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Tuberculosis resistance protein TOLLIP controls immune pathology by resolving the integrated stress response in alveolar macrophages

ABSTRACT: A functional polymorphism responsible for TOLLIP deficiency is associated with increased tuberculosis risk. However, TOLLIP’s role in TB pathogenesis is unknown. Tollip-/- mice developed severe Mycobacterium tuberculosis (Mtb) disease, characterized by macrophage and T cell inflammation from multiple cell populations alongside foam cell formation and lipid accumulation. Tollip-/- alveolar macrophages (AM) selectively accumulated lipid and underwent necrosis in an autonomous manner. Transcriptional and protein analysis analysis of Mtb-infected, Tollip-/- AM demonstrated increased EIF2 signaling, a key regulator of the integrated stress response (ISR) to variable environmental conditions. The ISR, inflammation, and lipid accumulation were linked, as incubation of the Mtb lipid mycolic acid with Mtb-infected Tollip-/- AM led to ISR activation and Mtb replication. Correspondingly, ISRIB, a small-molecule ISR inhibitor, selectively reduced Mtb intracellular carriage in AM and improved Mtb control, overcoming the inflammatory phenotypeinflammation. Targeting the ISR broadly improves Mtb control and immunopathology, offering a promising target for host-directed tuberculosis therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE243818 | GEO | 2023/09/27

REPOSITORIES: GEO

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