Identification of transcriptional regulatory network associated with response of host epithelial cells to SARS-CoV-2

Abstract

Identification of transcriptional regulatory mechanisms and signaling networks involved in the response of host cells to infection by SARS-CoV-2 is a powerful approach that provides a systems biology view of gene expression programs involved in COVID-19 and may enable the identification of novel therapeutic targets and strategies to mitigate the impact of this disease. In this study, our goal was to identify a transcriptional regulatory network that is associated with gene expression changes between samples infected by SARS-CoV-2 and those that are infected by other respiratory viruses to narrow the results on those enriched or specific to SARS-CoV-2. We combined a series of recently developed computational tools to identify transcriptional regulatory mechanisms involved in the response of epithelial cells to infection by SARS-CoV-2, and particularly regulatory mechanisms that are specific to this virus when compared to other viruses. In addition, using network-guided analyses, we identified kinases associated with this network. The results identified pathways associated with regulation of inflammation (MAPK14) and immunity (BTK, MBX) that may contribute to exacerbate organ damage linked with complications of COVID-19. The regulatory network identified herein reflects a combination of known hits and novel candidate pathways supporting the novel computational pipeline presented herein to quickly narrow down promising avenues of investigation when facing an emerging and novel disease such as COVID-19.

RAMEN Unveils Clinical Variable Networks for COVID-19 Severity and Long COVID Using Absorbing Random Walks and Genetic Algorithms

“…These pathways include "Reactome interferon alpha beta signaling" [73], "Reactome interferon signaling", "Reactome cytokine signaling in the immune system" [74], "Reactome antiviral mechanism by IFN-stimulated genes" [75], "Reactome DDX58 IFIH1-mediated induction of interferon alpha beta" [76], "WP Type I interferon induction and signaling during SARS-CoV-2 Infection" [77], "Kegg Medicus reference hydrolysis of sphingomyelin" [78], and "Reactome OAS antiviral response" [79]. Type I interferons are established immunological mediators of COVID-19 severity [80][81][82]. Interestingly, platelets are key regulators of coagulation, a process that can be severely disrupted in severe COVID-19 leading to life-threatening conditions [83].…”

FOXK2 targeting by the SCF-E3 ligase subunit FBXO24 for ubiquitin mediated degradation modulates mitochondrial respiration

“…Pathogens utilize a multitude of mechanism to undermine host metabolic, replicative, protein synthetic, and innate immune functions that impair cellular viability ( 1 , 2 , 3 , 4 , 5 ). Among these potential alterations, their impact on host transcription factors is multifaceted and can involve both activation and suppression of levels of various transcriptional programs ( 5 , 6 , 7 ).…”