IFN-β and IL-10 induce mTOR phosphorylation and regulate IFN-γ-induced autophagy during mycobacterial infection

Abstract

Abstract The ability of mycobacteria to block the antimicrobial activity through the IFN-β→IL-10 pathway is critical to suppress IFN-γ induced antimicrobial response and increase mycobacterial survival. Leprosy is an infectious disease, caused by Mycobacterium leprae and IFN-γ is prevalent in the self-limited tuberculoid (T-lep) and reversal reaction (RR) lesions, whereas, IFN-β is higher in the disseminated lepromatous (L-lep) lesions. Here we investigated the role of the IFN-β→IL-10 pathway in the regulation of the IFN-γ-induced autophagy in M. leprae-infected macrophages. IFN-γ induced 65% more colocalization of the autophagosome with M. leprae compared to media alone. IFN-β and IL-10 reduced by 60% of the colocalization of LC3 and M. leprae induced by IFN-γ. The blocking of IL-10 recovered in 70% of the IFN-γ-induced autophagosomal fusion. Autophagy is negatively regulated by the mTOR complex 1 activation and live M. leprae induced phosphorylation of mTOR in 40% compared to uninfected MDMs. IFN-γ decreased the mTOR phosphorylation in 50% compared to media alone in M. leprae-infected MDMs. IL-10 reversed in 50% the IFN-γ-inhibition of mTOR phosphorylation in M. leprae infected macrophages. The colocalization of LC3 and M. leprae PGL-1 is higher in T-lep and RR in comparison with L-lep patients. However, mTOR phosphorylation was strongly detected in L-lep lesions vs. T-lep/RR lesions. The ability of the IFN-β → IL-10 pathway to inhibit IFN-γ-induced autophagy through induction of mTOR phosphorylation can be key for mycobacterial surveillance and inhibition of antigen presentation leading to disease pathogenesis.