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

Abstract 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 HR...

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Published inNature communications Vol. 12; no. 1; p. 3669
Main Authors Michi, Aubrey N., Yipp, Bryan G., Dufour, Antoine, Lopes, Fernando, Proud, David
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group 16.06.2021
Nature Publishing Group UK
Nature Portfolio
Subjects
Bacterial diseases
Bacterial infections
Cell differentiation
Common cold
Complications
Damage
Defense
Epithelial cells
Epithelium
Glycolysis
Infections
Metabolic pathways
Metabolism
Metabolomics
Mitochondria
Molecular modelling
Pathology
PGC-1 protein
Proteomics
Respiratory tract
Rhinovirus
Viruses
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Summary:Abstract 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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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-23925-z