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. We found that Tollip−/− mice develop severe Mycobacterium tuberculosis (Mtb) disease, characterized by lipid-laden foamy macrophages. This phenotype was intrinsic to alveolar macrophages (AM), as Tollip−/− AM from mixed bone marrow chimeras selectively accumulated lipid and harbored Mtb. Global gene expression 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 and foam cell formation were linked, as Mtb lipid mycolic acid incubation with Tollip−/− macrophages led to lipid accumulation, ISR responses, and increased Mtb replication. Correspondingly, ISRIB, a small-molecule ISR inhibitor, restored Mtb control in Tollip−/− mice and substantially improved Mtb outcomes in resistant C57BL/6 mice. Targeting the ISR broadly improves Mtb control and immunopathology, offering a promising target for host-directed tuberculosis therapy.