Whole-Transcriptome RNA Sequencing Reveals Significant Differentially Expressed mRNAs, miRNAs, and lncRNAs and Related Regulating Biological Pathways in the Peripheral Blood of COVID-19 Patients

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially identified in China and currently worldwide dispersed, resulting in the coronavirus disease 2019 (COVID-19) pandemic. Notably, COVID-19 is characterized by systemic inflammation. However, the potential mechanisms of the “cytokine storm” of COVID-19 are still limited. In this study, fourteen peripheral blood samples from COVID-19 patients ( n = 10 ) and healthy donors ( n = 4 ) were collected to perform the whole-transcriptome sequencing. Lung tissues of COVID-19 patients (70%) presenting with ground-glass opacity. Also, the leukocytes and lymphocytes were significantly decreased in COVID-19 compared with the control group ( p < 0.05 ). In total, 25,482 differentially expressed messenger RNAs (DE mRNA), 23 differentially expressed microRNAs (DE miRNA), and 410 differentially expressed long noncoding RNAs (DE lncRNAs) were identified in the COVID-19 samples compared to the healthy controls. Gene Ontology (GO) analysis showed that the upregulated DE mRNAs were mainly involved in antigen processing and presentation of endogenous antigen, positive regulation of T cell mediated cytotoxicity, and positive regulation of gamma-delta T cell activation. The downregulated DE mRNAs were mainly concentrated in the glycogen biosynthetic process. We also established the protein-protein interaction (PPI) networks of up/downregulated DE mRNAs and identified 4 modules. Functional enrichment analyses indicated that these module targets were associated with positive regulation of cytokine production, cytokine-mediated signaling pathway, leukocyte differentiation, and migration. A total of 6 hub genes were selected in the PPI module networks including AKT1, TNFRSF1B, FCGR2A, CXCL8, STAT3, and TLR2. Moreover, a competing endogenous RNA network showed the interactions between lncRNAs, mRNAs, and miRNAs. Our results highlight the potential pathogenesis of excessive cytokine production such as MSTRG.119845.30/hsa-miR-20a-5p/TNFRSF1B, MSTRG.119845.30/hsa-miR-29b-2-5p/FCGR2A, and MSTRG.106112.2/hsa-miR-6501-5p/STAT3 axis, which may also play an important role in the development of ground-glass opacity in COVID-19 patients. This study gives new insights into inflammation regulatory mechanisms of coding and noncoding RNAs in COVID-19, which may provide novel diagnostic biomarkers and therapeutic avenues for COVID-19 patients.

Gene Expression Risk Scores for COVID-19 Illness Severity

“…Our findings are generally consistent with the limited data currently available in the literature on COVID-19 and gene expression [14,[28][29][30][31]. Specifically, Overmyer et al reported gene expression and metabolomic data from 128 COVID infected and non COVID infected persons, where 219 molecular features with high significance to COVID-19 status and severity were discovered.…”

Long Noncoding RNAs as Emerging Regulators of COVID-19

“…showed that a mass of upregulated differentially expressed lncRNAs positively regulated the differentiation of lymphocytes and T cells at the convalescence stages, which are closely linked with inflammatory factor genes TNF and IL1B (43). Likewise, another high-throughput sequencing of COVID-19 also revealed significant enrichment of lncRNAs in T cell-related pathways (45). Currently, there are no studies have shown the regulatory effect of lncRNA on viral antibody production.…”

“…Actually, both the IL-6 and NLRP3 signaling pathways are associated with activation of the nuclear factor κB (NF-κB) pathway ( 71 – 73 ). Beyond that, it has been reported that lncRNAs are directly involved in the regulation of the NF-κB signaling pathway, resulting in cytokine storms during severe COVID-19 infection ( 42 , 45 ). Of course, some lncRNAs can also be regulated by IL-6.…”

Phillyrin for COVID-19 and Influenza Co-infection: A Potential Therapeutic Strategy Targeting Host Based on Bioinformatics Analysis

“…MMP-9 can mediate the migration of neutrophils into the airway in response to Toll-like receptor signals induced by influenza viruses ( Callahan et al, 2021 ). The main characteristics of SARS-CoV-2 induced pulmonary complications include the overexpression of pro-inflammatory chemokines and cytokines, which can lead to a “cytokine storm.” After SARS-CoV-2 infects Calu-3 human lung epithelial cells, the pro-inflammatory chemokines CXCL9, CXCL10, and CXCL11 are up-regulated in an AKT-dependent manner ( Li et al, 2021 ). Furthermore, complete transcriptome RNA sequencing of the peripheral blood of COVID-19 patients revealed that AKT1 is one of the central genes in the differential gene PPI network ( Casalino-Matsuda et al, 2020 ).…”