Integrative Network Biology Framework Elucidates Molecular Mechanisms of SARS-CoV-2 Pathogenesis.

Kumar, Nilesh; Mishra, Bharat; Mehmood, Adeel; Athar, Mohammad; M Shahid Mukhtar,

COVID-19 (Coronavirus disease 2019) is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the pathophysiology of this virus is complex and largely unknown, we employed a network biology-fueled approach and integrated transcriptome data pertaining to lung epithelial cells-specific with human interactome to generate Calu-3-specific human-SARS-CoV-2 Interactome (CSI). Topological clustering and pathway enrichment analysis show that SARS-CoV-2 targets central nodes of the host-viral network, which participate in core functional pathways. Network centrality analyses discover 33 high-value SARS-CoV-2 targets, which are possibly involved in viral entry, proliferation and survival to establish infection and facilitate disease progression. Our probabilistic modeling framework elucidates critical regulatory circuitry and molecular events pertinent to COVID-19, particularly the host modifying responses and cytokine storm. Overall, our network-centric analyses reveal novel molecular components, uncover structural and functional modules, and provide molecular insights into the pathogenicity of SARS-CoV-2 that may help foster effective therapeutic design.