Cross-species sequence variability in host interferon antiviral pathway proteins and SARS-CoV-2 susceptibility

Cell entry and primary translation of genomic RNA are key events in the infection process for severe acute respiratory coronavirus 2 (SARS-CoV-2) to evade host innate immunity. Viral non-structural proteins (NSPs), structural, and accessory proteins suppress the interferon-I (IFN-I) antiviral response, leading to replication and spread of the COVID-19 disease. Zoonotic transmission has resulted in infections of more than 30 mammals. In previous studies the protein sequence conservation of the angiotensin converting enzyme 2 (ACE2) cell surface receptor and its binding affinity to the virus spike protein leading to cell entry have been evaluated. However, many species ranked as low susceptibility have become infected by the virus. In this study, the protein sequence conservation of 24 host protein targets was investigated including the entry proteins ACE2 and transmembrane serine protease 2 (TMPRSS2), 21 proteins in the IFN-I antiviral response pathway, and tethrin (bone marrow stromal antigen 2 [BST-2]), a protein that suppresses new virion release from cells. The Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool and other bioinformatics approaches were used to compare primary protein sequence similarity, conserved domains, and critical amino acids for the host-viral protein-protein interactions, based on published information. The results of this pathway approach suggest that variation in protein-protein interfaces is tolerated for many amino acid substitutions, and these substitutions follow taxonomic clades rather than correlating with empirically determined infected species. However, certain specific substitutions appear able to disrupt an interaction, with evidence that these may be specific to resistant species.