Leishmania donovani isolates with antimony-resistant but not -sensitive phenotype inhibit sodium antimony gluconate-induced dendritic cell activation

Academic Article

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 (Sb LD) and antimony-sensitive (Sb LD) was compared in vitro. Unlike Sb LD, infection of DCs with Sb LD induced more IL-10 production and inhibited SAG-induced secretion of proinflammatory cytokines, up-regulation of co-stimulatory molecules and leishmanicidal effects. Sb LD inhibited these effects of SAG by blocking activation of PI3K/AKT and NF- B pathways. In contrast, SbSLD failed to block activation of SAG (20 μg/ml)-induced PI3K/AKT pathway; which continued to stimulate NF- B signaling, induce leishmanicidal effects and promote DC activation. Notably, prolonged incubation of DCs with Sb LD also inhibited SAG (20 μg/ml)-induced activation of PI3K/AKT and NF- B pathways and leishmanicidal effects, which was restored by increasing the dose of SAG to 40 mg/ml. In contrast, Sb LD inhibited these SAG-induced events regardless of duration of DC exposure to Sb LD or dose of SAG. Interestingly, the inhibitory effects of isogenic Sb LD expressing ATP-binding cassette (ABC) transporter MRPA on SAG-induced leishmanicidal effects mimicked that of Sb LD to some extent, although antimony resistance in clinical LD isolates is known to be multifactorial. Furthermore, NF- B was found to transcriptionally regulate expression of murine cglutamylcysteine synthetase heavy-chain (mγGCS ) gene, presumably an important regulator of antimony resistance. Importantly, Sb LD but not Sb LD blocked SAG-induced mcGCS expression in DCs by preventing NF- B binding to the mγGCS promoter. Our findings demonstrate that Sb LD but not Sb LD prevents SAG-induced DC activation by suppressing a PI3K-dependent NF- B pathway and provide the evidence for differential host-pathogen interaction mediated by Sb LD and Sb LD. © 2010 Haldar et al. R S S R R S R R S R R S R S R S hc hc
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  • PLoS Pathogens  Journal
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    Author List

  • Haldar AK; Yadav V; Singhal E; Bisht KK; Singh A; Bhaumik S; Basu R; Sen P; Roy S
  • Start Page

  • 1
  • End Page

  • 21
  • Volume

  • 6
  • Issue

  • 5