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: 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
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 190 Issue 7 Pg. 3373-9 (Apr 01 2013) ISSN: 1550-6606 [Electronic] United States
• PMID: 23447684 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• NF-kappa B
• Toll-Like Receptor 5

Topics

• Adult
• Aged
• Animals
• Burkholderia pseudomallei (immunology, metabolism)
• Case-Control Studies
• Cell Line
• Cricetinae
• Cytokines (immunology, metabolism)
• Enzyme Activation
• Female
• Genetic Predisposition to Disease
• Genotype
• Humans
• Male
• Melioidosis (genetics, immunology, metabolism, mortality)
• Middle Aged
• Mutation
• NF-kappa B (metabolism)
• Toll-Like Receptor 5 (genetics, metabolism)