TOLLIP promotes durable alveolar macrophage-mediated immunity during Mycobacterium tuberculosis infection by resolving cellular stress from lipids

TOLLIP, a ubiquitin binding protein that controls multiple macrophage functions via endoplasmic reticulum transport and autophagy, is associated with human tuberculosis (TB) susceptibility and immune responses in genetic studies. We investigated how TOLLIP influences immunity during Mycobacterium tuberculosis (Mtb) infection in the mouse model. During early infection, Tollip-/- mice had reduced mycobacterial burden and increased innate immune responses, but later, Tollip-/- mice developed worse disease and many foam cells within their lung infiltrates. The delayed immune impairment was intrinsic to alveolar macrophages, associated with cellular stress, and accompanied by lipid accumulation. Further, this phenotype was reproducible with administration of exogenous lipids. Thus, TOLLIP expression in alveolar macrophages is necessary for durable protection from prolonged Mtb infection by resolving lipid-induced cellular stress. These descriptions define a critical role for TOLLIP as part of the lipid-induced ER stress response, which is responsible for Mtb progression during post-primary infection.