期刊
PLOS PATHOGENS
卷 6, 期 5, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1000907
关键词
-
资金
- Council of Scientific and Industrial Research, Government of India
The inability of sodium antimony gluconate (SAG)-unresponsive kala-azar patients to clear Leishmania donovani (LD) infection despite SAG therapy is partly due to an ill-defined immune-dysfunction. Since dendritic cells (DCs) typically initiate anti-leishmanial immunity, a role for DCs in aberrant LD clearance was investigated. Accordingly, regulation of SAG-induced activation of murine DCs following infection with LD isolates exhibiting two distinct phenotypes such as antimony-resistant ((SbLD)-L-R) and antimony-sensitive ((SbLD)-L-S) was compared in vitro. Unlike (SbLD)-L-S, infection of DCs with (SbLD)-L-R induced more IL-10 production and inhibited SAG-induced secretion of proinflammatory cytokines, up-regulation of co-stimulatory molecules and leishmanicidal effects. (SbLD)-L-R inhibited these effects of SAG by blocking activation of PI3K/AKT and NF-kappa B pathways. In contrast, (SbLD)-L-S failed to block activation of SAG (20 mu g/ml)-induced PI3K/AKT pathway; which continued to stimulate NF-kappa B signaling, induce leishmanicidal effects and promote DC activation. Notably, prolonged incubation of DCs with (SbLD)-L-S also inhibited SAG (20 mu g/ml)-induced activation of PI3K/AKT and NF-kappa B pathways and leishmanicidal effects, which was restored by increasing the dose of SAG to 40 mu g/ml. In contrast, (SbLD)-L-R inhibited these SAG-induced events regardless of duration of DC exposure to (SbLD)-L-R or dose of SAG. Interestingly, the inhibitory effects of isogenic (SbLD)-L-S expressing ATP-binding cassette (ABC) transporter MRPA on SAG-induced leishmanicidal effects mimicked that of (SbLD)-L-R to some extent, although antimony resistance in clinical LD isolates is known to be multifactorial. Furthermore, NF-kappa B was found to transcriptionally regulate expression of murine gamma glutamylcysteine synthetase heavy-chain (m gamma GCS(hc)) gene, presumably an important regulator of antimony resistance. Importantly, (SbLD)-L-R but not (SbLD)-L-S blocked SAG-induced m gamma GCS expression in DCs by preventing NF-kappa B binding to the m gamma GCS(hc) promoter. Our findings demonstrate that (SbLD)-L-R but not (SbLD)-L-S prevents SAG-induced DC activation by suppressing a PI3K-dependent NF-kappa B pathway and provide the evidence for differential host-pathogen interaction mediated by (SbLD)-L-R and (SbLD)-L-S.
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