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 | |
| State | Published - 3 Feb 2022 |
Keywords
- COVID-19
- SARS-CoV-2
- chronic kidney disease
- fibrosis
- human iPSC kidney organoids
- kidney injury
- protease blocker
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In: Cell Stem Cell, Vol. 29, No. 2, 03.02.2022, p. 217-231.e8.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids
AU - The COVID Moonshot consortium
AU - Jansen, Jitske
AU - Reimer, Katharina C.
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 - Garcia-Sastre, Adolfo
AU - White, Kris M.
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.
KW - COVID-19
KW - SARS-CoV-2
KW - chronic kidney disease
KW - fibrosis
KW - human iPSC kidney organoids
KW - kidney injury
KW - protease blocker
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 -