SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

Jitske Jansen; Katharina C Reimer; James S Nagai; Finny S Varghese; Gijs J Overheul; Marit de Beer; Rona Roverts; Deniz Daviran; Liline A S Fermin; Brigith Willemsen; Marcel Beukenboom; Sonja Djudjaj; Saskia von Stillfried; Larissa E van Eijk; Mirjam Mastik; Marian Bulthuis; Wilfred den Dunnen; Harry van Goor; Jan-Luuk Hillebrands; Sergio H Triana; Theodore Alexandrov; Marie-Cherelle Timm; Bartholomeus T van den Berge; Martijn van den Broek; Quincy Nlandu; Joelle Heijnert; Eric M J Bindels; Remco M Hoogenboezem; Fieke Mooren; Christoph Kuppe; Pascal Miesen; Katrien Grünberg; Ties Ijzermans; Eric J Steenbergen; Jan Czogalla; Michiel F Schreuder; Nico Sommerdijk; Anat Akiva; Peter Boor; Victor G Puelles; Jürgen Floege; Tobias B Huber; COVID Moonshot consortium; Ronald P van Rij; Ivan G Costa; Rebekka K Schneider; Bart Smeets; Rafael Kramann

doi:10.1016/j.stem.2021.12.010

SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

Cell Stem Cell. 2022 Feb 3;29(2):217-231.e8. doi: 10.1016/j.stem.2021.12.010. Epub 2021 Dec 25.

Authors

Jitske Jansen¹, Katharina C Reimer², James S Nagai³, Finny S Varghese⁴, Gijs J Overheul⁴, Marit de Beer⁵, Rona Roverts⁵, Deniz Daviran⁵, Liline A S Fermin⁵, Brigith Willemsen⁶, Marcel Beukenboom⁶, Sonja Djudjaj⁷, Saskia von Stillfried⁷, Larissa E van Eijk⁸, Mirjam Mastik⁸, Marian Bulthuis⁸, Wilfred den Dunnen⁸, Harry van Goor⁸, Jan-Luuk Hillebrands⁸, Sergio H Triana⁹, Theodore Alexandrov¹⁰, Marie-Cherelle Timm⁷, Bartholomeus T van den Berge¹¹, Martijn van den Broek¹², Quincy Nlandu⁶, Joelle Heijnert⁶, Eric M J Bindels¹³, Remco M Hoogenboezem¹³, Fieke Mooren⁶, Christoph Kuppe¹⁴, Pascal Miesen⁴, Katrien Grünberg⁶, Ties Ijzermans¹⁵, Eric J Steenbergen⁶, Jan Czogalla¹⁶, Michiel F Schreuder¹⁷, Nico Sommerdijk⁵, Anat Akiva⁵, Peter Boor¹⁸, Victor G Puelles¹⁶, Jürgen Floege¹⁹, Tobias B Huber¹⁶; COVID Moonshot consortium; Ronald P van Rij⁴, Ivan G Costa³, Rebekka K Schneider²⁰, Bart Smeets⁶, Rafael Kramann²¹

Collaborators

COVID Moonshot consortium:
Hagit Achdout, Anthony Aimon, Elad Bar-David, Haim Barr, Amir Ben-Shmuel, James Bennett, Melissa L Boby, Bruce Borden, Gregory R Bowman, Juliane Brun, Sarma Bvnbs, Mark Calmiano, Anna Carbery, Emma Cattermole, Eugene Chernychenko, John D Choder, Austin Clyde, Joseph E Coffland, Galit Cohen, Jason Cole, Alessandro Contini, Lisa Cox, Milan Cvitkovic, Alex Dias, Kim Donckers, David L Dotson, Alica Douangamath, Shirly Duberstein, Tim Dudgeon, Louise Dunnett, Peter K Eastman, Noam Erez, Charles J Eyermann, Mike Fairhead, Gwen Fate, Daren Fearon, Oleg Federov, Matteo Ferla, Rafaela S Fernandes, Lori Ferrins, Richard Foster, Holly Foster, Ronen Gabizon, Adolfo Garcia-Sastre, Victor O Gawriljuk, Paul Gehrtz, Carina Gileadi, Charline Giroud, William G Glass, Robert Glen, Itai Glinert, Andre S Godoy, Marian Gorichko, Tyler Gorrie-Stone, Ed J Griffen, Storm Hassell Hart, Jag Heer, Micheal Henry, Michelle Hill, Sam Horrell, Matthew F D Hurley, Tomer Israely, Andrew Jajack, Eric Jnoff, Dirk Jochmans, Tobias John, Steven De Jonghe, Anastassia L Kantsadi, Peter W Kenny, J L Kiappes, Lizbe Koekemoer, Boris Kovar, Tobias Krojer, Alpha A Lee, Bruce A Lefker, Haim Levy, Nir London, Petra Lukacik, Hannah Bruce Macdonald, Beth Maclean, Tika R Malla, Tatiana Matviiuk, Willam McCorkindale, Briana L McGovern, Sharon Melamed, Oleg Michurin, Halina Mikolajek, Bruce F Milne, Aaron Morris, Garret M Morris, Melody Jane Morwitzer, Demetri Moustakas, Aline M Nakamura, Jose Brandao Neto, Johan Neyts, Luong Nguyen, Gabriela D Noske, Vladas Oleinikovas, Glaucius Oliva, Gijs J Overheul, David Owen, Vladimir Psenak, Ruby Pai, Jin Pan, Nir Paran, Benjamin Perry, Maneesh Pingle, Jakir Pinjari, Boaz Politi, Ailsa Powell, Reut Puni, Victor L Rangel, Ranbabu N Reddi, St Patrick Reid, Efrat Resnick, Emily Grace Ripka, Matthew C Robinson, Ralph P Robinson, Jaime Rodriguez-Guerra, Romel Rosales, Dominic Rufa, Chris Schofield, Mikhail Shafeev, Aarif Shaikh, Jiye Shi, Khriesto Shurrush, Sukrit Sing, Assa Sittner, Rachael Skyner, Adam Smalley, Mihaela D Smilova, Leonardo J Solmesky, John Spencer, Claire Strain-Damarell, Vishwanath Swamy, Hadas Tamir, Rachael Tennant, Warren Thompson, Andrew Thompson, Warren Thompson, Susana Tomasia, Anthony Tumber, Ioannis Vakonakis, Ronald P van Rij, Laura van Geel, Finny S Varghese, Mariana Vaschetto, Einat B Vitner, Vincent Voelz, Andra Volkamer, Frank von Delft, Annette von Delft, Martin Walsh, Walter Ward, Charlie Weatherall, Shay Weiss, Kris M White, Conor Francis Wild, Matthew Wittmann, Nathan Wright, Yfat Yahalom-Ronen, Daniel Zaidmann, Hadeer Zidane, Nicole Zitzmann

Affiliations

¹ Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany; Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Amalia Children's Hospital, Nijmegen, the Netherlands.
² Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany; Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany; Institute for Biomedical Technologies, Department of Cell Biology, RWTH Aachen University, Aachen, Germany.
³ Institute for Computational Genomics, University Hospital RWTH Aachen, Germany; Joint Research Center for Computational Biomedicine, RWTH Aachen University Hospital, Aachen, Germany.
⁴ Department of Medical Microbiology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
⁵ Electron Microscopy Center, Radboudumc Technology Center Microscopy, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein, 6525 GA Nijmegen, the Netherlands.
⁶ Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
⁷ Department of Pathology and Electron Microscopy Facility, RWTH Aachen University, Aachen, Germany.
⁸ Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁹ Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
¹⁰ Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA; Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory, Heidelberg, Germany.
¹¹ Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
¹² Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Amalia Children's Hospital, Nijmegen, the Netherlands.
¹³ Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
¹⁴ Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany; Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
¹⁵ Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁶ Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁷ Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Amalia Children's Hospital, Nijmegen, the Netherlands.
¹⁸ Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany; Department of Pathology and Electron Microscopy Facility, RWTH Aachen University, Aachen, Germany.
¹⁹ Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
²⁰ Institute for Biomedical Technologies, Department of Cell Biology, RWTH Aachen University, Aachen, Germany; Department of Developmental Biology, Erasmus Medisch Centrum, Rotterdam, the Netherlands; Oncode Institute, Erasmus Medisch Centrum, Rotterdam, the Netherlands.
²¹ Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany; Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany; Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medisch Centrum, Rotterdam, the Netherlands. Electronic address: [email protected].

Abstract

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.

Keywords: COVID-19; SARS-CoV-2; chronic kidney disease; fibrosis; human iPSC kidney organoids; kidney injury; protease blocker.

MeSH terms

COVID-19* / complications
Fibrosis
Humans
Kidney
Organoids / pathology
Post-Acute COVID-19 Syndrome
SARS-CoV-2*