SARS-CoV-2 infection induces beta cell transdifferentiation

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

doi:10.1016/j.cmet.2021.05.015

SARS-CoV-2 infection induces beta cell transdifferentiation

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

Research output: Contribution to journal › Article › peer-review

138 Scopus citations

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.

Original language	English
Pages (from-to)	1577-1591.e7
Journal	Cell Metabolism
Volume	33
Issue number	8
DOIs	https://doi.org/10.1016/j.cmet.2021.05.015
State	Published - 3 Aug 2021

Keywords

COVID-19
EgIF2
PRSS1
diabetes
human islets
insulin
trypsin 1

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Tang, X., Uhl, S., Zhang, T., Xue, D., Li, B., Vandana, J. J., Acklin, J. A., Bonnycastle, L. L., Narisu, N., Erdos, M. R., Bram, Y., Chandar, V., Chong, A. C. N., Lacko, L. A., Min, Z., Lim, J. K., Borczuk, A. C., Xiang, J., Naji, A., ... Chen, S. (2021). SARS-CoV-2 infection induces beta cell transdifferentiation. Cell Metabolism, 33(8), 1577-1591.e7. https://doi.org/10.1016/j.cmet.2021.05.015

@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 = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = aug,

day = "3",

doi = "10.1016/j.cmet.2021.05.015",

language = "English",

volume = "33",

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Tang, X, Uhl, S, Zhang, T, Xue, D, Li, B, Vandana, JJ, Acklin, JA, Bonnycastle, LL, Narisu, N, Erdos, MR, Bram, Y, Chandar, V, Chong, ACN, Lacko, LA, Min, Z, Lim, JK, Borczuk, AC, Xiang, J, Naji, A, Collins, FS, Evans, T, Liu, C, tenOever, BR, Schwartz, RE & Chen, S 2021, 'SARS-CoV-2 infection induces beta cell transdifferentiation', Cell Metabolism, vol. 33, no. 8, pp. 1577-1591.e7. https://doi.org/10.1016/j.cmet.2021.05.015

TY - JOUR

T1 - SARS-CoV-2 infection induces beta cell transdifferentiation

AU - Tang, Xuming

AU - Uhl, Skyler

AU - Zhang, Tuo

AU - Xue, Dongxiang

AU - Li, Bo

AU - Vandana, J. Jeya

AU - Acklin, Joshua A.

AU - Bonnycastle, Lori L.

AU - Narisu, Narisu

AU - Erdos, Michael R.

AU - Bram, Yaron

AU - Chandar, Vasuretha

AU - Chong, Angie Chi Nok

AU - Lacko, Lauretta A.

AU - Min, Zaw

AU - Lim, Jean K.

AU - Borczuk, Alain C.

AU - Xiang, Jenny

AU - Naji, Ali

AU - Collins, Francis S.

AU - Evans, Todd

AU - Liu, Chengyang

AU - tenOever, Benjamin R.

AU - Schwartz, Robert E.

AU - Chen, Shuibing

PY - 2021/8/3

Y1 - 2021/8/3

N2 - 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.

AB - 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.

KW - COVID-19

KW - EgIF2

KW - PRSS1

KW - diabetes

KW - human islets

KW - insulin

KW - trypsin 1

UR - http://www.scopus.com/inward/record.url?scp=85107708383&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2021.05.015

DO - 10.1016/j.cmet.2021.05.015

M3 - Article

C2 - 34081913

AN - SCOPUS:85107708383

SN - 1550-4131

VL - 33

SP - 1577-1591.e7

JO - Cell Metabolism

JF - Cell Metabolism

IS - 8

ER -

SARS-CoV-2 infection induces beta cell transdifferentiation

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Keywords

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