Project Summary Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has infected more than 20 million people worldwide as of August 2020 and significantly altered our way of life. Despite its relative low case-fatality rate, the new coronavirus disease (COVID-19) can cause serious illness in people with pre-existing conditions like individuals with Down Syndrome (DS). It is projected that SARS-CoV-2 can cause 8.9-fold increased risk of COVID-19 related hospitalization and deaths in DS patients, yet we have limited experimental resource to understand the basic mechanisms underlying differential disease susceptibility and progression. Here we propose to use i) human induced pluripotent stem cells (iPSCs), ii) tissue-like organoids, iii) live SARS-CoV-2 virus and iv) serum collected from COVID-19 patients. We will generate 40 iPSC-derived organoids from DS and non-DS individuals and infect them with SARS-CoV-2. We will focus on two major clinical manifestations commonly observed in COVID-19 patients with critical conditions: viral myocarditis and severe pulmonary inflammation. For Aim 1, we will generate cardiac organoids composing of iPSC-derived cardiomyocytes, endothelial cells, and cardiac fibroblasts to assess their functional and structural changes after SARS-CoV-2 infection. For Aim 2, we will generate lung organoids composing of iPSC-derived lung epithelial cells, endothelial cells, alveolar macrophages, and identify an inflammatory signature after SARS-CoV-2 infection. For both Aims, we will perform single cell RNA sequencing to identify differential gene response among different cell types which contribute to phenotypic changes following SARS-CoV-2 infection.

PROJECT NARRATIVE Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can disproportionally infect and kill individuals with Down Syndrome (DS) at a greater rate than individuals without DS. To investigate the underlying health disparity of coronavirus disease (COVID-19), we plan to use organoids derived from human induced pluripotent stem cells (iPSCs) of DS versus non-DS individuals. Using live SARS-CoV-2 virus and serum collected from COVID-19 patients, we will investigate 1) whether the virus causes myocarditis in cardiac organoids and 2) characterize the inflammatory response in lung organoids from DS and non-DS individuals.