| First Author | Baral P | Year | 2012 |
| Journal | Infect Immun | Volume | 80 |
| Issue | 12 | Pages | 4223-31 |
| PubMed ID | 22988019 | Mgi Jnum | J:190642 |
| Mgi Id | MGI:5449329 | Doi | 10.1128/IAI.00718-12 |
| Citation | Baral P, et al. (2012) Involvement of signal regulatory protein alpha, a negative regulator of Toll-like receptor signaling, in impairing the MyD88-independent pathway and intracellular killing of Burkholderia pseudomallei-infected mouse macrophages. Infect Immun 80(12):4223-31 |
| abstractText | 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 alpha (SIRPalpha) 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 SIRPalpha expression in mouse macrophages. However, depletion of constitutively expressed SIRPalpha 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 IkappaBalpha with SIRPalpha depletion. Additionally, the downregulation of SIRPalpha expression with upregulation of iNOS was observed when the macrophages were pretreated with gamma interferon (IFN-gamma) prior to the infection, suggesting that the enhanced intracellular killing of bacteria by IFN-gamma is associated with the decreased SIRPalpha expression. Altogether our findings demonstrate that B. pseudomallei evades macrophage intracellular killing by preventing the downregulation of SIRPalpha that results in the inhibition of gene expression downstream of the MyD88-independent pathway. |
