TOLLIP inhibits lipid accumulation and the integrated stress response in alveolar macrophages to control Mycobacterium tuberculosis infection.

Autor: Venkatasubramanian S; Department of Medicine, University of Washington, Seattle, WA, USA., Plumlee CR; Seattle Children's Research Institute, Seattle, WA, USA., Dill-McFarland KA; Department of Medicine, University of Washington, Seattle, WA, USA., Cohen SB; Seattle Children's Research Institute, Seattle, WA, USA., Gern BH; Seattle Children's Research Institute, Seattle, WA, USA.; Department of Pediatrics, University of Washington, Seattle, WA, USA., Rane DA; Department of Medicine, University of Washington, Seattle, WA, USA., Meyer MK; Department of Medicine, University of Washington, Seattle, WA, USA., Saha A; Department of Medicine, University of Washington, Seattle, WA, USA., Hinderstein SA; Department of Medicine, University of Washington, Seattle, WA, USA., Pearson GL; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA., Lietzke AC; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA., Pacheco A; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA., Chow YH; Department of Medicine, University of Washington, Seattle, WA, USA., Hung CF; Department of Medicine, University of Washington, Seattle, WA, USA., Soleimanpour SA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.; VA Ann Arbor Healthcare System, Ann Arbor, MI, USA., Altman M; Department of Medicine, University of Washington, Seattle, WA, USA., Urdahl KB; Seattle Children's Research Institute, Seattle, WA, USA.; Departments of Pediatrics and Immunology, University of Washington, Seattle, WA, USA., Shah JA; Department of Medicine, University of Washington, Seattle, WA, USA. jashah@uw.edu.; VA Puget Sound Healthcare System, Seattle, WA, USA. jashah@uw.edu.
Jazyk: angličtina
Zdroj: Nature microbiology [Nat Microbiol] 2024 Apr; Vol. 9 (4), pp. 949-963. Date of Electronic Publication: 2024 Mar 25.
DOI: 10.1038/s41564-024-01641-w
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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