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Cell Stem Cell ; 29(2): 217-231.e8, 2022 02 03.
Article in English | MEDLINE | ID: covidwho-1586459


Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human-induced pluripotent stem-cell-derived kidney organoids with SARS-CoV-2. Single-cell RNA sequencing indicated injury and dedifferentiation of infected cells with activation of profibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in long COVID.

COVID-19 , SARS-CoV-2 , COVID-19/complications , Fibrosis , Humans , Kidney , Organoids/pathology , Post-Acute COVID-19 Syndrome
Nat Metab ; 3(2): 149-165, 2021 02.
Article in English | MEDLINE | ID: covidwho-1065968


Infection-related diabetes can arise as a result of virus-associated ß-cell destruction. Clinical data suggest that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), impairs glucose homoeostasis, but experimental evidence that SARS-CoV-2 can infect pancreatic tissue has been lacking. In the present study, we show that SARS-CoV-2 infects cells of the human exocrine and endocrine pancreas ex vivo and in vivo. We demonstrate that human ß-cells express viral entry proteins, and SARS-CoV-2 infects and replicates in cultured human islets. Infection is associated with morphological, transcriptional and functional changes, including reduced numbers of insulin-secretory granules in ß-cells and impaired glucose-stimulated insulin secretion. In COVID-19 full-body postmortem examinations, we detected SARS-CoV-2 nucleocapsid protein in pancreatic exocrine cells, and in cells that stain positive for the ß-cell marker NKX6.1 and are in close proximity to the islets of Langerhans in all four patients investigated. Our data identify the human pancreas as a target of SARS-CoV-2 infection and suggest that ß-cell infection could contribute to the metabolic dysregulation observed in patients with COVID-19.

Islets of Langerhans/virology , SARS-CoV-2/growth & development , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/biosynthesis , Angiotensin-Converting Enzyme 2/genetics , COVID-19/physiopathology , Cells, Cultured , Diabetes Mellitus , Female , Humans , Islets of Langerhans/cytology , Islets of Langerhans/physiopathology , Male , Pancreas, Exocrine/cytology , Pancreas, Exocrine/physiopathology , Pancreas, Exocrine/virology , Pancreatic Diseases/etiology , Pancreatic Diseases/virology , Serine Endopeptidases/biosynthesis , Serine Endopeptidases/genetics , Virus Internalization , Virus Replication