Background The recent emergence of COVID-19, rapid worldwide spread, and incomplete knowledge of molecular mechanisms underlying SARS-CoV-2 infection have limited development of therapeutic strategies. Our objective was to systematically investigate molecular regulatory mechanisms of COVID-19, using a combination of high throughput RNA-sequencing-based transcriptomics and systems biology approaches. Methods RNA-Seq data from peripheral blood mononuclear cells (PBMCs) of healthy persons, mild and severe 17 COVID-19 patients were analyzed to generate a gene expression matrix. Weighted gene co-expression network analysis (WGCNA) was used to identify co-expression modules in healthy samples as a reference set. For differential co-expression network analysis, module preservation and module-trait relationships approaches were used to identify key modules. Then, protein-protein interaction (PPI) networks, based on co-expressed hub genes, were constructed to identify hub genes/TFs with the highest information transfer (hub-high traffic genes) within candidate modules. Results Based on differential co-expression network analysis, connectivity patterns and network density, 72% (15 of 21) of modules identified in healthy samples were altered by SARS-CoV-2 infection. Therefore, SARS-CoV-2 caused systemic perturbations in host biological gene networks. In functional enrichment analysis, among 15 non-preserved modules and two significant highly-correlated modules (identified by MTRs), 9 modules were directly related to the host immune response and COVID-19 immunopathogenesis. Intriguingly, systemic investigation of SARS-CoV-2 infection identified signaling pathways and key genes/proteins associated with COVID-19’s main hallmarks, e.g., cytokine storm, respiratory distress syndrome (ARDS), acute lung injury (ALI), lymphopenia, coagulation disorders, thrombosis, and pregnancy complications, as well as comorbidities associated with COVID-19, e.g., asthma, diabetic complications, cardiovascular diseases (CVDs), liver disorders and acute kidney injury (AKI). Topological analysis with betweenness centrality (BC) identified 290 hub-high traffic genes, central in both co-expression and PPI networks. We also identified several transcriptional regulatory factors, including NFKB1 , HIF1A , AHR , and TP53 , with important immunoregulatory roles in SARS-CoV-2 infection. Moreover, several hub-high traffic genes, including IL6 , IL1B , IL10 , TNF , SOCS1 , SOCS3 , ICAM1 , PTEN , RHOA , GDI2 , SUMO1 , CASP1 , IRAK3 , HSPA5 , ADRB2 , PRF1 , GZMB , OASL , CCL5 , HSP90AA1 , HSPD1 , IFNG , MAPK1 , RAB5A , and TNFRSF1A had the highest rates of information transfer in 9 candidate modules and central roles in COVID-19 immunopathogenesis. Conclusion This study provides comprehensive information on molecular mechanisms of SARS-CoV-2-host interactions and identifies several hub-high traffic genes as promising therapeutic targets for the COVID-19 pandemic.
【저자키워드】 COVID-19 pandemic, Systems biology, Immunopathogenesis, systems immunology, WGCNA, hub-high traffic genes, therapeutic targets in infectious diseases, 【초록키워드】 COVID-19, SARS-CoV-2, Asthma, Respiratory distress syndrome, ARDS, Cytokine storm, thrombosis, knowledge, SARS-COV-2 infection, COVID-19 pandemic, hub genes, transcriptomics, co-expression network analysis, Comorbidities, IL6, Comorbidity, cardiovascular disease, cardiovascular diseases, cytokine, Acute kidney injury, Lung injury, molecular mechanism, acute lung injury, MAPK1, Peripheral blood, lymphopenia, Regulatory, Spread, Pregnancy, AKI, Host immune response, Immunopathogenesis, Peripheral blood mononuclear cells, Therapeutic strategies, Factors, Mild, complications, GzmB, AhR, signaling pathway, molecular, pregnancy complications, information, signaling pathways, protein-protein interaction, mechanism, WGCNA, functional enrichment, therapeutic targets, TNF, Liver disorders, gene networks, Combination, gene co-expression network, Analysis, PPI, PBMCs, Pathways, TP53, distress, HSPA5, COVID-19 patient, Perturbation, therapeutic target, mononuclear cells, respiratory distress, mononuclear cell, coagulation disorders, Diabetic, diabetic complications, approaches, IL1B, molecular mechanisms, syndrome, transfer, SOCS3, CCL5, Functional enrichment analysis, ADRB2, IRAK3, IFNg, NFkB1, HSP90AA1, IL10, HIF1a, ICAM1, RHOA, PTEN, OASL, Host, TNFRSF1A, PRF1, CASP1, GDI2, gene expression matrix, healthy samples, HSPD1, RAB5A, SARS-CoV-2-host interactions, SOCS1, SUMO1, Genes, co-expression, transcriptional, Result, highest, analyzed, identify, was used, caused, approach, healthy, generate, provide, were used, co-expressed, healthy sample, liver disorder, SARS-CoV-2-host interaction, with COVID-19, 【제목키워드】 COVID-19, target, network, Traffic, Potential,