Abstract
West Nile virus (WNV) is a re-emerging pathogen that can cause fatal encephalitis. In mice, susceptibility to WNV has been reported to result from a single point mutation in oas1b, which encodes 2′–5′ oligoadenylate synthetase 1b, a member of the type I interferon-regulated OAS gene family involved in viral RNA degradation. In man, the human ortholog of oas1b appears to be OAS1. The ‘A’ allele at SNP rs10774671 of OAS1 has previously been shown to alter splicing of OAS1 and to be associated with reduced OAS activity in PBMCs. Here we show that the frequency of this hypofunctional allele is increased in both symptomatic and asymptomatic WNV seroconverters (Caucasians from five US centers; total n = 501; OR = 1.6 [95% CI 1.2–2.0], P = 0.0002 in a recessive genetic model). We then directly tested the effect of this SNP on viral replication in a novel ex vivo model of WNV infection in primary human lymphoid tissue. Virus accumulation varied markedly among donors, and was highest for individuals homozygous for the ‘A’ allele (P<0.0001). Together, these data identify OAS1 SNP rs10774671 as a host genetic risk factor for initial infection with WNV in humans.
Highlights
West Nile virus (WNV) is a re-emerging flavivirus transmitted by mosquitoes to several species of birds
Structure and function of OAS1 SNP rs10774671 To investigate the role of the oligoadenylate synthetase (OAS) system in controlling outcome after WNV exposure in man, we scanned the OAS1 gene for known polymorphisms that occur in this region
This is based on association of the OAS1 ‘A’ allele at SNP rs10774671, which has previously been associated with low OAS enzymatic activity, with seropositivity for WNV using recessive and additive genetic models on patient samples collected from five US centers
Summary
West Nile virus (WNV) is a re-emerging flavivirus transmitted by mosquitoes to several species of birds. In the Western Hemisphere, it was first isolated from a patient during an outbreak of meningoencephalitis in New York in 1999 [2,3,4]. Since it has rapidly spread across the United States into Canada and Central and South America, and has caused annual outbreaks of disease. In addition to human infections, the virus has caused significant morbidity and mortality in birds and horses
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