Müller, Ingrid and Haldar, Arun Kumar and Yadav, Vinod and Singhal, Eshu and Bisht, Kamlesh Kumar and Singh, Alpana and Bhaumik, Suniti and Basu, R and Sen, Pradip and Roy, Syamal (2010) Leishmania donovani Isolates with Antimony-Resistant but Not -Sensitive Phenotype Inhibit Sodium Antimony Gluconate-Induced Dendritic Cell Activation. PLoS Pathogens, 6 (5). e1000907. ISSN 1553-7374
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Abstract
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 (SbRLD) and antimony-sensitive (SbSLD) was compared in vitro. Unlike SbSLD, infection of DCs with SbRLD induced more IL-10 production and inhibited SAG-induced secretion of proinflammatory cytokines, up-regulation of co-stimulatory molecules and leishmanicidal effects. SbRLD inhibited these effects of SAG by blocking activation of PI3K/AKT and NF-κB pathways. In contrast, SbSLD failed to block activation of SAG (20 µg/ml)-induced PI3K/AKT pathway; which continued to stimulate NF-κB signaling, induce leishmanicidal effects and promote DC activation. Notably, prolonged incubation of DCs with SbSLD also inhibited SAG (20 µg/ml)-induced activation of PI3K/AKT and NF-κB pathways and leishmanicidal effects, which was restored by increasing the dose of SAG to 40 µg/ml. In contrast, SbRLD inhibited these SAG-induced events regardless of duration of DC exposure to SbRLD or dose of SAG. Interestingly, the inhibitory effects of isogenic SbSLD expressing ATP-binding cassette (ABC) transporter MRPA on SAG-induced leishmanicidal effects mimicked that of SbRLD to some extent, although antimony resistance in clinical LD isolates is known to be multifactorial. Furthermore, NF-κB was found to transcriptionally regulate expression of murine γglutamylcysteine synthetase heavy-chain (mγGCShc) gene, presumably an important regulator of antimony resistance. Importantly, SbRLD but not SbSLD blocked SAG-induced mγGCS expression in DCs by preventing NF-κB binding to the mγGCShc promoter. Our findings demonstrate that SbRLD but not SbSLD prevents SAG-induced DC activation by suppressing a PI3K-dependent NF-κB pathway and provide the evidence for differential host-pathogen interaction mediated by SbRLD and SbSLD.
| Item Type: | Article |
|---|---|
| Additional Information: | OPEN ACCESS |
| Subjects: | Q Science > QR Microbiology |
| Depositing User: | Dr. K.P.S.Sengar |
| Date Deposited: | 28 Feb 2012 16:07 |
| Last Modified: | 28 Mar 2012 10:11 |
| URI: | http://crdd.osdd.net/open/id/eprint/1117 |
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