Interactome of SARS-CoV-2 Modulated Host Proteins With Computationally Predicted PPIs: Insights From Translational Systems Biology Studies

Abstract

Accelerated efforts to identify intervention strategies for the COVID-19 pandemic caused by SARS-CoV-2 need to be supported by deeper investigations into host invasion and response mechanisms. We constructed the neighborhood interactome network of the 332 human proteins targeted by SARS-CoV-2 proteins, augmenting it with 1,941 novel human protein-protein interactions predicted using our High-precision Protein-Protein Interaction Prediction (HiPPIP) model. Novel interactors, and the interactome as a whole, showed significant enrichment for genes differentially expressed in SARS-CoV-2-infected A549 and Calu-3 cells, postmortem lung samples of COVID-19 patients and blood samples of COVID-19 patients with severe clinical outcomes. The PPIs connected host proteins to COVID-19 blood biomarkers, ACE2 (SARS-CoV-2 entry receptor), genes differentiating SARS-CoV-2 infection from other respiratory virus infections, and SARS-CoV-targeted host proteins. Novel PPIs facilitated identification of the cilium organization functional module; we deduced the potential antiviral role of an interaction between the virus-targeted NUP98 and the cilia-associated CHMP5. Functional enrichment analyses revealed promyelocytic leukaemia bodies, midbody, cell cycle checkpoints and tristetraprolin pathway as potential viral targets. Network proximity of diabetes and hypertension associated genes to host proteins indicated a mechanistic basis for these co-morbidities in critically ill/non-surviving patients. Twenty-four drugs were identified using comparative transcriptome analysis, which include those undergoing COVID-19 clinical trials, showing broad-spectrum antiviral properties or proven activity against SARS-CoV-2 or SARS-CoV/MERS-CoV in cell-based assays. The interactome is available on a webserver at http://severus.dbmi.pitt.edu/corona/.