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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.

Mycobacterium indicus pranii (Mw) Re-Establishes Host Protective Immune Response in Leishmania donovani Infected Macrophages: Critical Role of IL-12