TOLLIP resolves lipid-induced EIF2 signaling in alveolar macrophages for durable Mycobacterium tuberculosis protection. Authors: Sambasivan Venkatasubramanian1, Courtney Plumlee2, Kim Dill-McFarland1, Gemma L. Pearson3, Sara B. Cohen2, Anne Lietzke3, Amanda Pacheco3, Sarah Hinderstein1, Scott A. Soleimanpour3,4, Matthew Altman1, Kevin B. Urdahl2,5, Javeed A. Shah1,7*. Affiliations: 1 Department of Medicine, University of Washington, Seattle, WA. 2 Seattle Children’s Research Institute, Seattle, WA. 3 Department of Internal Medicine, University of Michigan, Ann Arbor, MI. 4 VA Ann Arbor Healthcare System, Ann Arbor, MI. 5 Departments of Pediatrics and Immunology, University of Washington, Seattle, WA. 6 VA Puget Sound Healthcare System, Seattle, WA. Relative deficiency of TOLLIP expression in monocytes is associated with increased tuberculosis (TB) susceptibility in genetic studies, despite antagonizing host innate immune pathways that control Mycobacterium tuberculosis (Mtb) infection in vitro. In this study, we investigated the mechanisms by which TOLLIP influences Mtb immunity. Tollip-/- mice developed worsened disease, consistent with prior genetic observations, and developed large numbers of foam cells. Selective TOLLIP deletion in alveolar macrophages (AM) was sufficient to induce lipid accumulation and increased Mtb persistence 28 days after infection, despite increased antimicrobial responses. We developed a system to analyze sorted, Mtb-infected Tollip-/- AM from mixed bone marrow chimeric mice to measure global gene expression 28 days post-infection. This experiment revealed transcriptional profiles consistent with increased EIF2 signaling. Selective lipid administration to Tollip-/- macrophages induced lipid accumulation, and Mtb infection of lipid laden, Tollip-/- macrophages induced increased cellular stress pathways after Mtb infection, and impaired Mtb control. EIF2 overactivation induced increased Mtb replication within macrophages, irrespective of TOLLIP expression. In humans, TOLLIP and EIF2 signaling complex genes were enriched in human caseous granulomas, compared with healthy lung tissue. Our findings define a critical role for TOLLIP to prevent lipid-induced EIF2 activation that impairs Mtb-infected macrophage activity, and provide targets to improve Mtb clearance during chronic infection.