Leishmania donovani Isolates with Antimony-Resistant but Not -Sensitive Phenotype Inhibit Sodium Antimony Gluconate-Induced Dendritic Cell Activation
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Leishmania donovani Isolates with Antimony-Resistant
but Not -Sensitive Phenotype Inhibit Sodium Antimony
Gluconate-Induced Dendritic Cell Activation
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| Creator |
Haldar, Arun Kumar
Yadav, Vinod Singhal, Eshu Bisht, Kamlesh Kumar Singh, Alpana Bhaumik, Suniti Basu, Rajatava Sen, Pradip Roy, Syamal |
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| Subject |
Infectious Diseases and Immunology
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| Description |
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-kB
pathways. In contrast, SbSLD failed to block activation of SAG (20 mg/ml)-induced PI3K/AKT pathway; which continued to
stimulate NF-kB signaling, induce leishmanicidal effects and promote DC activation. Notably, prolonged incubation of DCs
with SbSLD also inhibited SAG (20 mg/ml)-induced activation of PI3K/AKT and NF-kB pathways and leishmanicidal effects,
which was restored by increasing the dose of SAG to 40 mg/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-kB was
found to transcriptionally regulate expression of murine cglutamylcysteine synthetase heavy-chain (mcGCShc) gene,
presumably an important regulator of antimony resistance. Importantly, SbRLD but not SbSLD blocked SAG-induced mcGCS
expression in DCs by preventing NF-kB binding to the mcGCShc promoter. Our findings demonstrate that SbRLD but not
SbSLD prevents SAG-induced DC activation by suppressing a PI3K-dependent NF-kB pathway and provide the evidence for
differential host-pathogen interaction mediated by SbRLD and SbSLD.
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| Date |
2010
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/103/1/PLOS_PATHOGENS_6(5)Article_Number_e1000907_;2010[84].pdf
Haldar, Arun Kumar and Yadav, Vinod and Singhal, Eshu and Bisht, Kamlesh Kumar and Singh, Alpana and Bhaumik, Suniti and Basu, Rajatava 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). |
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| Relation |
http://dx.doi.org/10.1371/journal.ppat.1000907
http://www.eprints.iicb.res.in/103/ |
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