Significance of the myxovirus resistance A (MxA) gene -123C>a single-nucleotide polymorphism in suppressed interferon beta induction of severe acute respiratory syndrome coronavirus infection.
Myxovirus resistance A (MxA) is an antiviral protein induced by interferon alpha and beta (IFN-alpha, IFN-beta) that can inhibit viral replication. The minor alleles of the -88G>T and -123C>A MxA promoter single-nucleotide polymorphisms (SNPs) are associated with increased promoter activity and altered response to IFN-alpha and IFN-beta treatment. Here, we demonstrate that the -123A minor allele provided stronger binding affinity to nuclear proteins extracted from IFN-beta-untreated cells than did the wild-type allele, whereas the -88T allele showed preferential binding after IFN-beta stimulation. Endogenous IFN-alpha and IFN-beta induction can be suppressed in severe acute respiratory syndrome (SARS) coronavirus infection. In support of our in vitro findings, a large case-control genetic-association study for SARS coronavirus infection confirmed that the -123A minor-allele carriers were significantly associated with lower risk of SARS coronavirus infection, whereas the -88T minor-allele carriers were insignificant after adjustment for confounding effects. This suggests that -123C>A plays a more important role in modulating basal MxA expression, thus contributing more significantly to innate immune response against viral infections that suppress endogenous IFN-alpha and IFN-beta induction such as SARS coronavirus.
Ching
Johannes Chi-Yun
JC
Department of Pathology, University of Hong Kong, Princess Margaret Hospital, Hong Kong.
Chan
Kelvin Yuen Kwong
KY
Lee
Eric Hing Leung
EH
Xu
Mei-Shu
MS
Ting
Campbell Kam Po
CK
So
Thomas M K
TM
Sham
Pak C
PC
Leung
Gabriel M
GM
Peiris
Joseph S M
JS
Khoo
Ui-Soon
US
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000276:immunology; D016899:Interferon-beta / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D064547:Myxovirus Resistance Proteins; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology*; D045169:Severe Acute Respiratory Syndrome / Q000235:genetics* / Q000276:immunology; D055815:Young Adult
D016898:Interferon-alpha; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D016899:Interferon-beta; D019204:GTP-Binding Proteins
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