Document Detail

Involvement of signal regulatory protein α, a negative regulator of Toll-like receptor signaling, in impairing the MyD88-independent pathway and intracellular killing of Burkholderia pseudomallei-infected mouse macrophages.
MedLine Citation:
PMID:  22988019     Owner:  NLM     Status:  MEDLINE    
The facultative intracellular gram-negative bacterium Burkholderia pseudomallei is the causative agent of melioidosis and is known for its ability to evade the Toll-like receptor (TLR)-mediated innate immune response. Previously it has been demonstrated that this bacterium was able to suppress the MyD88-independent pathway and can survive macrophage intracellular killing. However, the underlying mechanisms responsible for the suppression of this pathway are not fully understood. In the present study, we showed that both living and heat-killed B. pseudomallei bacteria restrict the TLR signaling response, particularly macrophage inducible nitric oxide synthase (iNOS) expression, by preventing downregulation of constitutively expressed signal regulatory protein α (SIRPα) molecule, a known negative regulator of TLR signaling. In contrast, a lipopolysaccharide (LPS) mutant of B. pseudomallei, a less virulent strain, was able to downregulate SIRPα expression in mouse macrophages. However, depletion of constitutively expressed SIRPα was able to induce the gene expression downstream of TLR signaling pathways (particularly the MyD88-independent pathway), such as that of the iNOS gene, leading to enhanced macrophage intracellular killing of B. pseudomallei. Induction of gene expression was consistent with the enhanced degradation pattern of IκBα with SIRPα depletion. Additionally, the downregulation of SIRPα expression with upregulation of iNOS was observed when the macrophages were pretreated with gamma interferon (IFN-γ) prior to the infection, suggesting that the enhanced intracellular killing of bacteria by IFN-γ is associated with the decreased SIRPα expression. Altogether our findings demonstrate that B. pseudomallei evades macrophage intracellular killing by preventing the downregulation of SIRPα that results in the inhibition of gene expression downstream of the MyD88-independent pathway.
Pankaj Baral; Pongsak Utaisincharoen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-09-17
Journal Detail:
Title:  Infection and immunity     Volume:  80     ISSN:  1098-5522     ISO Abbreviation:  Infect. Immun.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-13     Completed Date:  2013-02-07     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  0246127     Medline TA:  Infect Immun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4223-31     Citation Subset:  IM    
Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
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MeSH Terms
Burkholderia pseudomallei / growth & development,  pathogenicity*
Cell Line
Gene Expression Regulation / drug effects,  immunology*
Immune Evasion
Macrophages* / immunology,  microbiology
Melioidosis / immunology*,  microbiology
Myeloid Differentiation Factor 88 / genetics,  metabolism*
Receptors, Immunologic / genetics,  metabolism*
Signal Transduction
Toll-Like Receptors / metabolism
Reg. No./Substance:
0/Myd88 protein, mouse; 0/Myeloid Differentiation Factor 88; 0/Ptpns1 protein, mouse; 0/Receptors, Immunologic; 0/Toll-Like Receptors

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