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

•MTMR6 silencing reduces leishmania amastigote counts in macrophages.•MTMR6shRNA lowers parasite and IL-10, but elevates IL-12, expression in macrophages.•MTMR6shRNA reduces parasite load and increases Th1 cells in BALB/c mice.•MTMR6 silencing during priming with avirulent parasite reduces challenge infection. The protozoan parasite Leishmania donovani resides within mammalian macrophages and alters its antigen-presenting 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-γ-secreting T cells with anti-leishmanial activity in macrophage-T cell co-cultures. Lv-MTMR6shRNA reduced the infection, accompanied by increased IFN-γ 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.