结核分枝杆菌
微生物学
肺结核
牛分枝杆菌
巨噬细胞
免疫学
分枝杆菌
化学
细胞生物学
生物
医学
体外
病理
生物化学
作者
Sambasivan Venkatasubramanian,Courtney R. Plumlee,Kimberly A. Dill‐McFarland,Sara B Cohen,Benjamin H. Gern,Divya A. Rane,Magali Meyer,Aparajita Saha,Sarah Hinderstein,Gemma L. Pearson,Anne Lietzke,Amanda Pacheco,Yu‐Hua Chow,Chi F. Hung,Scott A. Soleimanpour,Matthew C. Altman,Kevin B. Urdahl,Javeed A. Shah
出处
期刊:Nature microbiology
日期:2024-03-25
标识
DOI:10.1038/s41564-024-01641-w
摘要
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). These phenotypes were linked, as incubation of the Mtb lipid mycolic acid with Mtb-infected Tollip−/− AM activated the ISR and increased Mtb replication. Correspondingly, the ISR inhibitor, ISRIB, reduced Mtb numbers in AM and improved Mtb control, overcoming the inflammatory phenotype. In conclusion, targeting the ISR offers a promising target for host-directed anti-TB therapy towards improved Mtb control and reduced immunopathology. Toll-interacting protein (TOLLIP) prevents inflammation and lipid accumulation in alveolar macrophages to limit integrated stress response activation, macrophage necrosis and promote control of Mycobacterium tuberculosis.
科研通智能强力驱动
Strongly Powered by AbleSci AI