Leishmania donovani Amastigotes Impair Gamma Interferon-Induced STAT1α Nuclear Translocation by Blocking the Interaction between STAT1α and Importin-α5
2010
Matte, Christine | Descoteaux, Albert
The protozoan parasite Leishmania donovani, the etiological agent of visceral leishmaniasis, is renowned for its capacity to sabotage macrophage functions and signaling pathways stimulated by activators such as gamma interferon (IFN-γ). Our knowledge of the strategies utilized by L. donovani to impair macrophage responsiveness to IFN-γ remains fragmentary. In the present study, we investigated the impact of an infection by the amastigote stage of L. donovani on IFN-γ responses and signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in mouse bone marrow-derived macrophages. The levels of IFN-γ-induced expression of major histocompatibility complex class II and inducible nitric oxide synthase (iNOS) were strongly reduced in L. donovani amastigote-infected macrophages. As the expression of those genes is mediated by the transcription factors STAT1α and IFN regulatory factor 1 (IRF-1), we investigated their activation in amastigote-infected macrophages treated with IFN-γ. We found that whereas STAT1α protein levels and the levels of phosphorylation on Tyr701 and Ser727 were normal, IRF-1 expression was inhibited in infected macrophages. This inhibition of IRF-1 expression correlated with a defective nuclear translocation of STAT1α, and further analyses revealed that the IFN-γ-induced STAT1α association with the nuclear transport adaptor importin-α5 was compromised in L. donovani amastigote-infected macrophages. Taken together, our results provide evidence for a novel mechanism used by L. donovani amastigotes to interfere with IFN-γ-activated macrophage functions and provide a better understanding of the strategies deployed by this parasite to ensure its intracellular survival.
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