Genetic variation in OAS1 is a risk factor for initial infection with West Nile virus in man.
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.
Lim
Jean K
JK
Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
Lisco
Andrea
A
McDermott
David H
DH
Huynh
Linda
L
Ward
Jerrold M
JM
Johnson
Bernard
B
Johnson
Hope
H
Pape
John
J
Foster
Gregory A
GA
Krysztof
David
D
Follmann
Dean
D
Stramer
Susan L
SL
Margolis
Leonid B
LB
Murphy
Philip M
PM
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D016009:Chi-Square Distribution; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007150:Immunohistochemistry; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D014066:Palatine Tonsil / Q000378:metabolism / Q000821:virology; D020641:Polymorphism, Single Nucleotide; D012367:RNA, Viral / Q000378:metabolism; D046509:Tissue Culture Techniques; D014779:Virus Replication; D014901:West Nile Fever / Q000235:genetics* / Q000821:virology*; D014902:West Nile virus / Q000502:physiology*
D012367:RNA, Viral; C475085:OAS1 protein, human; D015088:2',5'-Oligoadenylate Synthetase