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 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; Hagit Achdout; Anthony Aimon; Elad Bar-David; Haim Barr; Amir Ben-Shmuel; James Bennett; Rebekka K. Schneider; Rafael Kramann

doi:10.1016/j.stem.2021.12.010

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 journal › Article › Academic › peer-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 language	English
Pages (from-to)	217-231.e8
Journal	Cell Stem Cell
Volume	29
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2021.12.010
Publication status	Published - 3 Feb 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 (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. 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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Jansen, J., Reimer, K. C., The COVID Moonshot consortium, Nagai, J. S., Varghese, F. S., Overheul, G. J., de Beer, M., Roverts, R., Daviran, D., Fermin, L. A. S., Willemsen, B., Beukenboom, M., Djudjaj, S., von Stillfried, S., van Eijk, L. E., Mastik, M., Bulthuis, M., Dunnen, W. D., van Goor, H., ... Kramann, R. (2022). SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids. Cell Stem Cell, 29(2), 217-231.e8. https://doi.org/10.1016/j.stem.2021.12.010

@article{e6089341d672469da35f111f3f5eefa7,

title = "SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids",

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.",

author = "Jitske Jansen and Reimer, {Katharina C.} and {The COVID Moonshot consortium} and Nagai, {James S.} and Varghese, {Finny S.} and Overheul, {Gijs J.} and {de Beer}, Marit and Rona Roverts and Deniz Daviran and Fermin, {Liline A.S.} and Brigith Willemsen and Marcel Beukenboom and Sonja Djudjaj and {von Stillfried}, Saskia and {van Eijk}, {Larissa E.} and Mirjam Mastik and Marian Bulthuis and Dunnen, {Wilfred den} and {van Goor}, Harry and Hillebrands, {Jan Luuk} and Triana, {Sergio H.} and Theodore Alexandrov and Timm, {Marie Cherelle} and {van den Berge}, {Bartholomeus T.} and {van den Broek}, Martijn and Quincy Nlandu and Joelle Heijnert and Bindels, {Eric M.J.} and Hoogenboezem, {Remco M.} and Fieke Mooren and Christoph Kuppe and Pascal Miesen and Katrien Gr{\"u}nberg and Ties Ijzermans and Steenbergen, {Eric J.} and Jan Czogalla and Schreuder, {Michiel F.} and Nico Sommerdijk and Anat Akiva and Peter Boor and Puelles, {Victor G.} and J{\"u}rgen Floege and Huber, {Tobias B.} and Hagit Achdout and Anthony Aimon and Elad Bar-David and Haim Barr and Amir Ben-Shmuel and James Bennett and Schneider, {Rebekka K.} and Rafael Kramann",

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{\'e} Universit{\"a}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 (Charit{\'e} Universit{\"a}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{\textquoteright}s Hospital, Radboud University Medical Center) for support with statistical analysis regarding the COVID-19 patient cohort. Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2022",

month = feb,

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doi = "10.1016/j.stem.2021.12.010",

language = "English",

volume = "29",

pages = "217--231.e8",

journal = "Cell Stem Cell",

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Jansen, J, Reimer, KC, The COVID Moonshot consortium, Nagai, JS, Varghese, FS, Overheul, GJ, de Beer, M, Roverts, R, Daviran, D, Fermin, LAS, Willemsen, B, Beukenboom, M, Djudjaj, S, von Stillfried, S, van Eijk, LE, Mastik, M, Bulthuis, M, Dunnen, WD, van Goor, H, Hillebrands, JL, Triana, SH, Alexandrov, T, Timm, MC, van den Berge, BT, van den Broek, M, Nlandu, Q, Heijnert, J, Bindels, EMJ , Hoogenboezem, RM, Mooren, F, Kuppe, C, Miesen, P, Grünberg, K, Ijzermans, T, Steenbergen, EJ, Czogalla, J, Schreuder, MF, Sommerdijk, N, Akiva, A, Boor, P, Puelles, VG, Floege, J, Huber, TB, Achdout, H, Aimon, A, Bar-David, E, Barr, H, Ben-Shmuel, A, Bennett, J, Schneider, RK & Kramann, R 2022, 'SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids', Cell Stem Cell, vol. 29, no. 2, pp. 217-231.e8. https://doi.org/10.1016/j.stem.2021.12.010

TY - JOUR

T1 - SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

AU - Jansen, Jitske

AU - Reimer, Katharina C.

AU - The COVID Moonshot consortium

AU - Nagai, James S.

AU - Varghese, Finny S.

AU - Overheul, Gijs J.

AU - de Beer, Marit

AU - Roverts, Rona

AU - Daviran, Deniz

AU - Fermin, Liline A.S.

AU - Willemsen, Brigith

AU - Beukenboom, Marcel

AU - Djudjaj, Sonja

AU - von Stillfried, Saskia

AU - van Eijk, Larissa E.

AU - Mastik, Mirjam

AU - Bulthuis, Marian

AU - Dunnen, Wilfred den

AU - van Goor, Harry

AU - Hillebrands, Jan Luuk

AU - Triana, Sergio H.

AU - Alexandrov, Theodore

AU - Timm, Marie Cherelle

AU - van den Berge, Bartholomeus T.

AU - van den Broek, Martijn

AU - Nlandu, Quincy

AU - Heijnert, Joelle

AU - Bindels, Eric M.J.

AU - Hoogenboezem, Remco M.

AU - Mooren, Fieke

AU - Kuppe, Christoph

AU - Miesen, Pascal

AU - Grünberg, Katrien

AU - Ijzermans, Ties

AU - Steenbergen, Eric J.

AU - Czogalla, Jan

AU - Schreuder, Michiel F.

AU - Sommerdijk, Nico

AU - Akiva, Anat

AU - Boor, Peter

AU - Puelles, Victor G.

AU - Floege, Jürgen

AU - Huber, Tobias B.

AU - Achdout, Hagit

AU - Aimon, Anthony

AU - Bar-David, Elad

AU - Barr, Haim

AU - Ben-Shmuel, Amir

AU - Bennett, James

AU - Schneider, Rebekka K.

AU - Kramann, Rafael

N1 - 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. 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. Publisher Copyright: © 2021 The Author(s)

PY - 2022/2/3

Y1 - 2022/2/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85123016842&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2021.12.010

DO - 10.1016/j.stem.2021.12.010

M3 - Article

C2 - 35032430

AN - SCOPUS:85123016842

SN - 1934-5909

VL - 29

SP - 217-231.e8

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 2

ER -

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

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