SARS-CoV-2 Phylointeractomics Reveal Functional Evolution of Its Variants Across Susceptible Human Organs

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mainly infects the tissues of the human respiratory, nervous, digestive and urinary systems. Here, we conducted an integrated study of the viral–host protein‒protein interactions between 29 wildtype SARS-CoV-2 proteins and 15 SARS-CoV-2 variant S proteins and human lung-, bronchus-, neuron-, liver- and kidney-derived cells, identified 745,163 viral–host protein‒protein interactions and established phylointeractomics of SARS-CoV-2 variants across susceptible human organs. We highlighted interacting proteins involved in the function evolution of viral proteins under different cellular contexts, and identified several as potential drug targets for treating related complications and sequalae. The results reveal how various viral proteins contribute to the infection, replication and immune evasion by interacting with general and cell type-specific host proteins.