PGC-1\u03b1 mediates a metabolic host defense response in human airway epithelium during rhinovirus infections

Aubrey N Michi,Bryan G Yipp,Fernando Lopes,David Proud,Antoine Dufour

doi:10.1038/s41467-021-23925-z

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.

Highlights

Human rhinoviruses (HRV) are common cold viruses associated with exacerbations of lower airways diseases
We used confocal microscopy to investigate the effects of equivalent infectious doses of HRV-16, HRV-1A, and HRV-C15 on tight junction organization (ZO-1 and occludin) at 24 h post infection in highly differentiated air-liquid interface (ALI) cultures (Fig. 1a)
Given that HRV-C15 induced the greatest amount of epithelial barrier loss and is associated with more profound exacerbations in asthmatic children, we further investigated the mechanisms underlying HRV-C15-induced barrier dysfunction

Summary

Introduction

Human rhinoviruses (HRV) are common cold viruses associated with exacerbations of lower airways diseases. 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 have performed the in vitro study entirely in highly differentiated cultures of human bronchial epithelial cells derived from human lung donors cultured at the air–liquid interface (ALI) (Supplementary Table 1) and corroborated our findings in nasal epithelial scrapings obtained during experimental in vivo HRV infections. This has necessitated the development of a number of novel methods to examine intracellular pathways in such differentiated cells. To confirm the physiological relevance of this therapeutic target, we use data from two experimental human HRV infection studies in which we find that PGC-1α is downregulated in HRV-infected patients

Methods

Results

Conclusion