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

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. Tollip-/- mixed bone marrow chimera mice were infected with Mycobacterium tuberculosis for 28 days. Lung alveolar macrophages were isolated and sorted into Mtb-infected and bystander (uninfected) populations. Total RNA-seq was performed.