When pigs fly: the avian origin of a 'swine flu'.

The recent emergence of a novel H1N1 ‘swine flu’ and the H5N1 ‘avian flu’ has thrown into sharp relief the importance of natural populations of influenza viruses in predicting pandemic influenza. The influenza A virus has the potential to cause high levels of mortality in humans, and in contrast to its less virulent relatives, influenza B and C, influenza A virus is repeatedly reintroduced into the human population from animal reservoirs. Influenza A viruses possess an RNA genome that encodes 10 genes and are divided into eight segments. Segments might be viewed as individual chromosomes, each containing only one or two genes. Two of the gene products, haemagglutinin (HA) and neuroaminidase (NA), have antigenic potential (i.e. the ability to elicit an antibody response from its host). The name of an influenza subtype refers to the specific HA and NA alleles (e.g. H1N1 ‘1918 Spanish flu’, H3N2 ‘1968 Hong Kong flu’, H5N1 ‘avian flu’). Subtypes were traditionally distinguished by the inability of neutralizing antibodies to cross-react among them. So far, 16 HA and 9 NA antigenic subtypes have been identified (Dugan et al., 2008). Influenza virus generates variation via two processes: mutation and reassortment. Mutation allows for escape from the host immune system and has produced a diverse array of subtypes, possibly over the last several thousand years (Chen and Holmes, 2006). This gradual change is called ‘antigenic drift’ (but note that this nomenclature is slightly misleading because antigenic drift can be the product of natural selection, rather than genetic drift). Reassortment, a truly impressive evolutionary feature by which the influenza virus generates variation, is the exchange of genomic segments and can occur between distantly related lineages. This genetic exchange usually involves whole genomic segments; homologous recombination appears to be exceptionally rare within influenza gene segments (Boni et al., 2008). When two distantly related influenza subtypes, say H9N2 and H7N3, simultaneously infect a single host cell, they can reassort to produce novel antigenic combinations, such as H9N3 and H7N2; other segments not containing the HA and NA genes can also reassort, creating highly mosaic viral genomes. When reassortment occurs in NA and HA segments, it is termed ‘antigenic shift’ because it introduces a novel antigenic profile into a genetic background. Although influenza A virus has been found in a diverse array of animals, including birds, swine, horses, cats, aquatic mammals such as seals and whales, and humans (Webby et al., 2007), the viral genomic segments from each of these species have one thing in common: they can all be traced back to influenza in waterfowl and shorebirds, who act as the primary reservoirs of the virus (Webster et al., 1992). It is from these viral populations that all influenza A viruses originate (Olsen et al., 2006). In aquatic birds, influenza virus is generally asymptomatic and transmitted via the faecal-oral route. The virus remains viable in water for several days at ambient temperatures, providing an efficient mode of transmission (Webster et al., 1978). Moreover, influenza can spread over broad distances by the annual migrations of avian hosts (Olsen et al., 2006). These migrations result in both a greater range of the virus and its increased spread among various avian species. In fact, viruses isolated from multiple species at the same place and time are more likely to be closely related than viruses isolated from a single species at different places and/or times (Chen and Holmes, 2009). Avian influenza virus was once assumed to be in a sort of evolutionary stasis, in which the virus had reached a fitness maximum within its natural hosts (Webster et al., 1992; 2007). Sequence analysis of avian subtypes suggests that the opposite may be true. A study of Canadian ducks revealed that genetic subtypes in wild populations are constantly undergoing reassortment, thereby producing segments with a myriad of evolutionary histories (Hatchette et al., 2004). Due to extensive reassortment, there is no single phylogenetic tree of an influenza subtype, only a history of its genes. In addition, the substitution rate of influenza virus in birds is remarkably rapid, *For correspondence. E-mail wertheim@email.arizona. edu; Tel. (+1) 520 621 4881; Fax (+1) 520 621 9190. Environmental Microbiology (2009) 11(9), 2191–2192 doi:10.1111/j.1462-2920.2009. 02039.x