Regulation of a Metabolic Gene Signature in Response to Respiratory Viruses and Type I Interferon Signaling

Abstract

Respiratory viruses are the causative agents responsible for seasonal epidemics and occasional pandemic outbreaks and are a leading cause of death worldwide. Type I interferon (IFNα/β) signaling in the lung epithelial cells plays a major role in the innate immunity to respiratory viruses. Gene signatures are a set of differentially expressed genes in a particular disease or condition and are used to diagnose, monitor, and predict disease progression. These signatures can be used to identify regulatory modules and gene regulatory networks (GRNs) in mammalian signal transduction pathways. Considerable progress has been made in the identification of type I interferon-regulated gene signatures in the host response to respiratory viruses, including antiviral, immunomodulatory, apoptosis, and transcription factor signatures. Respiratory virus infections and host defenses require a dramatic change in the metabolic flux of macromolecules involved in nucleotide, lipid, and protein metabolism. The profiling of IFN-stimulated metabolic genes induced in the host response to several respiratory viruses led to the identification of a common gene signature in human lung epithelial cells and in the lungs of mouse models of respiratory virus infection. The regulation of the metabolic gene signature was correlated with the induction of IFN-beta (IFN-β) and IFN-inducible transcription factors at the RNA level in lung epithelial cells. Furthermore, the gene signature was also detected in response to bacterial lipopolysaccharide-induced acute lung injury. A protein interaction network analysis revealed that metabolic enzymes interact with IFN-regulated transcription factors and members of the unfolded protein response (UPR) to form a module and potentially regulate type I interferon signaling, constituting a feedback loop. In addition, components of the metabolic gene expression signature were differentially regulated in the lung tissues of COVID-19 patients compared with healthy controls. These results suggest that the metabolic gene signature is a potential therapeutic target for the treatment of respiratory virus infections and inflammatory diseases.