Activation of Toll-like receptors by Burkholderia pseudomallei.

Publisher: BioMed Central Country of Publication: England NLM ID: 100966980 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2172 (Electronic) Linking ISSN: 14712172 NLM ISO Abbreviation: BMC Immunol Subsets: MEDLINE

Original Publication: London : BioMed Central, [2000-

Burkholderia pseudomallei/*metabolism ; Macrophages/*metabolism ; Melioidosis/*metabolism ; Toll-Like Receptor 2/*metabolism ; Toll-Like Receptor 4/*metabolism; Animals ; Burkholderia pseudomallei/immunology ; Burkholderia pseudomallei/isolation & purification ; Cell Line ; Chemokine CXCL2/metabolism ; Humans ; Immunity, Innate ; Lipid A/immunology ; Lipid A/isolation & purification ; Lipid A/metabolism ; Lipopolysaccharides/immunology ; Lipopolysaccharides/isolation & purification ; Lipopolysaccharides/metabolism ; Liver Abscess/metabolism ; Liver Abscess/microbiology ; Lymphocyte Antigen 96/immunology ; Lymphocyte Antigen 96/metabolism ; Melioidosis/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myeloid Differentiation Factor 88/deficiency ; Myeloid Differentiation Factor 88/genetics ; Myeloid Differentiation Factor 88/metabolism ; Signal Transduction/immunology ; Toll-Like Receptor 2/deficiency ; Toll-Like Receptor 2/genetics ; Toll-Like Receptor 2/immunology ; Toll-Like Receptor 4/deficiency ; Toll-Like Receptor 4/genetics ; Toll-Like Receptor 4/immunology ; Transfection ; Tumor Necrosis Factor-alpha/metabolism

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.

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U54 AI057141 United States AI NIAID NIH HHS

0 (Chemokine CXCL2)
0 (Lipid A)
0 (Lipopolysaccharides)
0 (Lymphocyte Antigen 96)
0 (Myeloid Differentiation Factor 88)
0 (Toll-Like Receptor 2)
0 (Toll-Like Receptor 4)
0 (Tumor Necrosis Factor-alpha)

Date Created: 20080812 Date Completed: 20081029 Latest Revision: 20220311

20231215

PMC2527550

10.1186/1471-2172-9-46

18691413