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dc.contributor.authorWest, T. Eoinen_US
dc.contributor.authorErnst, Robert K.en_US
dc.contributor.authorJansson-Hutson, Malinka J.en_US
dc.contributor.authorSkerrett, Shawn J.en_US
dc.date.accessioned2010-05-06T20:09:45Z
dc.date.available2010-05-06T20:09:45Z
dc.date.issued2008en_US
dc.identifier.citationWest TE, Ernst R, Jansson-Hutson M, Skerrett S. Activation of Toll-like receptors by Burkholderia pseudomallei. BMC Immunology. 2008;9(1):46.en_US
dc.identifier.other10.1186/1471-2172-9-46en_US
dc.identifier.urihttp://www.biomedcentral.com/1471-2172/9/46en_US
dc.identifier.urihttp://hdl.handle.net/1773/15878
dc.description.abstractBackground: Melioidosis, a lethal tropical infection that is endemic in southeast Asia and northern Australia, is caused by the saprophytic Gram-negative bacterium Burkholderia pseudomallei. Overall mortality approaches 40% yet little is known about mechanisms of host defense. Toll-like receptors (TLRs) are host transmembrane receptors that recognize conserved pathogen molecular patterns and induce an inflammatory response. The lipopolysaccharide (LPS) of Gram-negative bacteria is a potent inducer of the host innate immune system. TLR4, in association with MD-2, is the archetype receptor for LPS although B. pseudomallei LPS has been previously identified as a TLR2 agonist. We examined TLR signaling induced by B. pseudomallei, B. pseudomallei LPS, and B. pseudomallei lipid A using gain-of-function transfection assays of NF-?B activation and studies of TLR-deficient macrophages. Results: In HEK293 cells transfected with murine or human TLRs, CD14, and MD-2, heat-killed B. pseudomallei activated TLR2 (in combination with TLR1 or TLR6) and TLR4. B. pseudomallei LPS and lipid A activated TLR4 and this TLR4-mediated signaling required MD-2. In TLR2-/- macrophages, stimulation with heat-killed B. pseudomallei augmented TNF-a and MIP-2 production whereas in TLR4-/- cells, TNF-a, MIP-2, and IL-10 production was reduced. Cytokine production by macrophages stimulated with B. pseudomallei LPS or lipid A was entirely dependent on TLR4 but was increased in the absence of TLR2. TLR adaptor molecule MyD88 strongly regulated TNF-a production in response to heat-killed B. pseudomallei. Conclusion: B. pseudomallei activates TLR2 and TLR4. In the presence of MD-2, B. pseudomallei LPS and lipid A are TLR4 ligands. Although the macrophage cytokine response to B. pseudomallei LPS or lipid A is completely dependent on TLR4, in TLR2-/- macrophages stimulated with B. pseudomallei, B. pseudomallei LPS or lipid A, cytokine production is augmented. Other MyD88-dependent signaling pathways may also be important in the host response to B. pseudomallei infection. These findings provide new insights into critical mechanisms of host defense in melioidosis.en_US
dc.description.sponsorshipTEW, RKE and SJS are supported by NIH award U54 AI057141. TEW is also supported by a Parker B. Francis Fellowship in Pulmonary Research.en_US
dc.language.isoen_USen_US
dc.titleActivation of Toll-like receptors by Burkholderia pseudomalleien_US
dc.typeArticleen_US


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