Comparative ACE2 variation and primate COVID-19 risk

Amanda D. Melin; Mareike C. Janiak; Frank Marrone; Paramjit S. Arora; James P. Higham

While the biology underlying susceptibility to SARS-CoV-2 infection remains to be fully elucidated, the viral target is well established. The SARS-CoV-2 virus binds to the cellular receptor protein angiotensin-converting enzyme-2 (ACE2), which is expressed on the extracellular surface of endothelial cells of diverse bodily tissues, including the lungs, kidneys, small intestine and renal tubes 11 . Characterizations of the infection dynamics of SARS-CoV-2 have demonstrated that the binding affinity for the human ACE2 receptor is high, which is a key factor in determining the susceptibility and transmission dynamics. When compared to SARS-CoV, which caused a serious global outbreak of disease in 2002-2003 12,13 , the binding affinity between SARS-CoV2 and ACE2 is estimated to be between 4-fold 14-17 and 10-to 20-fold greater 18 . Recent reports describing structural characterization of ACE2 in complex with the SARS-CoV2 spike protein receptor binding domain [14] [15] [16] [17] allow identification of the key binding residues that enable the host-pathogen protein-protein recognition. Approaches examining variation in ACE2 tissue expression and gene sequences can offer insight into variation in human susceptibility to COVID-19 19, 20 . Similarly, we can use such an approach to compare sequence variation across species, and hence try to predict the likely interspecific variation in susceptibility. Previous analysis of comparative variation at these sites enabled estimates of the affinity of the ACE2 receptor for SARS-CoV in nonhuman species 21 . Here, we undertake such an analysis for SARS-CoV-2 across the primate radiation.