Mycobacterium tuberculosis virulence lipid PDIM inhibits autophagy in mice.

Autor: Mittal E; Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. emittal@wustl.edu., Prasad GVRK; Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.; Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA., Upadhyay S; Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.; Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA., Sadadiwala J; Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.; Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA., Olive AJ; Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA., Yang G; Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.; Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA., Sassetti CM; Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, MA, USA., Philips JA; Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. philips.j.a@wustl.edu.; Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA. philips.j.a@wustl.edu.
Jazyk: angličtina
Zdroj: Nature microbiology [Nat Microbiol] 2024 Nov; Vol. 9 (11), pp. 2970-2984. Date of Electronic Publication: 2024 Sep 06.
DOI: 10.1038/s41564-024-01797-5
Abstrakt: Mycobacterium tuberculosis (Mtb) infects several lung macrophage populations, which have distinct abilities to restrict Mtb. What enables Mtb survival in certain macrophage populations is not well understood. Here we used transposon sequencing analysis of Mtb in wild-type and autophagy-deficient mouse macrophages lacking ATG5 or ATG7, and found that Mtb genes involved in phthiocerol dimycocerosate (PDIM) virulence lipid synthesis confer resistance to autophagy. Using ppsD mutant Mtb, we found that PDIM inhibits LC3-associated phagocytosis (LAP) by inhibiting phagosome recruitment of NADPH oxidase. In mice, PDIM protected Mtb from LAP and classical autophagy. During acute infection, PDIM was dispensable for Mtb survival in alveolar macrophages but required for survival in non-alveolar macrophages in an autophagy-dependent manner. During chronic infection, autophagy-deficient mice succumbed to infection with PDIM-deficient Mtb, with impairments in B-cell accumulation in lymphoid follicles. These findings demonstrate that PDIM contributes to Mtb virulence and immune evasion, revealing a contributory role for autophagy in B-cell responses.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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