Mycobacterium tuberculosis (Mtb) lipid mediated lysosomal rewiring in infected macrophages modulates intracellular Mtb trafficking and survival.

Intracellular pathogens commonly manipulate the host lysosomal system for their survival. However, whether this pathogen-induced alteration affects the organization and functioning of the lysosomal system itself is not known. Here, using in vitro and in vivo infections and quantitative image analysis, we show that the lysosomal content and activity are globally elevated in Mycobacterium tuberculosis (Mtb)-infected macrophages. We observed that this enhanced lysosomal state is sustained over time and defines an adaptive homeostasis in the infected macrophage. Lysosomal alterations are caused by mycobacterial surface components, notably the cell wall-associated lipid sulfolipid-1 (SL-1), which functions through the mTOR complex 1 (mTORC1)-transcription factor EB (TFEB) axis in the host cells. An Mtb mutant lacking SL-1, MtbΔpks2, shows attenuated lysosomal rewiring compared with the WT Mtb in both in vitro and in vivo infections. Exposing macrophages to purified SL-1 enhanced the trafficking of phagocytic cargo to lysosomes. Correspondingly, MtbΔpks2 exhibited a further reduction in lysosomal delivery compared with the WT. Reduced trafficking of this mutant Mtb strain to lysosomes correlated with enhanced intracellular bacterial survival. Our results reveal that global alteration of the host lysosomal system is a defining feature of Mtb-infected macrophages and suggest that this altered lysosomal state protects host cell integrity and contributes to the containment of the pathogen.