Robust lysosomal rewiring in Mtb infected macrophages mediated by Mtb lipids restricts the intracellular bacterial survival

Abstract

Intracellular pathogens commonly manipulate the host lysosomal system for their survival, however whether this affects the organization and functioning of the lysosomal system itself is not known. Here, we show using in vitro and in vivo infections that the lysosomal content and activity is globally elevated in M. tuberculosis infected macrophages. The enhanced lysosomal state is sustained over time and defines an adaptive homeostasis of the infected cell. Lysosomal alterations are caused by mycobacterial surface components, notably the cell wall lipid SL-1, which functions through the mTORC1-TFEB axis. Mtb mutant defective for SL-1 levels shows reduced lysosomal content and activity compared to wild type. Importantly, this phenotype is conserved during in vivo infection. The alteration in lysosomal phenotype in mutant Mtb lead to decreased lysosomal delivery of Mtb, and importantly, increased survival of intracellular Mtb. These results define the global alterations in the host lysosomal system as a crucial distinguishing feature of Mtb infected macrophages that is host protective and contribute to the containment of the pathogen.