Mammalian Target of Rapamycin Complex 1 Activation in Macrophages Contributes to Persistent Lung Inflammation following Respiratory Tract Viral Infection.

Autor:	Huckestein BR; Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania., Zeng K; Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania., Westcott R; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania., Alder JK; Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania., Antos D; Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania., Kolls JK; Center for Translational Research in Infection and Inflammation, Tulane School of Medicine, New Orleans, Louisiana., Alcorn JF; Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: john.alcorn@chp.edu.
Jazyk:	angličtina
Zdroj:	The American journal of pathology [Am J Pathol] 2024 Mar; Vol. 194 (3), pp. 384-401. Date of Electronic Publication: 2023 Dec 28.
DOI:	10.1016/j.ajpath.2023.11.017
Abstrakt:	Respiratory tract virus infections cause millions of hospitalizations worldwide each year. Severe infections lead to lung damage that coincides with persistent inflammation and a lengthy repair period. Vaccination and antiviral therapy help to mitigate severe infections before or during the acute stage of disease, but there are currently limited specific treatment options available to individuals experiencing the long-term sequelae of respiratory viral infection. Herein, C57BL/6 mice were infected with influenza A/PR/8/34 as a model for severe viral lung infection and allowed to recover for 21 days. Mice were treated with rapamycin, a well-characterized mammalian target of rapamycin complex 1 (mTORC1) inhibitor, on days 12 to 20 after infection, a time period after viral clearance. Persistent inflammation following severe influenza infection in mice was primarily driven by macrophages and T cells. Uniform manifold approximation and projection analysis of flow cytometry data revealed that lung macrophages had high activation of mTORC1, an energy-sensing kinase involved in inflammatory immune cell effector functions. Rapamycin treatment reduced lung inflammation and the frequency of exudate macrophages, T cells, and B cells in the lung, while not impacting epithelial progenitor cells or adaptive immune memory. These data highlight mTORC1's role in sustaining persistent inflammation following clearance of a viral respiratory pathogen and suggest a possible intervention for post-viral chronic lung inflammation. Competing Interests: Disclosure Statement None declared. (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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