Publication: Impaired TLR5 functionality is associated with survival in melioidosis
Issued Date
2013-04-01
Resource Type
ISSN
15506606
00221767
00221767
Other identifier(s)
2-s2.0-84875412590
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Mahidol University
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SCOPUS
Bibliographic Citation
Journal of Immunology. Vol.190, No.7 (2013), 3373-3379
Suggested Citation
T. Eoin West, Narisara Chantratita, Wirongrong Chierakul, Direk Limmathurotsakul, Vanaporn Wuthiekanun, Nicolle D. Myers, Mary J. Emond, Mark M. Wurfel, Thomas R. Hawn, Sharon J. Peacock, Shawn J. Skerrett Impaired TLR5 functionality is associated with survival in melioidosis. Journal of Immunology. Vol.190, No.7 (2013), 3373-3379. doi:10.4049/jimmunol.1202974 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/31935
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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, 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.