SARS-CoV-2 Infection Induces Beta Cell Transdifferentiation

Tang, Xuming; Uhl, Skyler; Zhang, Tuo; Xue, Dongxiang; Li, Bo; Vandana, J. Jeya; Acklin, Joshua A.; Bonnycastle, Lori L.; Narisu, Narisu; Erdos, Michael R.; Bram, Yaron; Chandar, Vasuretha; Nok Chong, Angie Chi; Lacko, Lauretta A.; Min, Zaw; Lim, Jean K.; Borczuk, Alain C.; Xiang, Jenny; Naji, Ali; Collins, Francis S.; Evans, Todd; Liu, Chengyang; tenOever, Benjamin R.; Schwartz, Robert E.; Chen, Shuibing

Recent clinical data has suggested a correlation between Coronavirus disease 19 (COVID-19) and diabetes. Here, we describe the detection of SARS-CoV-2 viral antigen in pancreatic beta cells in autopsy samples from individuals with COVID-19. Single-cell RNA-sequencing and immunostaining from ex vivo infections confirmed that multiple types of pancreatic islet cells were susceptible to SARS-CoV-2, eliciting a cellular stress response and the induction of chemokines. Upon SARS-CoV-2 infection, beta cells showed a lower expression of insulin and a higher expression of alpha and acinar cell markers, including glucagon and trypsin1, respectively, suggesting cellular transdifferentiation. Trajectory analysis indicated that SARS-CoV-2 induced eIF2 pathway-mediated beta cell transdifferentiation, a phenotype that could be reversed with trans-integrated stress response inhibitor (trans-ISRIB). Altogether, this study demonstrates an example of SARS-CoV-2 infection causing cell fate change, which provides further insight into the pathomechanisms of COVID-19.