Metallothionein 1E as a Central Regulator of Human Pancreatic Beta Cell Function and Survival

Abstract.COVID-19 was declared a pandemic by the World Health Organization. COVID19 is caused by severe acuterespiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the coronaviridae, a diverse family ofviruses that cause a range of diseases in humans and animals. Recent clinical studies show a strong associationwith COVID-19 and diabetes. Additional studies suggest that diabetes is not only a risk factor for severe COVID-19 disease but also that SARS-CoV-2 infection can induce a new onset diabetes. However, it is not clear whatdiabetes-associated cells are infected by the virus and how these cells respond to SARS-CoV-2 infection.A number of studies support the hypothesis that viral infections play a causative role in Type 1 diabetes (T1D).Enterovirus isolates obtained from newly diagnosed T1D patients can infect and destroy human islet cells in vitro.In T1D patients, beta cell mass decreases due to auto-immune destruction. Here, we assemble a multi-disciplinary investigator team, including expert beta cell biologist (Dr. Chen), stem cell biologists (Drs. Evans andSchwartz), and a virologist (Dr. tenOever) to systematically study the impact of SARS-CoV-2 on pancreaticendocrine cells and test the hypothesis that SARS-CoV-2 infection causes human pancreatic endocrine celldestruction. In preliminary studies, we found that human pluripotent stem cell (hPSC)-derived pancreaticendocrine cells are permissive to SARS-CoV-2 infection, which was further validated using adult primary humanislets. Transcript profiling following SARS-CoV-2 infection of hPSC-derived pancreatic endocrine cells revealedstriking upregulation of chemokines, similar to profiles of tissues obtained after autopsy of COVID-19 patients.In addition, we performed two high content chemical screens and identified several FDA-approved drugs thatshow anti-SARS-CoV-2 activities on both hPSC-derived colonic and lung organoids. Here, we propose tovalidate the SARS-CoV-2 infection using pancreatic samples from COVID-19 patients, examine the impact ofSARS-CoV-2 infection on human endocrine cells, and re-purpose FDA-approved drugs to protect humanpancreatic endocrine cells from SRAS-CoV-2 infection. Three aims are proposed:Aim 1. Validate SARS-CoV-2 infection in pancreatic samples from post-mortem COVID-19 patients.Aim 2. Examine the impact of SARS-CoV-2 infection on human pancreatic endocrine cell function and survival.Aim 3. Repurpose FDA-approved drugs to protect human pancreatic endocrine cells from SARS-CoV-2 infection.Through this study, we expect to provide direct pathogenic evidence of SARS-CoV-2 infection of humanpancreatic endocrine cells, understand the pathogenesis of SARS-CoV-2 infected pancreatic endocrine cells,and develop novel approaches to protect human endocrine cells from SARS-CoV-2 infection.