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Activation of Toll-like receptors by Burkholderia pseudomallei.
BMC Immunol. 2008 Aug 08; 9:46.BI

Abstract

BACKGROUND

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-kappaB 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-alpha and MIP-2 production whereas in TLR4-/- cells, TNF-alpha, 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-alpha 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.

Authors+Show Affiliations

Department of Medicine, University of Washington, Seattle, Washington, USA. tewest@u.washington.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18691413

Citation

West, T Eoin, et al. "Activation of Toll-like Receptors By Burkholderia Pseudomallei." BMC Immunology, vol. 9, 2008, p. 46.
West TE, Ernst RK, Jansson-Hutson MJ, et al. Activation of Toll-like receptors by Burkholderia pseudomallei. BMC Immunol. 2008;9:46.
West, T. E., Ernst, R. K., Jansson-Hutson, M. J., & Skerrett, S. J. (2008). Activation of Toll-like receptors by Burkholderia pseudomallei. BMC Immunology, 9, 46. https://doi.org/10.1186/1471-2172-9-46
West TE, et al. Activation of Toll-like Receptors By Burkholderia Pseudomallei. BMC Immunol. 2008 Aug 8;9:46. PubMed PMID: 18691413.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of Toll-like receptors by Burkholderia pseudomallei. AU - West,T Eoin, AU - Ernst,Robert K, AU - Jansson-Hutson,Malinka J, AU - Skerrett,Shawn J, Y1 - 2008/08/08/ PY - 2008/04/16/received PY - 2008/08/08/accepted PY - 2008/8/12/pubmed PY - 2008/10/31/medline PY - 2008/8/12/entrez SP - 46 EP - 46 JF - BMC immunology JO - BMC Immunol VL - 9 N2 - BACKGROUND: 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-kappaB 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-alpha and MIP-2 production whereas in TLR4-/- cells, TNF-alpha, 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-alpha 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. SN - 1471-2172 UR - https://www.unboundmedicine.com/medline/citation/18691413/Activation_of_Toll_like_receptors_by_Burkholderia_pseudomallei_ L2 - https://bmcimmunol.biomedcentral.com/articles/10.1186/1471-2172-9-46 DB - PRIME DP - Unbound Medicine ER -