Genetic Mutations and the Spread of Influenza Worldwide

The spread of influenza worldwide is a huge public health threat. The statistics alone for the United States are staggering. Each year in the US, an average of about 36,000 people die from influenza, and 200,000 people are hospitalized as a result of infection (CDC web site).

Influenza viruses are enveloped viruses belonging to the Orthomyxoviridae family. There are three types of influenza viruses, A, B, and C. Influenza A and B viruses are major causes of epidemics in humans. The A and B viruses contain a genome of eight negative-stranded RNA segments. The eight segments in influenza A viruses encode proteins including haemagglutinin (HA), matrix protein (M), neuraminidase (NA), nucleoprotein (NP), nonstructural protein (NS), polymerase basic 1 protein (PB1), polymerase basic 2 protein (PB2), and polymerase acidic protein (PA).

Genetic sequence mutations in influenza are important to study the associations between the structure and function of influenza viruses. These mutations are closely related to phenotypic changes, such as attenuation, drug resistance, and increased virulence. For example, the influenza A virus can be attenuated when alternative base pairs are introduced into the duplex region of the conserved viral RNA promoter of either the NS or the PA gene segments (Catchpole et al., 2003). Mutations in the HA segment can result in a virus resistant to NA inhibitors such as BCX-140 (Bantia et al., 1998).

Another example is that a group of mutations can convert an avirulent virus to a virulent variant. For instance, patterns of the mutations have been found in virulent variants of A/Hong Kong strains. These mutations are involved in nuclear localization signals and the interactions between the protein and RNA, which may be responsible for increased virulence (Brown et al., 2001).

The analyses of patterns of mutations that lead to attenuation would be helpful for designing new influenza vaccines and countering the spread of influenza worldwide. The discovery of patterns of mutations that cause increased virulence can help identify virulence genes and enhance our knowledge of molecular mechanisms of virulence in influenza virus, which is still largely unknown. Information on patterns of structural changes that result in the resistance to viral inhibitors can help overcome the drug resistance and improve the design of anti-viral drugs.

The above examples suggest that the discovery of patterns of genetic mutations may provide better insight into the structure-function relationship in influenza viruses. These analyses can help us track the structural variations and analyze the relevant functional changes.

Bantia, S., Ghate, A.A., Ananth, S.L., Babu, Y.S., Air, G.M., Walsh, G.M. (1998) Generation and characterization of a mutant of influenza A virus selected with the neuraminidase inhibitor BCX-140. Antimicrob Agents Chemother. 42, 801-807.

Brown, E.G., Liu, H., Kit, L.C., Baird, S., Nesrallah, M. (2001) Pattern of mutation in the genome of influenza A virus on adaptation to increased virulence in the mouse lung: identification of functional themes. Proc Natl Acad Sci U S A. 5, 6883-6888.

Catchpole, A.P., Mingay, L.J., Fodor, E., Brownlee, G.G. (2003) Alternative base pairs attenuate influenza A virus when introduced into the duplex region of the conserved viral RNA promoter of either the NS or the PA gene. J Gen Virol. 84, 507-515.

The Centers for Disease Control and Prevention (CDC) Web site: http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm