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 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-gamma coactivator 1 alpha (PGC-1 alpha), thereby restoring epithelial barrier function, improving viral defense, and attenuating disease pathology. Therefore, PGC-1 alpha 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. Epithelial host defense to rhinovirus infections is enhanced by targeting the mitochondrial metabolic regulator, PGC-1a. Using metabolomics and proteomics, Michi et al show that human airway epithelial cells mount a barrier-protective early glycolysis-shift in response to rhinovirus, and that by targeting PGC-1a early in infection, epithelial barrier function, viral defense and pathology are improved.

Automated summary

The study shows that targeting the mitochondrial metabolic regulator, PGC-1a, in early stages of rhinovirus infection can enhance epithelial host defense and improve barrier function, viral defense, and pathology. Efforts to promote glycolysis may help prevent severe respiratory complications or secondary bacterial infections.