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

Jitske Jansen, Katharina C. Reimer, The COVID Moonshot consortium, 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 HillebrandsSergio 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, Hagit Achdout, Anthony Aimon, Elad Bar-David, Haim Barr, Amir Ben-Shmuel, James Bennett, Rebekka K. Schneider, Rafael Kramann*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)217-231.e8
JournalCell Stem Cell
Volume29
Issue number2
DOIs
Publication statusAccepted/In press - 2022

Bibliographical note

Funding Information:
This work was supported by grants of the German Research Foundation (DFG: KR 4073/11-1; SFBTRR219, 322900939; and CRU344, 428857858, and CRU5011 InteraKD 445703531), a grant of the European Research Council (ERC-StG 677448), the Federal Ministry of Research and Education (BMBF NUM-COVID19, Organo-Strat 01KX2021), the Dutch Kidney Foundation (DKF) TASK FORCE consortium (CP1805), the Else Kroener Fresenius Foundation (2017_A144), and the ERA-CVD MENDAGE consortium (BMBF 01KL1907) all to R.K.; DFG (CRU 344, Z to I.G.C and CRU344 P2 to R.K.S.); and the BMBF eMed Consortium Fibromap (to V.G.P, R.K. R.K.S. and I.G.C.). R.K.S received support from the KWF Kankerbestrijding (11031/2017?1, Bas Mulder Award) and a grant by the ERC (deFiber; ERC-StG 757339). J.J. is supported by the Netherlands Organisation for Scientific Research (NWO Veni grant no: 091 501 61 81 01 36) and the DKF (grant no. 19OK005). B.S. is supported by the DKF (grant: 14A3D104) and the NWO (VIDI grant: 016.156.363). R.P.V.R. and G.J.O. are supported by the NWO VICI (grant: 16.VICI.170.090). P.B. is supported by the BMBF (DEFEAT PANDEMIcs, 01KX2021), the Federal Ministry of Health (German Registry for COVID-19 Autopsies-DeRegCOVID, www.DeRegCOVID.ukaachen.de; ZMVI1-2520COR201), and the German Research Foundation (DFG; SFB/TRR219 Project-IDs 322900939 and 454024652). S.D. received DFG support (DJ100/1-1) as well as support from VGP and TBH (SFB1192). M.d.B, R.R. N.S. and A.A. are supported by an ERC Advanced Investigator grant (H2020-ERC-2017-ADV-788982-COLMIN) to N.S. A.A. is supported by the NWO (VI.Veni.192.094). We thank Saskia de Wildt, Jeanne Pertijs (Radboudumc, Department of Pharmacology), and Robert M. Verdijk (Erasmus Medical Center, Department of Pathology) for providing tissue controls (Erasmus MC Tissue Bank) and Christian Drosten (Charit? Universit?tsmedizin Berlin, Institute of Virology) and Bart Haagmans (Erasmus Medical Center, Rotterdam) for providing the SARS-CoV-2 isolate. We thank Kioa L. Wijnsma (Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Radboud University Medical Center) for support with statistical analysis regarding the COVID-19 patient cohort. J.J. K.C.R. B.S. R.K.S. and R.K. designed the study. J.J. K.C.R. M.V.D.B. and B.T.V.D.B. cultured the iPSC-derived kidney organoids. T.I. E.J.S. K.G. P.B. S.V.S. V.G.P. J.C. T.B.H. H.V.G. J.-L.H. L.E.v.E. and W.D.D. obtained consent from patients, obtained ethical approvals, and provided tissue specimens. J.J. S.D. M.-C.T. M.V.D.B. B.T.V.D.B. B.W. R.R. M.B. F.M. Q.N. and J.H. performed tissue processing, IF, and trichrome stainings, as well as RNAscope experiments. M.B. R.R. D.D. L.A.S.F. N.S. and A.A. performed CLEM and 3D FIB-SEM analyses. L.E.E. M.M. M.B. W.D. H.G. and J.-L.H contributed tissue specimens and performed BRISH experiments. F.S.V. G.J.O. P.M. and R.P.V.R. designed and carried out SARS-CoV-2 infection experiments of the organoids. F.S.V. G.J.O. P.M. and K.C.R. performed data acquisition experiments for scRNA-seq. C.K. and K.C.R. isolated nuclei and performed data acquisition for snRNA-seq. J.S.N. and I.G.C. carried out the scRNA-seq and snRNA-seq data analyses. S.H.T. and T.A. provided protocols and assisted with tapSeq analysis. J.J. K.C.R. J.S.N. and R.K. wrote the manuscript. J.J. K.C.R. J.S.N. R.P.V.R. R.K.S. R.K. and I.G.C. arranged the figures. R.K.S. B.S. I.G.C. P.B. S.D. S.V.S. M.F.S. B.T.V.D.B, V.G.P. A.A. P.M. R.P.V.R. C.K. and R.K. edited the manuscript and advised on data analysis and interpretation. All authors read and approved the final manuscript. The authors declare no competing interests.

Funding Information:
This work was supported by grants of the German Research Foundation ( DFG : KR 4073/11-1 ; SFBTRR219, 322900939 ; and CRU344, 428857858 , and CRU5011 InteraKD 445703531 ), a grant of the European Research Council ( ERC-StG 677448 ), the Federal Ministry of Research and Education (BMBF NUM-COVID19, Organo-Strat 01KX2021 ), the Dutch Kidney Foundation (DKF) TASK FORCE consortium ( CP1805 ), the Else Kroener Fresenius Foundation ( 2017_A144 ), and the ERA-CVD MENDAGE consortium ( BMBF 01KL1907 ) all to R.K.; DFG ( CRU 344, Z to I.G.C and CRU344 P2 to R.K.S.); and the BMBF eMed Consortium Fibromap (to V.G.P, R.K., R.K.S., and I.G.C.). R.K.S received support from the KWF Kankerbestrijding ( 11031/2017–1 , Bas Mulder Award) and a grant by the ERC (deFiber; ERC-StG 757339 ). J.J. is supported by the Netherlands Organisation for Scientific Research ( NWO Veni grant no: 091 501 61 81 01 36 ) and the DKF (grant no. 19OK005 ). B.S. is supported by the DKF (grant: 14A3D104 ) and the NWO (VIDI grant: 016.156.363 ). R.P.V.R. and G.J.O. are supported by the NWO VICI (grant: 16.VICI.170.090 ). P.B. is supported by the BMBF (DEFEAT PANDEMIcs, 01KX2021 ), the Federal Ministry of Health ( German Registry for COVID-19 Autopsies-DeRegCOVID, www.DeRegCOVID.ukaachen.de ; ZMVI1-2520COR201 ), and the German Research Foundation (DFG; SFB/TRR219 Project-IDs 322900939 and 454024652 ). S.D. received DFG support ( DJ100/1-1 ) as well as support from VGP and TBH ( SFB1192 ). M.d.B, R.R., N.S., and A.A. are supported by an ERC Advanced Investigator grant ( H2020-ERC-2017-ADV-788982-COLMIN ) to N.S. A.A. is supported by the NWO ( VI.Veni.192.094 ). We thank Saskia de Wildt, Jeanne Pertijs (Radboudumc, Department of Pharmacology), and Robert M. Verdijk (Erasmus Medical Center, Department of Pathology) for providing tissue controls (Erasmus MC Tissue Bank) and Christian Drosten (Charité Universitätsmedizin Berlin, Institute of Virology) and Bart Haagmans (Erasmus Medical Center, Rotterdam) for providing the SARS-CoV-2 isolate. We thank Kioa L. Wijnsma (Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children’s Hospital, Radboud University Medical Center) for support with statistical analysis regarding the COVID-19 patient cohort.

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