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.
