Graphical abstract Highlights • MAPK1, MAPK3, AKT1, and SRC proteins are the critical drivers of signaling pathways and often overlap with the associated pathways during SARS-CoV-2 infection. • Viral proteins interact with MAVS, TRAF6, IRAK1, IRF3, and IRF7 and inhibit IFN-I and ISGs production. • TP53, TNF, MAPK3 proteins in Cytokines storm and VAMP8, ITGAM, and STOM in Neutrophils degranulation are regulatory proteins associated with the ARDS. • Proteomics data showed 28 candidates associated with complement and coagulation cascade during SARS-CoV-2 infection. • Our study suggests that therapeutic targeting of the downstream proteins of the complement system can mitigate SARS-CoV-2 pathogenesis. The emergence and continued spread of SARS-CoV-2 have resulted in a public health emergency across the globe. The lack of knowledge on the precise mechanism of viral pathogenesis is impeding medical intervention. In this study, we have taken both in silico and in vitro experimental approaches to unravel the mechanism of viral pathogenesis associated with complement and coagulation pathways. Based on the structural similarities of viral and host proteins, we initially generated a protein-protein interactome profile. Further computational analysis combined with Gene Ontology (GO) analysis and KEGG pathway analysis predicted key annotated pathways associated with viral pathogenesis. These include MAPK signaling, complement, and coagulation cascades, endocytosis, PD-L1 expression, PD-1 checkpoint pathway in cancer and C-type lectin receptor signaling pathways. Degree centrality analysis pinned down to MAPK1, MAPK3, AKT1, and SRC are crucial drivers of signaling pathways and often overlap with the associated pathways. Most strikingly, the complement and coagulation cascade and platelet activation pathways are interconnected, presumably directing thrombotic activity observed in severe or critical cases of COVID-19. This is complemented by in vitro studies of Huh7 cell infection and analysis of the transcriptome and proteomic profile of gene candidates during viral infection. The most known candidates associated with complement and coagulation cascade signaling by KEGG pathway analysis showed significant up-regulated fold change during viral infection. Collectively both in silico and in vitro studies suggest complement and coagulation cascade signaling are a mechanism for intravascular coagulation, thrombotic changes, and associated complications in severe COVID-19 patients.
【저자키워드】 SARS-CoV-2, ARDS, thrombosis, Cytokines storm, neutrophil degranulation, MAPK1/MAPK3, 【초록키워드】 COVID-19, Transcriptome, viral infection, platelet activation, knowledge, SARS-COV-2 infection, Cancer, viral pathogenesis, Infection, AKT1, complement, Gene ontology, in vitro, in silico, MAPK1, Coagulation, PD-L1, Regulatory, Spread, Protein, pathway, Complication, IFN-I, IRF3, signaling pathway, public health emergency, expression, Critical, SARS-CoV-2 pathogenesis, mechanism, proteomic, ISG, TNF, coagulation cascade, Signaling, host proteins, Analysis, MAVS, Pathways, TP53, IRF7, similarity, therapeutic targeting, changes, Critical case, Abstract, Fold change, overlap, severe COVID-19 patients, thrombotic, candidate, in vitro study, MAPK signaling, MAPK3, KEGG pathway analysis, intravascular coagulation, computational analysis, Traf6, cascades, medical intervention, MOST, Huh7, downstream, degranulation, ITGAM, mitigate, approach, degree, Cell, predicted, lack, globe, include, inhibit, up-regulated, driver, IRAK1, receptor signaling, SRC, STOM, VAMP8, 【제목키워드】 complement, in vitro, SARS-CoV-2 pathogenesis, coagulation cascade,