In-silico discovery of druggable molecular signatures that drive dengue fever to severe dengue fever highlighting common pathogenesis through single-cell RNA-Seq analysis

Dengue, also known as dengue fever (DF), is an infection spread by mosquitoes. It infects over 400 million people globally each year. Sometimes DF progresses to severe DF (sDF) for which patients suffer from life-threatening complications including internal bleeding, failure of cardiovascular systems and death. Although DF is a severe threat to human life, its diagnosis and therapeutic strategies have not yet reached a satisfactory level. In order to address these issues, at first, this study identified six key cell-types (myeloid dendritic cells (DCs), memory B cells, naive B cells, memory CD4 T cells, plasmacytoid DCs, and plasmablasts) associated with both DF and sDF by integrating two single-cell RNA-Seq (scRNA-seq) profile datasets (GSE220969 and GSE154386) and cell-cell communication (CCC) analyses. Top-ranked nine common host key genes (SYK, CYBB, SOCS3, HSPA5, IRF7, NFKB1, IL-6, ISG15, and TNFSF13B) were identified from the selected cell types through differential expression patterns and protein-protein interaction (PPI) network analyses, assuming their potential involvement in the development and progression of DF and sDF. The enrichment analysis of common host key-genes (chKGs) with gene ontology (GO) terms and KEGG-pathways disclosed molecular mechanisms about how chKGs are associated with the development and progression of DF to sDF. Finally, chKGs-guided three candidate drug agents (Entrectinib, Imatinib, and QL47) were recommended against dengue virus infection (DENVI) through molecular docking, drug-likeness screening, ADME/T analysis, DFT analysis. Therefore, the findings of this study may provide valuable insights for diagnosis and therapies against DENVI.