humans and pigs, and can cause severe illness and local epidemics.[8] However, influenza C is less common than the other types and usually seems to cause mild disease in children.[9][10]

[edit] Structure and properties

The following applies for Influenza A viruses, although other influenza strains are very similar in structure[11]:

The influenza A virus particle or virion is 80-120 nm in diameter and usually roughly spherical, although filamentous forms can occur.[12] 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).[13] 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.[14] The hemagglutinin (H) and neuraminidase (N) proteins are targets for antiviral drugs.[15] These proteins are also recognised by antibodies, i.e. they are antigens.[1] 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.
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Invasion and replication of the influenza virus. The steps in this process are discussed in the text.

[edit] Infection and replication

Influenza is spread by aerosol droplets expelled by infected people when they cough or sneeze. These infectious droplets are 0.5 to 5 µm in diameter and about 40,000 can be produced by a single sneeze.[16] When inhaled, the viruses bind through hemagglutinin onto sialic acid sugars on the surfaces of epithelial cells in the lung and throat (Stage 1 in infection figure).[17] 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).[18] 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).[19] 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.[20]

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).[21] 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.[17] 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 is a mutant.[22] The separation of the genome into eight separate segments of vRNA allows mixing or reassortment of vRNAs if more than one viral line has infected a single cell. The resulting rapid change in viral genetics produces antigenic shifts and allow the virus to infect new host species and quickly overcome protective immunity.[1]

[edit] Terminology

[edit] 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.

[edit] Genera versus species

Orthomyxoviridae include the following genera and species:

[edit] 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 [23].

Diagram of influenza nomenclature.
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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[24] [25].

Examples of the nomenclature are:

  1. A/Moscow/10/99 (H3N2)
  2. 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.

[edit] Sources

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  2. ^ a b c Hay A, Gregory V, Douglas A, Lin Y (Dec 29 2001). "The evolution of human influenza viruses." (PDF). Philos Trans R Soc Lond B Biol Sci 356 (1416): 1861-70. PMID 11779385.
  3. ^ 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 (2004). "Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome.". Proc Natl Acad Sci U S A 101 (5): 1356-61. PMID 14745020.
  4. ^ Osterhaus A, Rimmelzwaan G, Martina B, Bestebroer T, Fouchier R (2000). "Influenza B virus in seals.". Science 288 (5468): 1051-3. PMID 10807575.
  5. ^ Nobusawa E, Sato K (Apr 2006). "Comparison of the mutation rates of human influenza A and B viruses.". J Virol 80 (7): 3675-8. PMID 16537638.
  6. ^ Webster R, Bean W, Gorman O, Chambers T, Kawaoka Y (1992). "Evolution and ecology of influenza A viruses.". Microbiol Rev 56 (1): 152-79. PMID 1579108.
  7. ^ Zambon M (Nov 1999). "Epidemiology and pathogenesis of influenza.". J Antimicrob Chemother 44 Suppl B: 3-9. PMID 10877456.
  8. ^ Matsuzaki Y, Sugawara K, Mizuta K, Tsuchiya E, Muraki Y, Hongo S, Suzuki H, Nakamura K (2002). "Antigenic and genetic characterization of influenza C viruses which caused two outbreaks in Yamagata City, Japan, in 1996 and 1998.". J Clin Microbiol 40 (2): 422-9. PMID 11825952.
  9. ^ Matsuzaki Y, Katsushima N, Nagai Y, Shoji M, Itagaki T, Sakamoto M, Kitaoka S, Mizuta K, Nishimura H (May 1 2006). "Clinical features of influenza C virus infection in children.". J Infect Dis 193 (9): 1229-35. PMID 16586359.
  10. ^ Katagiri S, Ohizumi A, Homma M (Jul 1983). "An outbreak of type C influenza in a children's home.". J Infect Dis 148 (1): 51-6. PMID 6309999.
  11. ^ International Committee on Taxonomy of Viruses descriptions of: Orthomyxoviridae Influenzavirus B Influenzavirus C
  12. ^ International Committee on Taxonomy of Viruses. The Universal Virus Database, version 4: Influenza A.
  13. ^ 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 (Oct 20 2005). "Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution.". Nature 437 (7062): 1162-6. PMID 16208317.
  14. ^ Suzuki Y (2005). "Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses.". Biol Pharm Bull 28 (3): 399-408. PMID 15744059.
  15. ^ Wilson J, von Itzstein M (Jul 2003). "Recent strategies in the search for new anti-influenza therapies.". Curr Drug Targets 4 (5): 389-408. PMID 12816348.
  16. ^ Cole E, Cook C (1998). "Characterization of infectious aerosols in health care facilities: an aid to effective engineering controls and preventive strategies.". Am J Infect Control 26 (4): 453-64. PMID 9721404.
  17. ^ a b Wagner R, Matrosovich M, Klenk H (May-Jun 2002). "Functional balance between haemagglutinin and neuraminidase in influenza virus infections.". Rev Med Virol 12 (3): 159-66. PMID 11987141.
  18. ^ Lakadamyali M, Rust M, Babcock H, Zhuang X (Aug 5 2003). "Visualizing infection of individual influenza viruses.". Proc Natl Acad Sci U S A 100 (16): 9280-5. PMID 12883000.
  19. ^ Cros J, Palese P (Sep 2003). "Trafficking of viral genomic RNA into and out of the nucleus: influenza, Thogoto and Borna disease viruses.". Virus Res 95 (1-2): 3-12. PMID 12921991.
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  23. ^ (Yohannes et al., 2004)
  24. ^ 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
  25. ^ 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
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