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A diabetic milieu increases cellular susceptibility to SARS-CoV-2 infections in engineered human kidney organoids and diabetic patients

View ORCID ProfileElena Garreta, Patricia Prado, Megan Stanifer, Vanessa Monteil, Carmen Hurtado del Pozo, Asier Ullate-Agote, Amaia Vilas-Zornoza, Juan Pablo Romero, Gustav Jonsson, View ORCID ProfileRoger Oria, View ORCID ProfileAlexandra Leopoldi, Astrid Hagelkruys, Daniel Moya-Rull, Federico González, Andrés Marco, Carolina Tarantino, Pere Domingo-Pedrol, Omar HasanAli, Pedro Ventura-Aguiar, Josep María Campistol, Felipe Prosper, Ali Mirazimi, Steeve Boulant, Josef M. Penninger, Nuria Montserrat
doi: https://doi.org/10.1101/2021.08.13.456228
Elena Garreta
1Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
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  • ORCID record for Elena Garreta
Patricia Prado
1Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
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Megan Stanifer
2Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Heidelberg, Germany
3Research Group “Cellular Polarity and Viral Infection”, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Vanessa Monteil
4Karolinska Institute and Karolinska University Hospital, Unit of Clinical Microbiology, SE-17182, Stockholm, Sweden
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Carmen Hurtado del Pozo
1Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
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Asier Ullate-Agote
5Área de Hemato-Oncología, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra (IDISNA), Universidad de Navarra, 31008 Pamplona, Spain
6Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
7Departamento de Hematología, Clínica Universidad de Navarra, Universidad de Navarra, 31008 Pamplona, Spain
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Amaia Vilas-Zornoza
5Área de Hemato-Oncología, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra (IDISNA), Universidad de Navarra, 31008 Pamplona, Spain
6Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
7Departamento de Hematología, Clínica Universidad de Navarra, Universidad de Navarra, 31008 Pamplona, Spain
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Juan Pablo Romero
5Área de Hemato-Oncología, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra (IDISNA), Universidad de Navarra, 31008 Pamplona, Spain
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Gustav Jonsson
8IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr-Gasse 3, 1030 Vienna, Austria
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Roger Oria
9Center for Bioengineering and Tissue Regeneration, UCSF, San Francisco, California, USA
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Alexandra Leopoldi
8IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr-Gasse 3, 1030 Vienna, Austria
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Astrid Hagelkruys
8IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr-Gasse 3, 1030 Vienna, Austria
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Daniel Moya-Rull
1Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
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Federico González
1Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
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Andrés Marco
1Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
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Carolina Tarantino
1Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
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Pere Domingo-Pedrol
10Internal Medicine Department, Hospital Universitario de la Santa Creu i Sant Pau, Barcelona, Spain
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Omar HasanAli
11Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
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Pedro Ventura-Aguiar
12Nephrology and Kidney Transplant Department, Hospital Clínic Barcelona, Barcelona, Spain
13Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Fundació Clínic per a la Recerca Biomèdica (FCRB), Barcelona, Spain
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Josep María Campistol
12Nephrology and Kidney Transplant Department, Hospital Clínic Barcelona, Barcelona, Spain
13Laboratori Experimental de Nefrologia I Trasplantament (LENIT), Fundació Clínic per a la Recerca Biomèdica (FCRB), Barcelona, Spain
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Felipe Prosper
5Área de Hemato-Oncología, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra (IDISNA), Universidad de Navarra, 31008 Pamplona, Spain
6Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
7Departamento de Hematología, Clínica Universidad de Navarra, Universidad de Navarra, 31008 Pamplona, Spain
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Ali Mirazimi
4Karolinska Institute and Karolinska University Hospital, Unit of Clinical Microbiology, SE-17182, Stockholm, Sweden
14National Veterinary Institute, Uppsala, Sweden
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  • For correspondence: nmontserrat@ibecbarcelona.eu josef.penninger@ubc.ca s.boulant@dkfz-heidelberg.de ali.mirazimi@sva.se ali.mirazimi@ki.se
Steeve Boulant
3Research Group “Cellular Polarity and Viral Infection”, German Cancer Research Center (DKFZ), Heidelberg, Germany
15Department of Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany
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  • For correspondence: nmontserrat@ibecbarcelona.eu josef.penninger@ubc.ca s.boulant@dkfz-heidelberg.de ali.mirazimi@sva.se ali.mirazimi@ki.se
Josef M. Penninger
8IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr-Gasse 3, 1030 Vienna, Austria
11Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
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  • For correspondence: nmontserrat@ibecbarcelona.eu josef.penninger@ubc.ca s.boulant@dkfz-heidelberg.de ali.mirazimi@sva.se ali.mirazimi@ki.se
Nuria Montserrat
1Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
16Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
17Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Madrid, Spain
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  • For correspondence: nmontserrat@ibecbarcelona.eu josef.penninger@ubc.ca s.boulant@dkfz-heidelberg.de ali.mirazimi@sva.se ali.mirazimi@ki.se
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Summary

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 Statement

A 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.

Footnotes

  • ↵18 Lead Contact.

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE181002

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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A diabetic milieu increases cellular susceptibility to SARS-CoV-2 infections in engineered human kidney organoids and diabetic patients
Elena Garreta, Patricia Prado, Megan Stanifer, Vanessa Monteil, Carmen Hurtado del Pozo, Asier Ullate-Agote, Amaia Vilas-Zornoza, Juan Pablo Romero, Gustav Jonsson, Roger Oria, Alexandra Leopoldi, Astrid Hagelkruys, Daniel Moya-Rull, Federico González, Andrés Marco, Carolina Tarantino, Pere Domingo-Pedrol, Omar HasanAli, Pedro Ventura-Aguiar, Josep María Campistol, Felipe Prosper, Ali Mirazimi, Steeve Boulant, Josef M. Penninger, Nuria Montserrat
bioRxiv 2021.08.13.456228; doi: https://doi.org/10.1101/2021.08.13.456228
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A diabetic milieu increases cellular susceptibility to SARS-CoV-2 infections in engineered human kidney organoids and diabetic patients
Elena Garreta, Patricia Prado, Megan Stanifer, Vanessa Monteil, Carmen Hurtado del Pozo, Asier Ullate-Agote, Amaia Vilas-Zornoza, Juan Pablo Romero, Gustav Jonsson, Roger Oria, Alexandra Leopoldi, Astrid Hagelkruys, Daniel Moya-Rull, Federico González, Andrés Marco, Carolina Tarantino, Pere Domingo-Pedrol, Omar HasanAli, Pedro Ventura-Aguiar, Josep María Campistol, Felipe Prosper, Ali Mirazimi, Steeve Boulant, Josef M. Penninger, Nuria Montserrat
bioRxiv 2021.08.13.456228; doi: https://doi.org/10.1101/2021.08.13.456228

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