Mycobacterium tuberculosis resides in lysosome-poor monocyte-derived lung cells during persistent infection

Mycobacterium tuberculosis (Mtb) infects multiple lung myeloid cell subsets and causes persistent infection despite innate and adaptive immune responses. However, the mechanisms allowing Mtb to evade elimination are not fully understood. Here, using new methods, we determined that after T cell responses have developed, CD11clo monocyte-derived lung cells termed MNC1 (mononuclear cell subset 1), harbor more live Mtb compared to alveolar macrophages (AM), neutrophils, and less permissive CD11chi MNC2. Bulk RNA sequencing revealed that the lysosome biogenesis pathway is downregulated in MNC1. Functional assays confirmed that Mtb-permissive MNC1 are deficient in lysosome content, acidification, and proteolytic activity compared to AM, and have less nuclear TFEB, a master regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in MNC1 in vivo. Instead, Mtb recruits MNC1 and MNC2 to the lungs for its spread from AM to these cell subsets as a virulence mechanism that requires the Mtb ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome function of primary macrophages in vitro and MNC1 and MNC2 in vivo, improving control of Mtb infection. Our results indicate that Mtb exploits lysosome-poor monocyte-derived cells for in vivo persistence; targeting lysosome biogenesis may be an effective approach to host-directed therapy for tuberculosis, enabling permissive lung cells to restrict and kill Mtb through phagolysosome and autolysosome maturation. ### Competing Interest Statement The authors have declared no competing interest.