Contribution of genetic variation of ACE2, the receptor for SARS-CoV-2, to COVID-19 disease expression and development of therapeutics [Added supplement: COVID-19 Variant Supplement]

The coronavirus causing the COVID-19 pandemic infects by binding to a receptor called ACE2 on the surface of cells lining the lung. One reason for the virulence of this new virus is the strength of its binding to ACE2. However, one of the leading mysteries of the outbreak has been the wide range of responses to infection, from a complete absence of disease in some, to life-threatening pneumonia in others. Regional difference across the world in disease expression have also been reported, as has a striking increased severity of COVID-19 in men compared to women. Here, we propose to investigate whether genetic variation in the human ACE2 receptor protein underlies these differences. We will test this by making all possible mutations in the ACE2 gene and testing impact on binding to the viral protein. Results from our study will have important impact on new development of therapeutics by improving computational models of ACE2-virus interactions used to design drugs blocking this binding. Another important outcome from our study would be the identification of genetic variants of ACE2 with heightened binding affinity for the viral protein. Such variants can be used as novel therapeutics by out competing virus in a patient's system, preventing virus from infecting host cells. Critically, once established, our platform will be highly versatile and readily allow testing new strains of the COVID-19 virus for increased or decreased infectivity. This platform will also be invaluable to provide a more rapid response to any new virus that appears in the future that infects cells by binding the ACE2 receptor.