Common human Toll-like receptor 4 polymorphisms--role in susceptibility to respiratory syncytial virus infection and functional immunological relevance.
Evidence suggests that Toll-like receptor 4 (TLR4) contributes to immune recognition of respiratory syncytial virus (RSV). The TLR4 gene harbours a polymorphism-Asp299Gly-previously associated with reduced TLR4 signalling. To understand of how host genetic variation influences the outcome of RSV infection in children, we examined the association between the TLR4 299Gly allele and severe RSV disease. By genotyping 236 children with RSV infection and 219 healthy controls we found no association between the risk of severe RSV infection and Asp299Gly polymorphisms (P>0.05), and we demonstrate that the TLR4 Asp299Gly genotype does not influence susceptibility to either RSV serotype A or B (P>0.05). Finally, examining the functional impact of the TLR4 Asp299Gly polymorphism (n=58), we demonstrate that proinflammatory cytokine production following TLR4 activation was indistinguishable between homozygous (Asp/Asp) and heterozygous (Asp/Gly) subjects. We conclude that the Asp299Gly TLR4 polymorphism does not alter receptor function and does not influence the risk of severe RSV infection.
Paulus
Stéphane C
SC
Department of Pediatrics, BC Children's Hospital and Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
Hirschfeld
Aaron F
AF
Victor
Rachel E
RE
Brunstein
John
J
Thomas
Eva
E
Turvey
Stuart E
SE
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D020641:Polymorphism, Single Nucleotide; D018357:Respiratory Syncytial Virus Infections / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology*; D012307:Risk Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha