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PGC-1α mediates a metabolic host defense response in human airway epithelium during rhinovirus infections

Human rhinoviruses (HRV) are common cold viruses associated with exacerbations of lower airways diseases. Although viral induced epithelial damage mediates inflammation, the molecular mechanisms responsible for airway epithelial damage and dysfunction remain undefined. Using experimental HRV infecti...

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Autores principales: Michi, Aubrey N., Yipp, Bryan G., Dufour, Antoine, Lopes, Fernando, Proud, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209127/
https://www.ncbi.nlm.nih.gov/pubmed/34135327
http://dx.doi.org/10.1038/s41467-021-23925-z
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author Michi, Aubrey N.
Yipp, Bryan G.
Dufour, Antoine
Lopes, Fernando
Proud, David
author_facet Michi, Aubrey N.
Yipp, Bryan G.
Dufour, Antoine
Lopes, Fernando
Proud, David
author_sort Michi, Aubrey N.
collection PubMed
description Human rhinoviruses (HRV) are common cold viruses associated with exacerbations of lower airways diseases. Although viral induced epithelial damage mediates inflammation, the molecular mechanisms responsible for airway epithelial damage and dysfunction remain undefined. Using experimental HRV infection studies in highly differentiated human bronchial epithelial cells grown at air-liquid interface (ALI), we examine the links between viral host defense, cellular metabolism, and epithelial barrier function. We observe that early HRV-C15 infection induces a transitory barrier-protective metabolic state characterized by glycolysis that ultimately becomes exhausted as the infection progresses and leads to cellular damage. Pharmacological promotion of glycolysis induces ROS-dependent upregulation of the mitochondrial metabolic regulator, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), thereby restoring epithelial barrier function, improving viral defense, and attenuating disease pathology. Therefore, PGC-1α regulates a metabolic pathway essential to host defense that can be therapeutically targeted to rescue airway epithelial barrier dysfunction and potentially prevent severe respiratory complications or secondary bacterial infections.
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spelling pubmed-82091272021-07-01 PGC-1α mediates a metabolic host defense response in human airway epithelium during rhinovirus infections Michi, Aubrey N. Yipp, Bryan G. Dufour, Antoine Lopes, Fernando Proud, David Nat Commun Article Human rhinoviruses (HRV) are common cold viruses associated with exacerbations of lower airways diseases. Although viral induced epithelial damage mediates inflammation, the molecular mechanisms responsible for airway epithelial damage and dysfunction remain undefined. Using experimental HRV infection studies in highly differentiated human bronchial epithelial cells grown at air-liquid interface (ALI), we examine the links between viral host defense, cellular metabolism, and epithelial barrier function. We observe that early HRV-C15 infection induces a transitory barrier-protective metabolic state characterized by glycolysis that ultimately becomes exhausted as the infection progresses and leads to cellular damage. Pharmacological promotion of glycolysis induces ROS-dependent upregulation of the mitochondrial metabolic regulator, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), thereby restoring epithelial barrier function, improving viral defense, and attenuating disease pathology. Therefore, PGC-1α regulates a metabolic pathway essential to host defense that can be therapeutically targeted to rescue airway epithelial barrier dysfunction and potentially prevent severe respiratory complications or secondary bacterial infections. Nature Publishing Group UK 2021-06-16 /pmc/articles/PMC8209127/ /pubmed/34135327 http://dx.doi.org/10.1038/s41467-021-23925-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Michi, Aubrey N.
Yipp, Bryan G.
Dufour, Antoine
Lopes, Fernando
Proud, David
PGC-1α mediates a metabolic host defense response in human airway epithelium during rhinovirus infections
title PGC-1α mediates a metabolic host defense response in human airway epithelium during rhinovirus infections
title_full PGC-1α mediates a metabolic host defense response in human airway epithelium during rhinovirus infections
title_fullStr PGC-1α mediates a metabolic host defense response in human airway epithelium during rhinovirus infections
title_full_unstemmed PGC-1α mediates a metabolic host defense response in human airway epithelium during rhinovirus infections
title_short PGC-1α mediates a metabolic host defense response in human airway epithelium during rhinovirus infections
title_sort pgc-1α mediates a metabolic host defense response in human airway epithelium during rhinovirus infections
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209127/
https://www.ncbi.nlm.nih.gov/pubmed/34135327
http://dx.doi.org/10.1038/s41467-021-23925-z
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