The tuberculosis resistance protein TOLLIP prevents disease progression by regulating the integrated stress response in alveolar macrophages.

Abstract

Abstract Genetic variation associated with decreased TOLLIP expression in macrophages is a tuberculosis (TB) risk factor. However, the fundamental mechanisms underlying TOLLIP’s role in TB pathogenesis and macrophage function are unknown. To understand why TOLLIP strongly influences Mtb-macrophage interactions, we infected B6 mice lacking Tollip (Tollip−/−) with Mtb and evaluated lung-resident macrophage function and clinical response. Tollip−/− mice developed worsened Mtb disease with profuse lipid-laden foamy macrophages in their lungs. This phenotype was intrinsic to AM, as Tollip−/− AM, but not other lung-resident macrophage subtypes, from mixed bone marrow chimeras selectively harbored excessive Mtb bacilli and intracellular lipid. Global gene expression analysis of Mtb-infected, Tollip−/− AM demonstrated alteration in dozens of genes consistent with the integrated stress response (ISR), which adapts cells to variable environmental conditions and is associated with TB progression. Administration of mycolic acid, an Mtb cell wall lipid, to Tollip−/− macrophages induced lipid accumulation, ISR, and increased intracellular Mtb burden. Pharmacologic ISR inhibition restored host defense in Tollip−/− mice and improved Mtb outcomes overall. In humans, TOLLIP mRNA expression was increased in caseous TB granulomas, providing translational relevance for our observations. Taken together, TOLLIP deficiency in AMs induces foam cell formation and ISR after Mtb infection, which permits increased replication and drives immunopathology. These findings illustrate a major mechanism by which TOLLIP-deficient individuals are susceptible to TB disease and suggest novel targets for TB host-directed therapy.