Profiling transcription factor sub-networks in type I interferon signaling and in response to SARS-CoV-2 infection

Abstract

Type I interferons (IFN /{beta}) play a central role in innate immunity to respiratory viruses, including coronaviruses. Genetic defects in type I interferon signaling were reported in a significant proportion of critically ill COVID-19 patients. Extensive studies on interferon-induced intracellular signal transduction pathways led to the elucidation of the Jak-Stat pathway. Furthermore, advances in gene expression profiling by microarrays have revealed that type I interferon rapidly induced multiple transcription factor mRNA levels. In this study, transcription factor profiling in the transcriptome was used to gain novel insights into the role of inducible transcription factors in response to type I interferon signaling in immune cells and in lung epithelial cells after SARS-CoV-2 infection. Modeling the interferon-inducible transcription factor mRNA data in terms of distinct sub-networks based on biological functions such as antiviral response, immune modulation, and cell growth revealed enrichment of specific transcription factors in mouse and human immune cells. The evolutionarily conserved core type I interferon gene expression consists of the inducible transcriptional factor mRNA of the antiviral response sub-network and enriched in granulocytes. Analysis of the type I interferon-inducible transcription factor sub-networks as distinct protein-protein interaction pathways revealed insights into the role of critical hubs in signaling. Interrogation of multiple microarray datasets revealed that SARS-CoV-2 induced high levels of IFN-beta and interferon-inducible transcription factor mRNA in human lung epithelial cells. Transcription factor mRNA of the three major sub-networks regulating antiviral, immune modulation, and cell growth were differentially regulated in human lung epithelial cell lines after SARS-CoV-2 infection and in the tissue samples of COVID-19 patients. A subset of type I interferon-inducible transcription factors and inflammatory mediators were specifically enriched in the lungs and neutrophils of COVID-19 patients. The emerging complex picture of type I IFN transcriptional regulation consists of a rapid transcriptional switch mediated by the Jak-Stat cascade and a graded output of the inducible transcription factor activation that enables temporal regulation of gene expression.