Real-time assessment of SARS-CoV-2 variants of concern on ACE2 variants found in susceptible populations to understand mechanisms of heightened disease expression and to direct targeted vaccination efforts
The COVID‑19 pandemic has had greatest impact on marginalized populations including Indigenous, Black and Latino communities. A leading question of the COVID‑19 pandemic is why distinct ethnic or regional groups exhibit increased infection rates, and why individual responses to infection are so varied, from asymptomatic to life-threatening pneumonia. One likely answer is genetic diversity in the gene encoding the cell-surface receptor protein for the SARS-CoV-2 virus, called ACE2. Genetic variation is common in ACE2, with distinct variants found in ethnic and geographic populations exhibiting heightened susceptibility to the pandemic, including Indigenous, Black and Latino peoples. Some ethnic group-associated ACE2 variants have been shown to alter binding to viral proteins, potentially underlying increased susceptibility. ACE2 genetic variants have also been implicated in comorbidities linked to poor COVID‑19 outcomes, including diabetes, obesity and cardiovascular disease. Here, we propose to study how population variants of ACE2, including those found in Indigenous, and other susceptible populations, impact ACE2 functions that may alter COVID‑19 disease. Given the rapid emergence of natural mutations of the SARS-CoV-2 virus underlying COVID-19, we will also test multiple variants of the viral spike protein for impact on binding to ACE2 variants. These include the mutations found in the Alpha, Beta, Delta, Gamma, and Lamda variants exhibiting increased transmissibility. We will identify human variants of ACE2 expressed in distinct ethnic groups that may confer enhanced susceptibility to infection to specific variants the virus. We will also identify how genetic variants and viral protein binding alters ACE2 function relevant to normal ACE2 physiology and pathophysiology linked to COVID‑19 comorbidities. Our results will be critical for directing development of novel therapeutics and targeted population vaccination efforts in response to new viral variants.