Genetic Variation in OAS1 Is a Risk Factor for Initial Infection with West Nile Virus in Man

PLoS Pathogens

Dean Follmann¹  Gregory A. Foster²  Susan L. Stramer²  David Krysztof²  John Pape³  Jerrold M. Ward⁴  Hope Johnson⁵  Bernard Johnson⁵  David H. McDermott⁶  Linda Huynh⁶  Jean K. Lim⁶  Philip M. Murphy⁶  Andrea Lisco⁷  Leonid B. Margolis⁷ 

[1] American Red Cross, Gaithersburg, Maryland, United States of America;Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America;Colorado Department of Public Health and Environment, Denver, Colorado, United States of America;Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America;Illinois Department of Public Health, Division of Laboratories, Chicago, Illinois, United States of America;Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America;Section on Intercellular Interactions, Laboratory of Cellular and Molecular Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: West Nile virus;    Molecular genetics;    Viral replication;    Variant genotypes;    Alleles;    Tonsils;    Lymphoid tissue;    Infectious disease control;   

DOI  :  10.1371/journal.ppat.1000321

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY