ABSTRACT
Introduction: Viral infections may trigger diabetes. Clinical data suggest infection with the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), may impact glucose homeostasis in patients. Notably, cases of new-onset diabetes upon SARS-CoV-2 infection have been reported. However, experimental evidence of pancreatic infection is still controversial. Aims & Methods: Here, we employ cadaveric human pancreatic islets, as well as pancreatic tissue from deceased COVID-19 patients to investigate the impact of SARS-CoV-2 on the pancreas. Results: We show that human β-cells express viral entry proteins ACE2 and TMPRSS2, making them susceptible to SARS-CoV-2 infection and replication. Our data further demonstrates that SARS-CoV-2 infects and replicates in ex vivo cultured human islets and infection. This infection is associated with morphological, transcriptional and functional changes, such as reduction of insulin-secretory granules in β-cells and impaired glucose-stimulated insulin secretion. In COVID-19 post-mortem examinations, we detected SARS-CoV-2 nucleocapsid protein in pancreatic exocrine cells, and in cells that stain positive for the β-cell marker NKX6.1 in all patients investigated. Conclusion: Taken together, our data define the human pancreas as a target of SARS-CoV-2 infection and suggest that β-cell infection might contribute to the metabolic dysregulation observed in patients with COVID- 19.
ABSTRACT
Background: The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), mainly affects the lung, but may also result in extrapulmonary manifestations such as lesions in kidneys, heart, brain, gastrointestinal and endocrine organs. Clinical data suggest that a SARS-CoV-2 infection disturbs glucose homeostasis, and cases of new-onset diabetes mellitus after SARS-CoV-2 infection have been reported. However, experimental evidence that SARS-CoV-2 can infect pancreatic tissue is lacking. We here explored whether pancreatic tissue is susceptible to SARS-CoV-2 infection. Methods: We analyzed healthy human pancreas tissue and cells for ACE2 and TMPRSS2 expression by immunohistochemistry. We exposed human Langerhans islets to SARS-CoV-2 ex vivo and determined viral infection by staining for SARS-CoV-2 spike and nucleoprotein. Viral replication was monitored by detection of released viral RNA by qPCR and infectious titers by TCID50 titration. In addition, infection and the impact of SARS-CoV-2 on cell morphology was examined by electron microscopy. Consequential changes in cell functionality were analyzed by determining insulin secretion and performing transcriptomics. Finally, we performed immunohistochemistry staining of pancreatic sections of four COVID-19 deceased individuals for the presence of SARS-CoV-2 nucleoprotein. Results: Our results show that SARS-CoV-2 infects cells of the human exocrine and endocrine pancreas ex vivo and in vivo. We demonstrate that human β-cells express ACE2 and TMPRSS2, and support SARS-CoV-2 replication. The infection was associated with morphological, transcriptional and functional changes, including reduced numbers of insulin secretory granules in β-cells, upregulation of antiviral gene expression, and impaired glucose-stimulated insulin secretion. Finally, all four analyzed full body autopsies of COVID-19 patients showed SARSCoV-2 nucleoprotein in pancreatic cells, including those that stain positive for the β-cell marker NKX6.1. Conclusion: Our data demonstrate that the human pancreas is a target of SARS-CoV-2 ex vivo and in vivo and suggest that β-cell infection may contribute to pancreatic dysregulation observed in COVID-19 patients.