Virus and Host Determinants of West Nile Virus Pathogenesis

West Nile virus (WNV) is a small, enveloped, mosquitotransmitted, positive-stranded RNA virus of the Flaviviridae family. This virus is related to other arthropod-borne viruses that cause human disease globally, including dengue, yellow fever, and Japanese encephalitis viruses. WNV cycles in nature primarily between Culex mosquitoes and birds, but also infects human, horses, and other vertebrates. Over the latter half of the 20th century, outbreaks of WNV infection have been reported in Europe, Asia, and Australia. In 1999, WNV was introduced into the Western Hemisphere in New York City. Early during the WNV epidemic in the United States, it became apparent that certain species of birds, including crows, blue jays, and ravens, were vulnerable to lethal infection. This phenotype was not described in prior outbreaks in other parts of the world. Genome sequencing combined with reverse genetic approaches has provided some insight as to why WNV became virulent for some avian species. Although the exact molecular mechanism remains uncertain, a single amino acid change in the NS3 helicase in North American WNV isolates gene associates with pathogenesis in crows [1]. After its entry into North America, there was an initial period of sequence conservation among strains. However, by 2002, two sequence subtypes were detected, one of which differed in the envelope (E) protein at amino acid 159 (WNV 2002). WNV 2002 has emerged as the dominant WNV genotype in North America. Experiments in mosquitoes have begun to explain why this strain displaced WNV 1999 and promoted the rapid spread across the continent. The change at residue 159 allows greater viral replication in the mosquito at higher temperatures, which translates into higher transmission of the virus to birds, the natural vertebrate host of WNV [2,3]. Thus, a single amino acid change in WNV has led to rapid geographic expansion and increased intensity of transmission.