Gene expression changes in COVID-19 patients impact pathways related to circadian rhythm, phosphatidylinositol signaling, cytokine storm, and platelet aggregation

Abstract

The emergence of SARS-CoV-2 and the resulting COVID-19 disease pandemic had a grave impact on human society causing severely ill patients were to be placed on mechanical ventilators. The severity of the disease depended on such factors as age and the presence of pre-existing conditions. Although with the earnest effort, vaccines have been developed against the disease, there is still a long way to go to completely eradicate COVID-19. Currently, there are concerns about the complications associated with COVID-19 patients and associated conditions. This research aimed to find correlation between gene expression profiles of COVID-19 patients and factors such as age, severity, and mechanical ventilators. To do this, we probe COVID-19 patient data for dysregulated genes and pathways in severe disease. The relevant data was selected from the Gene Expression Omnibus (GEO) datasets GSE152418, GSE171110 and GSE157103. We identified differentially expressed genes (DEGs) between defined groups: COVID-19 patients and control individuals, severe ill and moderately ill COVID-19 patients, young (<40 years) and old (>70 years), and patients who require versus do not require mechanical ventilation. Analyses of over-represented pathways among DEGs and identification of enriched gene sets among cohorts provided further etiological insights. The impact of DEGs on protein-protein interactions (PPIs) between products of these genes were evaluated. The results highlight pathways related to immune response as well as inflammation, cancer, circadian clock, and PI signaling in COVID-19 patients. Key genes regulating circadian clock and PI signaling were downregulated, however, various genes and proteins regulating inflammation and cancer were upregulated in the COVID-19 patients. The product of the up-regulated gene, FLT3, which promotes phosphorylation of STAT5A/STAT5β, resulting in increased cytokine production is connected to VAV1 and TET proteins which play a role in cytokine production. Among old patients, besides pathways related to inflammation and the immune system, pathways such as platelet activation, signaling and aggregation as well as extracellular matrix organization were affected by gene expression dysregulation. In patients requiring mechanical ventilation, pathways impacted include PD-1 signaling, TCR signaling, translocation of ZAP-70 to immunological synapse, and phosphorylation of CD3 and TCR zeta chains. These observations shed insights into relevant genes and pathways impacting COVID-19 patients.