Mycobacterium indicus pranii (Mw) re-establishes host protective immune response in Leishmania donovani infected macrophages: critical role of IL-12

• Published in: PloS one 2012-07, Vol.7 (7), p.e40265
• Main Authors: Adhikari, Anupam, Gupta, Gaurav, Majumder, Saikat, Banerjee, Sayantan, Bhattacharjee, Surajit, Bhattacharya, Parna, Kumari, Sangeeta, Haldar, Subhadra, Majumdar, Suchandra Bhattacharyya, Saha, Bhaskar, Majumdar, Subrata
• Format: Article
• Language: English
• Subjects: Amphotericin B; Amphotericin B - pharmacology; Amphotericin B - therapeutic use; Animals; Antiprotozoal Agents - pharmacology; Antiprotozoal Agents - therapeutic use; Biocompatibility; Biology; Cells, Cultured; Chemokines; Chemotherapy; Crosstalk; Cytokines; Cytokines - metabolism; Cytokines - physiology; Cytotoxicity; Disease susceptibility; Drug dosages; Health aspects; Immune response; Immune system; Immunosuppression; Immunosuppressive agents; Immunotherapy; Infection; Infections; Inflammation; Interleukin 12; Interleukin-12 - metabolism; Interleukin-12 - physiology; Kinases; Leishmania; Leishmania donovani; Leishmania donovani - immunology; Leishmaniasis; Leishmaniasis, Visceral - immunology; Leishmaniasis, Visceral - parasitology; Leishmaniasis, Visceral - therapy; Liver - parasitology; Lymphocytes T; Macrophage Activation; Macrophages; Macrophages - immunology; Macrophages - parasitology; Male; MAP Kinase Signaling System; Medicine; Mice; Mice, Inbred BALB C; Mice, Knockout; Mycobacterium; Mycobacterium tuberculosis; Nitrates; Nitric oxide; Nitric Oxide - metabolism; Nontuberculous Mycobacteria - immunology; Parasites; Parasitic diseases; Proteins; Protozoa; Reactive Oxygen Species - metabolism; Spleen - parasitology; Th1 Cells - immunology; Th1 Cells - secretion; Toxicity; Transcription factors; Tuberculosis; Vector-borne diseases; Visceral leishmaniasis
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0040265

Leishmania donovani, a protozoan parasite, causes a strong immunosuppression in a susceptible host and inflicts the fatal disease visceral leishmaniasis. Relatively high toxicity, low therapeutic index, and failure in reinstating host-protective anti-leishmanial immune responses have made anti-leishmanial drugs patient non-compliant and an immuno-modulatory treatment a necessity. Therefore, we have tested the anti-leishmanial efficacy of a combination of a novel immunomodulator, Mycobacterium indicus pranii (Mw), and an anti-leishmanial drug, Amphotericin B (AmpB). We observe that Mw alone or with a suboptimal dose of AmpB offers significant protection against L. donovani infection by activating the macrophages. Our experiments examining the anti-leishmanial activity of Mw alone or with AmpB also indicate a p38MAPK and ERK-1/2 regulated pro-inflammatory responses. The Mw-AmpB combination induced nitric oxide production, restored Th1 response, and significantly reduced parasite burden in wild type macrophages but not in IL-12-deficient macrophages indicating a pivotal role for IL-12 in the induction of host-protection by Mw and AmpB treatments. In addition, we observed that Mw alone or in combination with suboptimal dose of AmpB render protection against L. donovani infection in susceptible BALB/c mice. However, these treatments failed to render protection in IL-12-deficient mice in vivo which added further support that IL-12 played a central role in this chemo immunotherapeutic approach. Thus, we demonstrate a novel chemo-immunotherapeutic approach- Mw and AmpB crosstalk eliminating the parasite-induced immunosuppression and inducing collateral host-protective effects.