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Impaired TLR5 functionality is associated with survival in melioidosis.
Title | Impaired TLR5 functionality is associated with survival in melioidosis. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | T West, E, Chantratita, N, Chierakul, W, Limmathurotsakul, D, Wuthiekanun, V, Myers, ND, Emond, MJ, Wurfel, MM, Hawn, TR, Peacock, SJ, Skerrett, SJ |
Journal | J Immunol |
Volume | 190 |
Issue | 7 |
Pagination | 3373-9 |
Date Published | 2013 Apr 1 |
ISSN | 1550-6606 |
Keywords | Adult, Aged, Animals, Burkholderia pseudomallei, Case-Control Studies, Cell Line, Cricetinae, Cytokines, Enzyme Activation, Female, Genetic Predisposition to Disease, Genotype, Humans, Male, Melioidosis, Middle Aged, Mutation, NF-kappa B, Toll-Like Receptor 5 |
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. |
DOI | 10.4049/jimmunol.1202974 |
Alternate Journal | J. Immunol. |
PubMed ID | 23447684 |