Abstract
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.
Highlights
Leishmaniasis comprises a spectrum of diseases with distinct clinical outcomes caused by the genus Leishmania
It was observed that the treatment of uninfected and infected macrophages with Mw at doses of 107cells/ml or with Amphotericin B (AmpB) (0.5 mg/ml) reduced cell survivability by less than 10% whereas lower doses of Mw (104– 106) and AmpB (0.01–0.10 mg/ml) had no cytotoxic effects on both uninfected and infected macrophages
It was observed that Mw at a dose of 107 cells/ml provided significant protection against L. donovani infection corresponding to 67% and 72% parasitic clearance at 24 h and 48 h respectively, in comparison to infected macrophages (Figure 1A)
Summary
Leishmaniasis comprises a spectrum of diseases with distinct clinical outcomes caused by the genus Leishmania. Depending on the species variation, the clinical manifestation of the disease can be categorized into 3 different types: cutaneous, mucocutaneous and visceral leishmaniasis [1]. Among these different forms of the disease, visceral leishmaniasis (VL) caused by Leishmania donovani is the most severe one [2]. The disease-promoting cytokines, transforming growth factor b (TGF-b) and interleukin (IL)-10 are enhanced in L. donovani infection [5,6]. Host protection or disease-promotion is a function of the IL-12 to IL-10 ratio [7], which is primarily regulated by the reciprocal signaling through extracellular stressregulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK) [8]
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