title: Screen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis.
abstract: Melioidosis is a severe infection caused by the flagellated bacterium Burkholderia pseudomallei. The nonsense polymorphism TLR51174C>T is associated with improved outcome in Thais with melioidosis. We hypothesized that other TLR5 variants may modulate the host response and determine outcome in melioidosis. We genotyped 12 TLR5 variants selected de novo from the HapMap database and examined the association of each with cytokines induced by flagellin stimulation of whole blood from healthy Thai subjects. We found a blunted cytokine response for three related markers that were in linkage disequilibrium (LD) with a non-synonymous variant, TLR51846T>C. Carriers of TLR51846T>C had broadly impaired cytokine responses induced by flagellin. TLR51846T>C was associated with protection against death in melioidosis patients (odds ratio: 0.62, 95% confidence interval: 0.42-0.93, P=0.021). We observed no impairment in TLR51846C-dependent nuclear factor κB activation, however, suggesting an alternative mechanism for the effect. We found that TLR51846T>C was in strong LD with TLR51174C>T. Many of the blunted cytokine responses observed and the association of TLR51846T>C with survival in melioidosis patients may be attributable to TLR51174C>T, but we could not exclude an independent effect of TLR51846T>C. These data identify novel associations for TLR51846T>C, enhance our understanding of TLR5 genetic architecture in Thais and highlight the role of TLR5 in melioidosis.
authors.affiliation: 1] Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand [2] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: N
authors.initials: N
authors.lastname: Chantratita
authors.affiliation: 1] Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand [2] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: S
authors.initials: S
authors.lastname: Tandhavanant
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: N D
authors.initials: ND
authors.lastname: Myers
authors.affiliation: 1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand [2] Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: W
authors.initials: W
authors.lastname: Chierakul
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Robertson
authors.affiliation: Department of Medicine, Sappasithiprasong Hospital, Ubon Ratchathani, Thailand.
authors.forename: W
authors.initials: W
authors.lastname: Mahavanakul
authors.affiliation: Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: P
authors.initials: P
authors.lastname: Singhasivanon
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Emond
authors.affiliation: 1] Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand [2] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand [3] Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: S J
authors.initials: SJ
authors.lastname: Peacock
authors.affiliation: 1] Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA, USA [2] International Respiratory and Severe Illness Center, University of Washington, Seattle, WA, USA.
authors.forename: T E
authors.initials: TE
authors.lastname: West
mesh_terms: D000328:Adult; D016957:Burkholderia pseudomallei / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000097:blood; D005260:Female; D005408:Flagellin / Q000276:immunology*; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D015810:Linkage Disequilibrium; D008297:Male; D008554:Melioidosis / Q000097:blood / Q000276:immunology / Q000401:mortality*; D016328:NF-kappa B / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D012486:Salmonella typhimurium / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051198:Toll-Like Receptor 5 / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D016207:Cytokines; D016328:NF-kappa B; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D005408:Flagellin