West Nile Virus - Where did It Come from and Where Might It Go?

Abstract

In October 1999, the Centers for Disease Control and Prevention (CDC) reported on an outbreak of human arboviral encephalitis in New York City, beginning in late August (1). The encephalitis was initially thought to be due to St Louis encephalitis (SLE) virus because of positive serological results from the cerebrospinal fluid (CSF) and serum of affected patients. At the same time, there was an increase in avian mortality including wild crows and exotic birds at the Bronx Zoo (2). Because avian mortality is not common with SLE, other pathogenic arboviruses were investigated as the cause of this unusual phenomenon. Subsequent DNA sequencing of human and avian viral isolates indicated that they were closely related to West Nile (WN) virus, not previously isolated in the Western Hemisphere (1). Serological testing of CSF and serum, including those specimens positive for SLE virus, from a number of patients was positive for antibody to WN virus (3). A new infectious disease had emerged in the Americas. WN virus is an arthropod-borne virus belonging to the Japanese encephalitis complex of the Flavivirus genus (4). Flaviviruses are lipid-enveloped, single stranded RNA viruses, with a genome of approximately 11,000 nucleotides. Flaviviruses belong to the family Flaviviridae with Pestivirus (of veterinary importance) being the other genus in this family. There are over 68 viruses in this genus, of which 30 are known to cause human disease (5). Within the genus, the flaviviruses are classified into distinct species or serotypes by antigenic distinctions. There are at least eight antigenic complexes, six of which contain human pathogens. Japanese encephalitis, SLE, Murray Valley encephalitis, Kunjin, Kokobera, Koutango, Usutu and WN viruses all belong to the Japanese encephalitis complex (4). Viruses within the Japanese encephalitis complex share up to 77% of their amino acid sequences, resulting in cross-reactive serological tests and providing an explanation for the original identification of the outbreak as due to SLE virus. Although the Flaviviruses are closely related antigenically and cross-react in serological tests with polyclonal antisera, most have a distinctive geographical distribution (6). WN virus was first isolated in the WN province of Uganda in 1937 (7). The first recorded epidemics were reported in Israel in the 1950s (8,9) and in Europe in 1962 (1). Sporadic cases and outbreaks have been reported from Africa (10,11), India (12) and Romania (13). The virus is the most widely distributed of the arboviruses, causing infections in Africa, the Middle East and South Asia, where it is endemic, and in Europe more sporadically (13-15). However, it had never been identified in the Americas before 1999. A closely related serotype, Kunjin, has been found in Australia and Southeast Asia (15). Subtypes of WN virus are distinguished by antigenic variations in the envelope (E) protein and the presence of an N-glycosylation site at amino acids 154 to 156 (16). Two lineages have been proposed: lineage I includes Kunjin and WN virus from Europe, the Middle East, and North, Central and West Africa; and lineage II includes WN virus from West, Central and East Africa, and Madagascar. The complete nucleotide sequence of one of the viral isolates (from the dead Chilean flamingo at the Bronx zoo) was determined (6). Analysis showed it to be a lineage I WN virus (16), and most closely related to WN virus isolated recently from North Africa, Romania, Kenya, Italy and the Middle East (6). Lanciotti et al (6) demonstrated a high degree of sequence similarity among the various strains circulating throughout New York City and surrounding counties and states. The ecology of WN virus has recently been described by Hubalek and Halouzka (15). Similar to other Flaviviruses, WN virus has an arthropod vector, which serves as a true biological vector. Mosquitoes, mainly bird-feeding species, are the principal vectors. WN virus has been isolated from 43 mosquito species, predominantly Culex but also Aedes and Anopheles species. Experimental and field evidence demonstrates vertical transmission from parent to offspring mosquitoes (17-19). While the exact role of vertical transmission is