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

Cell Metab. 2021 Aug 3;33(8):1565-1576.e5. doi: 10.1016/j.cmet.2021.05.013. Epub 2021 May 18.

Authors

Chien-Ting Wu¹, Peter V Lidsky², Yinghong Xiao², Ivan T Lee³, Ran Cheng⁴, Tsuguhisa Nakayama⁵, Sizun Jiang⁶, Janos Demeter¹, Romina J Bevacqua⁷, Charles A Chang⁸, Robert L Whitener⁷, Anna K Stalder⁹, Bokai Zhu⁶, Han Chen⁶, Yury Goltsev⁶, Alexandar Tzankov⁹, Jayakar V Nayak¹⁰, Garry P Nolan⁶, Matthias S Matter¹¹, Raul Andino¹², Peter K Jackson¹³

Affiliations

¹ Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA, USA.
⁵ Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA; Department of Otorhinolaryngology, Jikei University School of Medicine, Tokyo, Japan.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁸ Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA.
⁹ Institute of Pathology, University of Basel, Schönbeinstrasse 40, 4003 Basel, Switzerland.
¹⁰ Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA.
¹¹ Institute of Pathology, University of Basel, Schönbeinstrasse 40, 4003 Basel, Switzerland. Electronic address: matthias.matter@usb.ch.
¹² Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: raul.andino@ucsf.edu.
¹³ Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA. Electronic address: pjackson@stanford.edu.

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.

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

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Adult
Aged
Aged, 80 and over
Angiotensin-Converting Enzyme 2 / metabolism
Antigens, CD / metabolism
Apoptosis
Apoptosis Regulatory Proteins / metabolism
COVID-19 / complications
COVID-19 / diagnosis
COVID-19 / virology*
Case-Control Studies
Diabetes Mellitus / diagnosis
Diabetes Mellitus / metabolism
Diabetes Mellitus / virology*
Female
Host-Pathogen Interactions
Humans
Insulin / metabolism
Insulin-Secreting Cells / metabolism
Insulin-Secreting Cells / virology*
Male
Middle Aged
Neuropilin-1 / metabolism*
Receptors, Transferrin / metabolism
Receptors, Virus / metabolism*
SARS-CoV-2 / metabolism
SARS-CoV-2 / pathogenicity*
Serine Endopeptidases / metabolism
Spike Glycoprotein, Coronavirus / metabolism
Virus Internalization*

Substances

Antigens, CD
Apoptosis Regulatory Proteins
CD71 antigen
Insulin
NRP1 protein, human
Receptors, Transferrin
Receptors, Virus
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2
Neuropilin-1
ACE2 protein, human
Angiotensin-Converting Enzyme 2
Serine Endopeptidases
TMPRSS2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding