Impaired TLR5 functionality is associated with survival in melioidosis.

Journal article

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: West, T; Chantratita, N; Chierakul, W; Limmathurotsakul, D; Wuthiekanun, V

• Publication status: Published
• Journal: Journal of Immunology
• Volume: 190
• Issue: 7
• Pages: 3373-3379
• Publication date: 2013-04-01
• DOI: 10.4049/jimmunol.1202974
• EISSN: 1550-6606
• ISSN: 0022-1767
• Language: English
• Keywords: Toll-Like Receptor 5; Cricetinae; Burkholderia pseudomallei; Animals; Genetic Predisposition to Disease; Genotype; Aged; Enzyme Activation; Cytokines; Humans; Middle Aged; Female; Melioidosis; Male; Cell Line; NF-kappa B; Case-Control Studies; Adult; Mutation