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.

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.

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' terminal 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 Serotypes
Genus / 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

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:

1.  A/Brazliane/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 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 A 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.

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