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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 (Sb R LD) and antimony-sensitive (Sb S LD) was compared  in vitro . Unlike Sb S LD, infection of DCs with Sb R LD induced more IL-10 production and inhibited SAG-induced secretion of proinflammatory cytokines, up-regulation of co-stimulatory molecules and leishmanicidal effects. Sb R LD inhibited these effects of SAG by blocking activation of PI3K/AKT and NF-κB pathways. In contrast, Sb S LD 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 Sb S LD 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, Sb R LD inhibited these SAG-induced events regardless of duration of DC exposure to Sb R LD or dose of SAG. Interestingly, the inhibitory effects of isogenic Sb S LD expressing ATP-binding cassette (ABC) transporter MRPA on SAG-induced leishmanicidal effects mimicked that of Sb R LD 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 (mγGCS hc ) gene, presumably an important regulator of antimony resistance. Importantly, Sb R LD but not Sb S LD blocked SAG-induced mγGCS expression in DCs by preventing NF-κB binding to the mγGCS hc  promoter. Our findings demonstrate that Sb R LD but not Sb S LD prevents SAG-induced DC activation by suppressing a PI3K-dependent NF-κB pathway and provide the evidence for differential host-pathogen interaction mediated by Sb R LD and Sb S LD.

Leishmania donovani Isolates with Antimony-Resistant but Not -Sensitive Phenotype Inhibit Sodium Antimony Gluconate-Induced Dendritic Cell Activation