Orthomyxoviridae
The Orthomyxoviridae (influenza viruses) are a major determinant of morbidity and mortality caused by respiratory disease, and outbreaks of infection sometimes occur in worldwide epidemics. Influenza has been responsible for millions of deaths worldwide. Mutability and high frequency of genetic reassortment and resultant antigenic changes in the viral surface glycoproteins make influenza viruses formidable challenges for control efforts. Influenza type A is antigenically highly variable and is responsible for most cases of epidemic influenza. Influenza type B may exhibit antigenic changes and sometimes causes epidemics. Influenza type C is antigenically stable and causes only mild illness in immunocompetent individuals.
The Orthomyxoviridae (orthos, Greek for "straight"; myxa, Greek for "mucus")are a family of RNA viruses that includes five genera: Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus and Thogotovirus. .The first three genera contain viruses that cause influenza in vertebrates, including birds, humans, and other mammals. Isaviruses infect salmon; thogotoviruses infect vertebrates and invertebrates, such as mosquitoes and sea lice.
The three genera of Influenzavirus, which are identified by antigenic differences in their nucleoprotein and matrix protein infect vertebrates .
Properties of Orthomyxoviruses
Important properties of Influenza viruses are summarized as following :
Virion: Spherical, pleomorphic, 80–120 nm in diameter (helical nucleocapsid, 9 nm)Composition: RNA (1%), protein (73%), lipid (20%), carbohydrate (6%)
Genome: Single-stranded RNA, segmented (eight molecules), negative-sense, 13.6 kb overall size
Proteins: Nine structural proteins, one nonstructural
Envelope: Contains viral hemagglutinin (HA) and neuraminidase (NA) proteins
Replication: Nuclear transcription; capped 5' termini of cellular RNA scavenged as primers; particles mature by budding from plasma membrane
Outstanding characteristics:
Genetic reassortment common among members of the same genus
Influenza viruses cause worldwide epidemics
Classification
In a phylogenetic-based taxonomy the "RNA viruses" includes the "negative-sense ssRNA viruses" which includes the Order "Mononegavirales", and the Family "Orthomyxoviridae" . The genera-associated species and serotypes of Orthomyxoviridae are shown in the following table.
Orthomyxoviridae Genera, Species, and SerotypesGenus / Species (* indicates type species) / Serotypes or Subtypes / Hosts
Influenzavirus A / Influenza A virus* / H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2, H10N7 / Human, pig, bird, horse
Influenzavirus B / Influenza B virus* / Human, seal
Influenzavirus C / Influenza C virus* / Human, pig
Isavirus / Infectious salmon anemia virus* / Atlantic salmon
Thogotovirus / Thogoto virus* / Tick, mosquito, mammal (including human)
Dhori virus / Batken virus, Dhori virus
Quaranfil virus, Johnston Atoll virus, Lake Chad virus
Types
There are three genera of influenza virus: Influenzavirus A, Influenzavirus B and Influenzavirus C. Each genus includes only one species, or type: Influenza A virus, Influenza B virus, and Influenza C virus, respectively. Influenza A and C infect multiple species, while influenza B almost exclusively infects humans.
Influenza A
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.
Examples of the nomenclature are:
- A/Brisbane/59/2007 (H1N1)
- A/Moscow/10/99 (H3N2)
The type A viruses are the most virulent human pathogens among the three influenza types and causes the most severe disease. The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:
- H1N1 caused "Spanish Flu" in 1918, "Swine flu" in 2009.
- H2N2 caused "Asian Flu".
- H3N2 caused "Hong Kong Flu".
- H5N1 is a pandemic threat.
- H7N7 has unusual zoonotic potential
- H1N2 is endemic in humans and pigs.
- H9N2, H7N2, H7N3, H10N7.
Influenza B
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. This type of influenza mutates at a rate 2-3 times lower than type Aand consequently is less genetically diverse, with only one influenza B serotypeAs 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. This reduced rate of antigenic change, combined with its limited host range
Influenza C
The influenza C virus infects humans and pigs, and can cause severe illness and local epidemics. However, influenza C is less common than the other types and usually seems to cause mild disease in children.
Structure & Function of Hemagglutinin
The HA protein of influenza virus binds virus particles to susceptible cells and is the major antigen against which neutralizing (protective) antibodies are directed. Variability in HA is primarily responsible for the continual evolution of new strains and subsequent influenza epidemics. Hemagglutinin derives its name from its ability to agglutinate erythrocytes under certain conditions.
The amino acid sequence for HA can be calculated from the sequence of the HA gene, and the three-dimensional structure of the protein has been revealed by x-ray crystallography, so it is possible to correlate functions of the HA molecule with its structure.
The primary sequence of HA contains 566 amino acids A short signal sequence at the amino terminal inserts the polypeptide into the endoplasmic reticulum; the signal is then removed. The HA protein is cleaved into two subunits, HA1 and HA2, that remain tightly associated by a disulfide bridge. A hydrophobic stretch near the carboxyl terminal of HA2 anchors the HA molecule in the membrane, with a short hydrophilic tail extending into the cytoplasm. Oligosaccharide residues are added at several sites.
Structure & Function of Neuraminidase
The antigenicity of NA, the other glycoprotein on the surface of influenza virus particles, is also important in determining the subtype of influenza virus isolates.
The spike on the virus particle is a tetramer, composed of four identical monomers . A slender stalk is topped with a box-shaped head. There is a catalytic site for NA on the top of each head, so that each NA spike contains four active sites.
The NA functions at the end of the viral replication cycle. It is a sialidase enzyme that removes sialic acid from glycoconjugates. It facilitates release of virus particles from infected cell surfaces during the budding process and helps prevent self-aggregation of virions by removing sialic acid residues from viral glycoproteins. It is possible that NA helps the virus negotiate through the mucin layer in the respiratory tract to reach the target epithelial cells
Life 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. 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.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). 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). 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 cRNA (Steps 3a and b). 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.
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). 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.
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 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 (antigenic shift is a property of influenza virus and results in the sudden appearance of a serotypec which has a potential to cause a pandemic ( major antigenic changes in HA or NA ).while the antigenic drift that occurs within a serotype such as H1N1 resulted in appearance of aviriant with minor antigenic differences from parent strainis due to the accumulation of point mutations in the gene resulting in amino acid changes in the protein )
Clinical Findings
Uncomplicated Influenza , Pneumonia , Reye's Syndrome
Serology
Antibodies to several viral proteins (hemagglutinin, neuraminidase, nucleoprotein, and matrix) are produced during infection with influenza virus. The immune response against the HA glycoprotein is associated with resistance to infection.
Treatment