Abstract: Diversity in the rates of progression and mortality of COVID-19 disease within infected African American (AAs) subgroups are clearly not just a function of the underlying health conditions that increase the rate of mortality for COVID -19 patients, such as hypertension, obesity and diabetes, but may also be affected by host genetic factors. Here we propose a series of studies to advance the understanding of our knowledge in relative to the health inequity in COVID-19 disease. This is a multiple-collaborative study between Genomic, Imaging research labs and Statistical studies. Research teams in Morehouse School of Medicine (MSM) have established intimate relationships that position the institute to focus their research works on underserved minorities. We plan to develop and disseminate technological approaches in identifying host factors that disproportionately affect AAs COVID-19 infected patients. Given that the discovery, and establishment of translational implementation of novel solutions to health disparities in high-risk minority COVID-19 infected is our overall goals. Recently, angiotensin-converting enzyme 2 (ACE2), encoded on the X-chromosome, has been shown to be a functional receptor for COVID-19 to enter host target cells and the concern might arise regarding whether ACE2 variants between and within subgroups would increase the morbidity and mortality of COVID-19 infected patients. Therefore, the long-term goal is to compare how genetic variants of the ACE2 receptor, chemokine (CCL2) and human leukocyte antigen (HLA) genes (influence the immune system’s response to viruses and bacteria), affects COVID-19 disease severity among people but no underlining disease like diabetes, heart or lung disease with those with mild or no disease manifestations. Short-term goal; we will focus on two aims; Aim: 1-Determine genetic variations in ACE2 gene on obtained DNA samples from COVID-19 infected patients and evaluate for potential correlation between ACE2 variant frequencies in relationship to COVID-19 disease progression and mortalities between and within AAs and non-Hispanic Caucasian CAs subgroup;. COVID-19 is caused by SARS-CoV-2 which uses host cell ACE2, TMPRSS2, EZRIN and other proteins for entry. Differences in ACE2 or TMPRSS2/EZRIN genes expression and SNPs may justify the disease disparity and aim 2 will address how COVID-19 spike engagement with host cell receptor is precisely regulated and how host cells respond to cytokines elicited by COVID-19 infection using lung organoids. A recent correlation study suggested that the decrease expression of ACE2 /TMPRSS2/EZRIN are predictors of decreased susceptibility to COVID-19 infection and could be attributed to COVID-19 morbidity in Africa American patients. Aim-2: Modeling COVID-19-elicited disease disparity using lung organoids. Clinical validation of ACE2 and EZRIN will help to develop better strategies for COVID 19 diagnosis and treatment to reduce the observed COVID-19 disease...