Authors: Wu, Chien-Ting; Lidsky, Peter V.; Xiao, Yinghong; Lee, Ivan T.; Cheng, Ran; Nakayama, Tsuguhisa; Jiang, Sizun; Demeter, Janos; Bevacqua, Romina J.; Chang, Charles A.; Whitener, Robert L.; Stalder, Anna K.; Zhu, Bokai; Chen, Han; Goltsev, Yury; Tzankov, Alexandar; Nayak, Jayakar V.; Nolan, Garry P.; Matter, Matthias S.; Andino, Raul; Jackson, Peter K.
Issue: Cell Metab. 2021 Aug 3;33(8):1565-1576.e5.
Emerging evidence points towards an intricate relationship between the pandemic of coronavirus disease 2019 (COVID-19) and diabetes. While pre-existing diabetes is associated with severe COVID-19, it is unclear if COVID-19 severity is a cause or consequence of diabetes. To mechanistically link COVID-19 to diabetes, we tested whether insulin-producing pancreatic β-cells can be infected by SARS-CoV-2 and cause β-cell depletion. We found that the SARS-CoV-2 receptor, ACE2 and related entry factors (TMPRSS2, NRP1, TRFC) are expressed in β-cells, with selectively high expression of NRP1. We discovered that SARS-CoV-2 infects human pancreatic β-cells in patients who succumbed to COVID-19 and selectively infects human islet β-cells in vitro. We demonstrated SARS-CoV-2 infection attenuates pancreatic insulin levels and secretion, and induces β-cell apoptosis, each rescued by NRP1 inhibition. Phosphoproteomic pathway analysis of infected islets indicates apoptotic β-cell signaling, similar to that observed in Type 1 diabetes (T1D). In summary, our study shows SARS-CoV-2 can directly induce β-cell killing