Understanding the connection between recycling endosomes and autophagy and interpreting its role in Mycobacterium tuberculosis survival.

Abstract

Autophagy and endosomal pathways are major host targets for pathogenic modulation during infection. Studies indicate that these two pathways are intimately linked and these links are exploited by pathogens for their survival. Although vital during pathogenesis, these connections remain far from understood. This study explores a possible link between the two pathways and asks the question of how that affects Mycobacterium tuberculosis survival in macrophages. SB, a glycogen synthase kinase 3 (GSK3) inhibitor, was found to redistribute Rab11 in cells and affect normal recycling of Rab11 cargo. Cytokines play a major role in regulating the pathophysiology of cells. Thus, we investigated how SB mediated perturbation of the pro-inflammatory cytokine IL-6, a Rab11 cargo that is inducible by LPS, might affect autophagy induction in macrophages. We found that SB reduced the LPS mediated inhibition on IFN-γ induced autophagy. This is a very important result as it can explain the role that GSK3 plays in regulating normal recycling and autophagy induction in macrophages. Mtb induces host IL-6 levels so as to inhibit host IFN-γ response. Thus studying the mechanism of how SB (by GSK3 inhibition) decreases IL-6 levels in host and by inducing host autophagy reduces Mtb survival, is therapeutically important.