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

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(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-kappaB pathways. In contrast, Sb(S)LD failed to block activation of SAG (20 microg/ml)-induced PI3K/AKT pathway; which continued to stimulate NF-kappaB signaling, induce leishmanicidal effects and promote DC activation. Notably, prolonged incubation of DCs with Sb(S)LD also inhibited SAG (20 microg/ml)-induced activation of PI3K/AKT and NF-kappaB pathways and leishmanicidal effects, which was restored by increasing the dose of SAG to 40 microg/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-kappaB was found to transcriptionally regulate expression of murine gammaglutamylcysteine synthetase heavy-chain (mgammaGCS(hc)) gene, presumably an important regulator of antimony resistance. Importantly, Sb(R)LD but not Sb(S)LD blocked SAG-induced mgammaGCS expression in DCs by preventing NF-kappaB binding to the mgammaGCS(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-kappaB pathway and provide the evidence for differential host-pathogen interaction mediated by Sb(R)LD and Sb(S)LD.

• Authors: Arun Kumar Haldar, Vinod Yadav, Eshu Singhal, Kamlesh Kumar Bisht, Alpana Singh, Suniti Bhaumik, Rajatava Basu, Pradip Sen, Syamal Roy
• Journal: PLoS pathogens (PLoS Pathog) Vol. 6 Issue 5 Pg. e1000907 (May 20 2010) ISSN: 1553-7374 [Electronic] United States
• PMID: 20502630 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiprotozoal Agents
• NF-kappa B
• Interleukin-10
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Glutamate-Cysteine Ligase
• Antimony Sodium Gluconate

Topics

• Animals
• Antimony Sodium Gluconate (pharmacology)
• Antiprotozoal Agents (pharmacology)
• Cricetinae
• Dendritic Cells (drug effects, metabolism, parasitology)
• Drug Resistance
• Female
• Gene Expression (drug effects)
• Glutamate-Cysteine Ligase (genetics, metabolism)
• Host-Parasite Interactions (drug effects)
• Interleukin-10 (metabolism)
• Leishmania donovani (drug effects, growth & development)
• Leishmaniasis, Visceral (drug therapy, immunology, parasitology)
• Male
• Mesocricetus
• Mice
• Mice, Inbred BALB C
• NF-kappa B (metabolism)
• Phenotype
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (immunology)