Extended Data Fig. 8: Overall experimental model.

a) Basal homeostasis. During chronic Mtb infection, lipid products are released in Mtb-infected AM. TOLLIP prevents lipid accumulation and controls inflammation, which maintains EIF2 signaling at a basal level. b) Tollip^−/− AM. Tollip^−/− mice develop excess TNF and IFNg responses from macrophages and T cells. Mtb-infected Tollip^−/− AM undergo lipid accumulation, which increases EIF2 phosphorylation. Excess pEIF2 induces sensitivity to inflammation in AM. c) Chronic infection in Tollip^−/− AM. During prolonged infection, increased and prolonged EIF2 phosphorylation from lipids and inflammation leads to cellular necrosis, decreasing the Mtb burden within individual AM and releasing extracellular Mtb. d) ISRIB treatment. ISRIB improves AM host defense, which improves Mtb control in both B6 and Tollip^−/− mouse models, making it an effective therapeutic across genetic backgrounds.