RT Journal Article SR Electronic T1 A diabetic milieu increases cellular susceptibility to SARS-CoV-2 infections in engineered human kidney organoids and diabetic patients JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.08.13.456228 DO 10.1101/2021.08.13.456228 A1 Elena Garreta A1 Patricia Prado A1 Megan Stanifer A1 Vanessa Monteil A1 Carmen Hurtado del Pozo A1 Asier Ullate-Agote A1 Amaia Vilas-Zornoza A1 Juan Pablo Romero A1 Gustav Jonsson A1 Roger Oria A1 Alexandra Leopoldi A1 Astrid Hagelkruys A1 Daniel Moya-Rull A1 Federico González A1 Andrés Marco A1 Carolina Tarantino A1 Pere Domingo-Pedrol A1 Omar HasanAli A1 Pedro Ventura-Aguiar A1 Josep María Campistol A1 Felipe Prosper A1 Ali Mirazimi A1 Steeve Boulant A1 Josef M. Penninger A1 Nuria Montserrat YR 2021 UL http://biorxiv.org/content/early/2021/08/13/2021.08.13.456228.abstract AB SARS-CoV-2 infections lead to a high risk of hospitalization and mortality in diabetic patients. Why diabetic individuals are more prone to develop severe COVID-19 remains unclear. Here, we established a novel human kidney organoid model that mimics early hallmarks of diabetic nephropathy. High oscillatory glucose exposure resulted in metabolic changes, expansion of extracellular membrane components, gene expression changes determined by scRNAseq, and marked upregulation of angiotensin-converting enzyme 2 (ACE2). Upon SARS-CoV-2 infection, hyperglycemic conditions lead to markedly higher viral loads in kidney organoids compared to normoglycemia. Genetic deletion of ACE2, but not of the candidate receptor BSG/CD147, in kidney organoids demonstrated the essential role of ACE2 in SARS-CoV-2 infections and completely prevented SARS-CoV-2 infection in the diabetogenic microenvironment. These data introduce a novel organoid model for diabetic kidney disease and show that diabetic-induced ACE2 licenses the diabetic kidney to enhanced SARS-CoV-2 replication.Competing Interest StatementA patent has been submitted to use human organoids to study SARS-CoV-2 infections and possibly develop new therapies. J.M.P. is shareholder of Apeiron Biologics that is developing soluble ACE2 for COVID-19 therapy.