Abstract
Abstract Type I interferons (IFN α/β) play a central role in innate immunity to respiratory viruses, including coronaviruses. 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. 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 sub-networks were differentially regulated in human lung epithelial cell lines after SARS-CoV-2 infection and in 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.
Highlights
Interferons (IFN) are pleiotropic cytokines and exert a wide range of biological activities that include antiviral, antiproliferative, and immunoregulatory e ects (1-3)
The human type I interferon-induced transcription factor data was obtained from gene expression pro ling of a heterogenous mixture of cells from the peripheral blood monocytic cells (PBMC) while the mouse list was derived from a puri ed population of B-lymphocytes, dendritic cells, granulocytes, natural killer cells, macrophages, and T-lymphocytes
Enhanced in ammatory response mediated by interferons and cytokines was reported ln COVID-19 patients leading to an unbalanced cytokine response [27, 70, 71, 72]
Summary
Interferons (IFN) are pleiotropic cytokines and exert a wide range of biological activities that include antiviral, antiproliferative, and immunoregulatory e ects (1-3). There are 2 major classes of type I interferons consisting of IFN-alpha (IFN-α) represented by 14 isoforms and one IFN-beta (IFN-β). Type I IFN is produced by many cell types, including leukocytes, dendritic cells, and broblasts. The amount of IFN-α versus IFN-β produced varies depending on cell type and on the virus/stimulus [1, 2, 3, 4]. The biological e ects of interferons are mainly mediated by the rapid and dramatic changes in gene expression of several hundred genes [5]. The role of the Janus kinase and signal transducers and activators of transcription (Jak-Stat) pathway and transcriptional regulation by interferon-stimulated gene complex (ISGF-3) consisting of Stat, Stat and, Irf-9 in Type I
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