West Nile Virus Inhibits the Signal Transduction P
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病菌学杂志 2005年第3期
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania
ABSTRACT
West Nile virus (WNV) is a human pathogen that can cause neurological disorders, including meningoencephalitis. Experiments with mice and mammalian cell cultures revealed that WNV exhibited resistance to the innate immune program induced by alpha interferon (IFN-). We have investigated the nature of this inhibition and have found that WNV replication inhibited the activation of many known IFN-inducible genes, because it prevented the phosphorylation and activation of the Janus kinases JAK1 and Tyk2. As a consequence, activation of the transcription factors STAT1 and STAT2 did not occur in WNV-infected cells. Moreover, we demonstrated that the viral nonstructural proteins are responsible for this effect. Thus, our results provided an explanation for the observed resistance of WNV to IFN- in cells of vertebrate origin.
INTRODUCTION
West Nile virus (WNV) is an enveloped positive-strand RNA virus which, along with other mosquito-borne human pathogenic viruses, including Yellow fever virus and dengue viruses, belongs to the genus Flavivirus in the family Flaviviridae (3). WNV infects migratory and other birds, which produce high virus titers in their blood and thereby permit transmission of the virus to mosquitoes and, eventually, to humans. Although WNV was isolated from an individual in Uganda more than 6 decades ago, it has been recognized as a major human pathogen only recently, when outbreaks of human encephalitis were reported in Romania, Russia, Israel, and, in particular, in New York City in 1999 (1, 19, 31). Subsequently, the virus has spread throughout the continental United States. Whether recent disease outbreaks were a consequence of the emergence of new, pathogenic WNV strains or reflected a lack of immunity in the population is not yet known. Phylogenetic analyses based on the nucleotide sequence of a segment of the envelope gene led to the classification of WNV isolates into two lineages (19). This analysis also revealed a close relationship among the WNV isolates involved in the recent outbreaks in the western hemisphere.
Infectious cDNA clones were first reported for Kunjin virus, a subtype of WNV belonging to lineage 1, and later for two WNV isolates representing both lineages (16, 32, 36). The genomes are approximately 11 kb long and contain a large open reading frame that is flanked by noncoding regions containing the promoters for RNA-dependent RNA synthesis (3, 35). The polyprotein is processed into 10 polypeptides by cellular and viral proteases. Three of these products are struct
ABSTRACT
West Nile virus (WNV) is a human pathogen that can cause neurological disorders, including meningoencephalitis. Experiments with mice and mammalian cell cultures revealed that WNV exhibited resistance to the innate immune program induced by alpha interferon (IFN-). We have investigated the nature of this inhibition and have found that WNV replication inhibited the activation of many known IFN-inducible genes, because it prevented the phosphorylation and activation of the Janus kinases JAK1 and Tyk2. As a consequence, activation of the transcription factors STAT1 and STAT2 did not occur in WNV-infected cells. Moreover, we demonstrated that the viral nonstructural proteins are responsible for this effect. Thus, our results provided an explanation for the observed resistance of WNV to IFN- in cells of vertebrate origin.
INTRODUCTION
West Nile virus (WNV) is an enveloped positive-strand RNA virus which, along with other mosquito-borne human pathogenic viruses, including Yellow fever virus and dengue viruses, belongs to the genus Flavivirus in the family Flaviviridae (3). WNV infects migratory and other birds, which produce high virus titers in their blood and thereby permit transmission of the virus to mosquitoes and, eventually, to humans. Although WNV was isolated from an individual in Uganda more than 6 decades ago, it has been recognized as a major human pathogen only recently, when outbreaks of human encephalitis were reported in Romania, Russia, Israel, and, in particular, in New York City in 1999 (1, 19, 31). Subsequently, the virus has spread throughout the continental United States. Whether recent disease outbreaks were a consequence of the emergence of new, pathogenic WNV strains or reflected a lack of immunity in the population is not yet known. Phylogenetic analyses based on the nucleotide sequence of a segment of the envelope gene led to the classification of WNV isolates into two lineages (19). This analysis also revealed a close relationship among the WNV isolates involved in the recent outbreaks in the western hemisphere.
Infectious cDNA clones were first reported for Kunjin virus, a subtype of WNV belonging to lineage 1, and later for two WNV isolates representing both lineages (16, 32, 36). The genomes are approximately 11 kb long and contain a large open reading frame that is flanked by noncoding regions containing the promoters for RNA-dependent RNA synthesis (3, 35). The polyprotein is processed into 10 polypeptides by cellular and viral proteases. Three of these products are struct