@article{66acaa0a12c04e669944647fddd4096c,
title = "SARS-CoV-2 infection induces beta cell transdifferentiation",
abstract = "Recent clinical data have suggested a correlation between coronavirus disease 2019 (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.",
keywords = "COVID-19, EgIF2, PRSS1, diabetes, human islets, insulin, trypsin 1",
author = "Xuming Tang and Skyler Uhl and Tuo Zhang and Dongxiang Xue and Bo Li and Vandana, {J. Jeya} and Acklin, {Joshua A.} and Bonnycastle, {Lori L.} and Narisu Narisu and Erdos, {Michael R.} and Yaron Bram and Vasuretha Chandar and Chong, {Angie Chi Nok} and Lacko, {Lauretta A.} and Zaw Min and Lim, {Jean K.} and Borczuk, {Alain C.} and Jenny Xiang and Ali Naji and Collins, {Francis S.} and Todd Evans and Chengyang Liu and tenOever, {Benjamin R.} and Schwartz, {Robert E.} and Shuibing Chen",
note = "Funding Information: This work was supported by the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK, DP3DK111907, R01DK116075, R01DK119667, R01DK119667-02S1, R01 DK124463, and U01 DK127777, S.C.); American Diabetes Association (7–20-COVID-211, S.C.); Department of Surgery, Weill Cornell Medicine (T.E. and S.C.); Bill and Melinda Gates Foundation (S.C. T.E. R.E.S. and B.R.T.); National Cancer Institute (NCI) R01CA234614, National Institute of Allergy and Infectious Diseases (NIAID) 2R01AI107301, and NIDDK R01DK121072 and 1RO3DK117252; Department of Medicine, Weill Cornell Medicine (R.E.S.); the Defense Advanced Research Projects Agency (W911NF-16-C-0050, B.R.T.); the Marc Haas Foundation (B.R.T.); National Institutes of Health Intramural Research Program of the National Human Genome Research Institute (ZIA HG000024, F.S.C.); and F32 postdoctoral fellowship (Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD 1F32HD096810-01A1, L.A.L.). S.C. and R.E.S. are supported as Irma Hirschl Trust Research Award Scholars. Human islets received from the University of Pennsylvania human islet center were funded by the NIDDK-supported Human Pancreas Analysis Program (HPAP) (https://hpap.pmacs.upenn.edu/citation) grants UC4 DK112217 to A.N. We also thank Drs. Tingfen Yan and Chad Krilow of the Collins group for data processing and bioinformatics support, as well as Dr. Kohei Oishi of the tenOever lab for providing data for SARS-CoV-2 growth curves in Vero E6 cells. S.C. R.E.S. T.E. F.S.C. and B.R.T. conceived the project. S.C. and X.T. designed the experiments. X.T. performed human islets culture, confocal imaging, western blot, and flow cytometry analysis. S.U. performed SARS-CoV-2-related experiments and insulin secretion study. X.T. and D.X. performed immunostaining and quantification. B.L. performed high-throughput chemical screen. L.A.L. performed 3D reconstruction of confocal images. J.J.V. and A.C.N.C. provided EndoC-betaH1 cells. C.L. Z.M. and A.N. performed the human islet isolation. J.A.A. and J.K.L. performed ELISA analysis. T.Z. J.X. L.L.B. N.N. and M.R.E. performed the scRNA-seq and bioinformatics analysis. R.E.S. Y.B. V.C. and A.C.B. collected autopsy samples and performed qRT-PCR. S.C. X.T. S.U. T.Z. and D.X. analyzed the data and wrote the manuscript. R.E.S. is on the scientific advisory board of Miromatrix Inc. and is a paid consultant and speaker for Alnylam Inc. The other authors declare no competing interests. Funding Information: This work was supported by the National Institute of Diabetes, Digestive and Kidney Diseases ( NIDDK , DP3DK111907 , R01DK116075 , R01DK119667 , R01DK119667-02S1 , R01 DK124463 , and U01 DK127777 , S.C.); American Diabetes Association ( 7–20-COVID-211 , S.C.); Department of Surgery, Weill Cornell Medicine (T.E. and S.C.); Bill and Melinda Gates Foundation (S.C., T.E., R.E.S., and B.R.T.); National Cancer Institute ( NCI) R01CA234614 , National Institute of Allergy and Infectious Diseases ( NIAID) 2R01AI107301 , and NIDDK R01DK121072 and 1RO3DK117252 ; Department of Medicine, Weill Cornell Medicine (R.E.S.); the Defense Advanced Research Projects Agency ( W911NF-16-C-0050 , B.R.T.); the Marc Haas Foundation (B.R.T.); National Institutes of Health Intramural Research Program of the National Human Genome Research Institute ( ZIA HG000024 , F.S.C.); and F32 postdoctoral fellowship (Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD 1F32HD096810-01A1 , L.A.L.). S.C. and R.E.S. are supported as Irma Hirschl Trust Research Award Scholars. Human islets received from the University of Pennsylvania human islet center were funded by the NIDDK-supported Human Pancreas Analysis Program (HPAP) ( https://hpap.pmacs.upenn.edu/citation ) grants UC4 DK112217 to A.N. We also thank Drs. Tingfen Yan and Chad Krilow of the Collins group for data processing and bioinformatics support, as well as Dr. Kohei Oishi of the tenOever lab for providing data for SARS-CoV-2 growth curves in Vero E6 cells. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = aug,
day = "3",
doi = "10.1016/j.cmet.2021.05.015",
language = "English",
volume = "33",
pages = "1577--1591.e7",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "8",
}