SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment

Chien-Ting Wu; Peter V. Lidsky; Yinghong Xiao; Ivan T. Lee; Ran Cheng; Tsuguhisa Nakayama; Sizun Jiang; Janos Demeter; Romina J. Bevacqua; Charles A. Chang; Robert L. Whitener; Anna K. Stalder; Bokai Zhu; Han Chen; Yury Goltsev; Alexandar Tzankov; Jayakar V. Nayak; Garry P. Nolan; Matthias S. Matter; Raul Andino; Peter K. Jackson

doi:10.1016/j.cmet.2021.05.013

SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment

Chien-Ting Wu, Peter V. Lidsky, Yinghong Xiao, Ivan T. Lee, Ran Cheng, Tsuguhisa Nakayama, Sizun Jiang, Janos Demeter, Romina J. Bevacqua, Charles A. Chang, Robert L. Whitener, Anna K. Stalder, Bokai Zhu, Han Chen, Yury Goltsev, Alexandar Tzankov, Jayakar V. Nayak, Garry P. Nolan, Matthias S. Matter^*, Raul Andino^*Peter K. Jackson^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

294 Citations (Scopus)

Abstract

Emerging evidence points toward an intricate relationship between the pandemic of coronavirus disease 2019 (COVID-19) and diabetes. While preexisting diabetes is associated with severe COVID-19, it is unclear whether 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, and 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 that 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. © 2021 Elsevier Inc.

Original language	English
Pages (from-to)	1565-1576.e5
Journal	Cell Metabolism
Volume	33
Issue number	8
Online published	18 May 2021
DOIs	https://doi.org/10.1016/j.cmet.2021.05.013
Publication status	Published - 3 Aug 2021
Externally published	Yes

Research Keywords

ACE2
apoptosis
COVID-19
insulin
neuropilin 1
pancreatic beta cell
phosphoproteomics
SARS-CoV-2
SARS-CoV-2 spike protein
type 1 diabetes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Wu, C.-T., Lidsky, P. V., Xiao, Y., Lee, I. T., Cheng, R., Nakayama, T., Jiang, S., Demeter, J., Bevacqua, R. J., Chang, C. A., Whitener, R. L., Stalder, A. K., Zhu, B., Chen, H., Goltsev, Y., Tzankov, A., Nayak, J. V., Nolan, G. P., Matter, M. S., ... Jackson, P. K. (2021). SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment. Cell Metabolism, 33(8), 1565-1576.e5. https://doi.org/10.1016/j.cmet.2021.05.013

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title = "SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment",

abstract = "Emerging evidence points toward an intricate relationship between the pandemic of coronavirus disease 2019 (COVID-19) and diabetes. While preexisting diabetes is associated with severe COVID-19, it is unclear whether 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, and 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 that 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. {\textcopyright} 2021 Elsevier Inc.",

keywords = "ACE2, apoptosis, COVID-19, insulin, neuropilin 1, pancreatic beta cell, phosphoproteomics, SARS-CoV-2, SARS-CoV-2 spike protein, type 1 diabetes",

author = "Chien-Ting Wu and Lidsky, {Peter V.} and Yinghong Xiao and Lee, {Ivan T.} and Ran Cheng and Tsuguhisa Nakayama and Sizun Jiang and Janos Demeter and Bevacqua, {Romina J.} and Chang, {Charles A.} and Whitener, {Robert L.} and Stalder, {Anna K.} and Bokai Zhu and Han Chen and Yury Goltsev and Alexandar Tzankov and Nayak, {Jayakar V.} and Nolan, {Garry P.} and Matter, {Matthias S.} and Raul Andino and Jackson, {Peter K.}",

year = "2021",

month = aug,

day = "3",

doi = "10.1016/j.cmet.2021.05.013",

language = "English",

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Wu, C-T, Lidsky, PV, Xiao, Y, Lee, IT, Cheng, R, Nakayama, T, Jiang, S, Demeter, J, Bevacqua, RJ, Chang, CA, Whitener, RL, Stalder, AK, Zhu, B, Chen, H, Goltsev, Y, Tzankov, A, Nayak, JV, Nolan, GP, Matter, MS, Andino, R & Jackson, PK 2021, 'SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment', Cell Metabolism, vol. 33, no. 8, pp. 1565-1576.e5. https://doi.org/10.1016/j.cmet.2021.05.013

TY - JOUR

T1 - SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment

AU - Wu, Chien-Ting

AU - Lidsky, Peter V.

AU - Xiao, Yinghong

AU - Lee, Ivan T.

AU - Cheng, Ran

AU - Nakayama, Tsuguhisa

AU - Jiang, Sizun

AU - Demeter, Janos

AU - Bevacqua, Romina J.

AU - Chang, Charles A.

AU - Whitener, Robert L.

AU - Stalder, Anna K.

AU - Zhu, Bokai

AU - Chen, Han

AU - Goltsev, Yury

AU - Tzankov, Alexandar

AU - Nayak, Jayakar V.

AU - Nolan, Garry P.

AU - Matter, Matthias S.

AU - Andino, Raul

AU - Jackson, Peter K.

PY - 2021/8/3

Y1 - 2021/8/3

N2 - Emerging evidence points toward an intricate relationship between the pandemic of coronavirus disease 2019 (COVID-19) and diabetes. While preexisting diabetes is associated with severe COVID-19, it is unclear whether 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, and 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 that 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. © 2021 Elsevier Inc.

AB - Emerging evidence points toward an intricate relationship between the pandemic of coronavirus disease 2019 (COVID-19) and diabetes. While preexisting diabetes is associated with severe COVID-19, it is unclear whether 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, and 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 that 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. © 2021 Elsevier Inc.

KW - ACE2

KW - apoptosis

KW - COVID-19

KW - insulin

KW - neuropilin 1

KW - pancreatic beta cell

KW - phosphoproteomics

KW - SARS-CoV-2

KW - SARS-CoV-2 spike protein

KW - type 1 diabetes

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UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-85107280522&origin=recordpage

U2 - 10.1016/j.cmet.2021.05.013

DO - 10.1016/j.cmet.2021.05.013

M3 - RGC 21 - Publication in refereed journal

C2 - 34081912

SN - 1550-4131

VL - 33

SP - 1565-1576.e5

JO - Cell Metabolism

JF - Cell Metabolism

IS - 8

ER -

SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment

Abstract

Research Keywords

UN SDGs

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