Myotubularin-related protein-6 silencing protects mice from Leishmania donovani infection

The protozoan parasite Leishmania donovani resides within mammalian macrophages and alters its antigenpresenting functions to negatively regulate host -protective T cell responses. This negative regulation of human T cell responses in vitro is attributed to myotubularin-related protein -6 (MTMR6), an ion channel -associated phosphatase. As mouse and human MTMR6 share homology, we studied whether MTMR6 silencing by lentivirally expressed MTMR6shRNA (Lv-MTMR6shRNA) reduced Leishmania growth in macrophages and whether MTMR6 silencing in Leishmania-susceptible BALB/c mice reduced the infection and reinstated host -protective T cell functions. MTMR6 silencing reduced amastigote count and IL -10 production, increased IL -12 expression and, induced IFN-gamma-secreting T cells with anti-leishmanial activity in macrophage -T cell co -cultures. LvMTMR6shRNA reduced the infection, accompanied by increased IFN-gamma expression, in susceptible BALB/c mice. Delays in Lv-MTMR6shRNA treatment by 7 days post -infection significantly reduced the infection suggesting MTMR6 as a plausible therapeutic target. Priming of BALB/c mice with avirulent parasites and Lv-MTMR6shRNA reduced parasite burden in challenge infection. These results indicate that MTMR6 is the first receptor -regulated ion channel -associated phosphatase regulating anti-leishmanial immune responses.