-induced cholesterol accumulation in infected macrophages suppresses autophagy via mTORC1 activation.

serovar Typhimurium is a Gram-negative bacillus that infects the host intestinal epithelium and resident macrophages. Many intracellular pathogens induce an autophagic response in host cells but have evolved mechanisms to subvert that response. Autophagy is closely linked to cellular cholesterol levels; mTORC1 senses increased cholesterol in lysosomal membranes, leading to its hyperactivity and suppression of autophagy. Previous studies indicate that infection induces dramatic accumulation of cholesterol in macrophages, a fraction of which localizes to containing vacuoles (SCVs). We previously reported that the bacterial effector protein SseJ triggers cholesterol accumulation through a signaling cascade involving focal adhesion kinase (FAK) and Akt. Here we show that mTORC1 is recruited to SCVs and is hyperactivated in a cholesterol-dependent manner. If cholesterol accumulation is prevented pharmacologically or through mutation of , autophagy is induced and bacterial survival is attenuated. Notably, the host lipid transfer protein OSBP (oxysterol binding protein 1) is also recruited to SCVs and its activity is necessary for both cholesterol transfer to SCVs and mTORC1 activation during infection. Finally, lipidomic analysis of -infected macrophages revealed new insights into how may manipulate lipid homeostasis to benefit its survival. We propose that Typhimurium induces cholesterol accumulation through SseJ to activate mTORC1, preventing autophagic clearance of bacteria.