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- Title
Mycobacterium tuberculosis resides in lysosome-poor monocyte-derived lung cells during chronic infection.
- Authors
Zheng, Weihao; Chang, I-Chang; Limberis, Jason; Budzik, Jonathan M.; Zha, Beth Shoshana; Howard, Zachary; Chen, Lucas; Ernst, Joel D.
- Abstract
Mycobacterium tuberculosis (Mtb) infects lung myeloid cells, but the specific Mtb-permissive cells and host mechanisms supporting Mtb persistence during chronic infection are incompletely characterized. We report that after the development of T cell responses, CD11clo monocyte-derived cells harbor more live Mtb than alveolar macrophages (AM), neutrophils, and CD11chi monocyte-derived cells. Transcriptomic and functional studies revealed that the lysosome pathway is underexpressed in this highly permissive subset, characterized by less lysosome content, acidification, and proteolytic activity than AM, along with less nuclear TFEB, a regulator of lysosome biogenesis. Mtb infection does not drive lysosome deficiency in CD11clo monocyte-derived cells but promotes recruitment of monocytes that develop into permissive lung cells, mediated by the Mtb ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB and enhances lysosome functions of macrophages in vitro and in vivo, improving control of Mtb infection. Our results suggest that Mtb exploits lysosome-poor lung cells for persistence and targeting lysosome biogenesis is a potential host-directed therapy for tuberculosis. Author summary: Mycobacterium tuberculosis is notorious for its ability to replicate in mononuclear phagocytes and cause chronic lung infection despite development of immune responses. However, emerging evidence indicates that, depending on the stage of infection, some macrophages are more permissive than others for intracellular M. tuberculosis survival. We discovered that CD11clo monocyte-derived cells harbor more live M. tuberculosis than other lung myeloid cells such as alveolar macrophages, neutrophils, and CD11chi monocyte-derived cells when assessed after full development of adaptive immune responses. Compared to alveolar macrophages, these cells show reduced nuclear TFEB, a regulator of lysosome biogenesis, and lysosome activity, a crucial defense mechanism. M. tuberculosis infection doesn't directly induce lysosome deficiency in infected cells; instead, it recruits monocytes that develop into permissive lung cells, facilitated by the Mtb ESX-1 secretion system. The c-Abl tyrosine kinase inhibitor nilotinib activates TFEB, enhancing lysosome functions in macrophages and improving the control of M. tuberculosis infection in vitro and in vivo. Our findings providing new insights into the host mechanisms involved in M. tuberculosis persistence, shedding new light on developing effective treatments for tuberculosis by targeting lysosome biogenesis and addressing the challenge of persistent infections.
- Subjects
LYSOSOMES; MYCOBACTERIUM tuberculosis; MACROPHAGES; LUNGS; MYELOID cells; ALVEOLAR macrophages; TUBERCULOSIS in cattle
- Publication
PLoS Pathogens, 2024, Vol 20, Issue 5, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1012205