Influenza classification

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Overview
Influenza, commonly known as flu, is an infectious disease of birds and mammals caused by RNA viruses of the biological family Orthomyxoviridae (the influenza viruses). In humans, common symptoms of influenza infection are fever, sore throat, muscle pains, severe headache, coughing, weakness and general discomfort.

Influenza virus classification


The influenza virus is an RNA virus of the family Orthomyxoviridae, which comprises the influenzaviruses, Isavirus, and Thogotovirus. There are three types of influenza virus: Influenzavirus A, Influenzavirus B, and Influenzavirus C. Influenza A and C infect multiple species, while influenza B almost exclusively infects humans. Wild aquatic birds are the natural hosts for a large variety of influenza A viruses. Occasionally viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics. The type A viruses are the most virulent human pathogens among the three influenza types and cause 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 2007–8 flu season.
 * H7N7 has unusual zoonotic potential.
 * 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. 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. However, influenza B mutates enough that lasting immunity is not possible. 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.

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 and properties
The following applies for Influenza A viruses, although other strains are very similar in structure:

The influenza A virus particle or virion is 80–120 nm in diameter and usually roughly spherical, although filamentous forms can occur. 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 10 proteins (HA (hemagglutinin), NA (neuraminidase), NP (nucleoprotein), M1, M2, NS1, PA, PB1, PB1-F2, PB2). 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. The hemagglutinin (HA or H) and neuraminidase (NA or N) proteins are targets for antiviral drugs. 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.

Infection and replication


Influenza viruses bind through hemagglutinin onto sialic acid sugars on the surfaces of epithelial cells; typically in the nose, throat and lungs of mammals and intestines of birds (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 transcriptase 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 vRNA (Steps 3a and b). 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.

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.

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. 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. This is important in the emergence of pandemics, as discussed in Epidemiology.