T. Eoin WestNarisara ChantratitaWirongrong ChierakulDirek LimmathurotsakulVanaporn WuthiekanunNicolle D. MyersMary J. EmondMark M. WurfelThomas R. HawnSharon J. PeacockShawn J. SkerrettHarborview Medical CenterUniversity of Washington, SeattleMahidol UniversityUniversity of Cambridge2018-10-192018-10-192013-04-01Journal of Immunology. Vol.190, No.7 (2013), 3373-337915506606002217672-s2.0-84875412590https://repository.li.mahidol.ac.th/handle/20.500.14594/31935Melioidosis is infection caused by the flagellated saprophyte Burkholderia pseudomallei. TLR5 is a pathogen recognition receptor activated by bacterial flagellin. We studied a genetic variant that encodes a defective TLR5 protein, TLR51174C>T, to elucidate the role of TLR5 in melioidosis. We measured NF-κB activation induced by B. pseudomallei in human embryonic kidney-293 cells transfected with TLR5 and found that B. pseudomallei induced TLR51174C-but not TLR51174T-dependent activation of NF-κB. We tested the association of TLR51174C>Twith outcome in 600 Thai subjects with melioidosis. In a dominant model, TLR51174C>Twas associated with protection against in-hospital death (adjusted odds ratio: 0.20; 95% confidence interval: 0.08-0.50; p = 0.001) and organ failure (adjusted odds ratio: 0.37; 95% confidence interval: 0.19-0.71; p = 0.003). We analyzed blood cytokine production induced by flagellin or heat-killed B. pseudomallei by TLR51174C>Tgenotype in healthy subjects. Flagellin induced lower monocyte-normalized levels of IL-6, IL-8, TNF-α, IL-10, MCP-1, IL-1ra, G-CSF, and IL-1β in carriers of TLR51174Tcompared with carriers of TLR51174C. B. pseudomallei induced lower monocyte-normalized levels of IL-10 in carriers of TLR51174T. We conclude that the hypofunctional genetic variant TLR51174C>Tis associated with reduced organ failure and improved survival in melioidosis. This conclusion suggests a deleterious immunoregulatory effect of TLR5 that may be mediated by IL-10 and identifies this receptor as a potential therapeutic target in melioidosis. Copyright © 2013 by The American Association of Immunologists, Inc.Mahidol UniversityImmunology and MicrobiologyArticleSCOPUS10.4049/jimmunol.1202974