title: Impaired TLR5 functionality is associated with survival in melioidosis.
abstract: Melioidosis 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, TLR5(1174C)>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 TLR5(1174C)- but not TLR5(1174T)-dependent activation of NF-κB. We tested the association of TLR5(1174C)>T with outcome in 600 Thai subjects with melioidosis. In a dominant model, TLR5(1174C)>T was 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 TLR5(1174C)>T genotype 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 TLR5(1174T) compared with carriers of TLR5(1174C). B. pseudomallei induced lower monocyte-normalized levels of IL-10 in carriers of TLR5(1174T). We conclude that the hypofunctional genetic variant TLR5(1174C)>T is 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.
authors: International Respiratory and Severe Illness Center, University of Washington, Seattle, WA 98104, USA. tewest@uw.edu
authors: T Eoin
authors: TE
authors: West
authors: Narisara
authors: N
authors: Chantratita
authors: Wirongrong
authors: W
authors: Chierakul
authors: Direk
authors: D
authors: Limmathurotsakul
authors: Vanaporn
authors: V
authors: Wuthiekanun
authors: Nicolle D
authors: ND
authors: Myers
authors: Mary J
authors: MJ
authors: Emond
authors: Mark M
authors: MM
authors: Wurfel
authors: Thomas R
authors: TR
authors: Hawn
authors: Sharon J
authors: SJ
authors: Peacock
authors: Shawn J
authors: SJ
authors: Skerrett
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016957:Burkholderia pseudomallei / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D006224:Cricetinae; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008554:Melioidosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000401:mortality*; D008875:Middle Aged; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D051198:Toll-Like Receptor 5