Mycobacterium indicus pranii ( Mw )-mediated protection against visceral leishmaniasis by reciprocal regulation of host dual-specificity phosphatases

<span class="paragraphSection"><div class="boxTitle">Abstract</div><span style="font-style:italic;">Leishmania donovani</span> resides within the host macrophages by dampening host defence mechanisms and thereby it modulates the host cell functions for its survival. Multiple host cell factors compete during the interplay between the host and the parasite. Roles for dual-specificity phosphatases (DUSPs) are implicated in various pathological conditions. However, the reciprocity of these DUSPs was unknown in <span style="font-style:italic;">L. donovani</span> infection in a susceptible model. Here, we show that <span style="font-style:italic;">Mycobacterium indicus pranii</span> (<span style="font-style:italic;">Mw</span>), an immunomodulator, reciprocally regulates DUSP1 and DUSP6 through the TLR4 pathway. Association of PKC-β with DUSP6 increases after <span style="font-style:italic;">Mw</span> treatment resulting in decreased IL-10, phosphorylation of ERK1/2 and Arginase-1, whereas <span style="font-style:italic;">Mw</span> treatment decreases the association between PKC-ε and DUSP1 resulting in increased IL-12, phosphorylation of p38 and inducible nitric oxide synthase expression. Silencing of DUSP1 or over-expression of DUSP6 in <span style="font-style:italic;">L. donovani</span>-infected BALB/c mice decreases the parasite burden by inducing IL-12 and reducing IL-10 production. Therefore, we identify DUSP1 and DUSP6 as therapeutic targets, functions of which could be favourably modulated by <span style="font-style:italic;">Mw</span> during <span style="font-style:italic;">L. donovani</span> infection.</span>

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