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 into the host is 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 the 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 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 in 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 tissues that exhibit 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 were 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 changes in the host immune system, cell cycle and signal transduction mechanisms. Further investigation showed the presence of similar signalling events in the kidneys, placenta, pancreas, testis, small intestine and adrenal gland as well. Overall, our results will help in understanding the immune molecular regulatory networks influenced by the ACE2 mediated interaction in other body tissues, which may aid in identifying the secondary health complications associated with SARS-CoV-2 infection.

Keywords: ACE2/AGT-axis; COVID-19; SARS-CoV-2; immune response.

Figure 1.

ACE2 interacting protein network in the lungs. Network describing the attachment of SARS-CoV-2 with ACE2 receptor (highlighted in blue), that modulate the signalling of 133 proteins (highlighted in yellow), that form 298 interaction (black edges) in the lungs. The arrow edges indicate direct interacting proteins with the ACE2 receptor.

Figure 2.

Molecular enrichment of the ACE2 network. Functional Enrichment analysis of 133 proteins in the lung protein network showed the molecular functions related to hydrolase, protein kinase, carboxypeptidase, metallopeptidase and cytokine activity. Found to modulate type 1 angiotensin receptor binding (AGTR1), G-protein coupled receptor, insulin receptor, ribonucleotide, chemokine and cytokine receptor binding. Circumference of the circle represents number proteins associated with molecular function. An increase in color intensity and circumference of the circle in the network represents the number of proteins involved in the respective molecular function. Arrow represents the functional connectivity between the functional nodes.

Figure 3.

Pathway analysis of ACE2 network. The pathway analysis based on Reactom database suggests most of the proteins in the ACE2 network were found to be associated with functions such as the disease, immune system, autophagy, cell cycle, programmed cell death, transcription, DNA repair and signal transduction.

Figure 4.

Immuno-modulation influenced by the ACE2 network in the SARS-CoV-2 infection. The network visualizes the immune signals that are modulated by the binding of the SARS-CoV-2 with the ACE2 receptor. The dotted lines highlight the interaction of immune molecules influenced by the ACE2 receptor. Red nodes represent immune molecules altered in SARS-CoV-2 infection, whereas the unaltered immune molecules are represented by the green nodes.

Figure 5.

ACE2 interacting immune molecules in human tissues. The bar represents the number of genes associated with ACE2 mediated immune response in tissues.