SARS-CoV-2/human interactome reveals ACE2 locus crosstalk with the immune regulatory network in the host.

Abstract

Severe acute respiratory syndrome, coronavirus 2 (SARS-CoV-2), remains to be a threat across the globe. SARS-CoV-2 entry to the host-mediated by binding of viral spike protein to the Human angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 is an essential member of the Renin-Angiotensin system (RAS) involved in maintaining blood pressure and vascular remodelling. Although ACE2 receptor is the entry point to the host, recent studies show activation of ACE2 to modulate the host to develop a suitable environment for its replication. However, the ACE2 activating the immune signals on SARS-CoV-2 attachment is still under investigation. We have used a systems biological approach to construct the host regulatory network upon SARS-CoV-2 attachment to the ACE2 receptor. Since lungs are the primary infection site, we integrate human lung gene expression profile along with the host regulatory network to demonstrate the altered host signalling mechanism on viral infection. Further, the network was functionally enriched to determine immune modulation in the network. We also used the proteomic database to assess the occurrence of similar signalling events in other human tissue that exhibits lineage of infection across different organs. The constructed network contains 133 host proteins with 298 interactions that directly or indirectly connect to the ACE2 receptor. Among 133 proteins, 29 found to be differentially regulated in the host lungs on SARS-CoV-2 infection. Altered proteins connect multiple proteins in a network that modulates kinase, carboxypeptidase and cytokine activity, leading to change in the host immune system, cell cycle, and signal transduction mechanism. Further investigation showed the presence of similar signalling events in the kidney, placenta, pancreas, testis, stomach, small intestine and adrenal gland suggesting the possible the mechanistic lineage of viral infection in other tissue. Overall, our results will help advance our understanding of the immune molecular regulatory network influenced by the ACE2 mediated interaction in other body tissues, which could help in finding the secondary health complications associated with SARS-CoV-2 infection.