Sambasivan Venkatasubramanian, Courtney R Plumlee, Kimberly A Dill-McFarland, Sara B Cohen, Benjamin H Gern, Divya A Rane, Mackenzie K Meyer, Aparajita Saha, Sarah A Hinderstein, Gemma L Pearson, Anne C Lietzke, Amanda Pacheco, Yu-Hua Chow, Chi F Hung, Scott A Soleimanpour, Matthew Altman, Kevin B Urdahl, Javeed A Shah
A polymorphism causing deficiencies in Toll-interacting protein (TOLLIP), an inhibitory adaptor protein affecting endosomal trafficking, is associated with increased tuberculosis (TB) risk. It is, however, unclear how TOLLIP affects TB pathogenesis. Here we show that TB severity is increased in Tollip-/- mice, characterized by macrophage- and T cell-driven inflammation, foam cell formation and lipid accumulation. Tollip-/- alveolar macrophages (AM) specifically accumulated lipid and underwent necrosis. Transcriptional and protein analyses of Mycobacterium tuberculosis (Mtb)-infected, Tollip-/- AM revealed increased EIF2 signalling and downstream upregulation of the integrated stress response (ISR)...
April 2024: Nature Microbiology