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; 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; 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; Susana Tomasia; Anthony Tumber; Ioannis Vakonakis; Ronald P. van Rij; Laura van Geel; 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; 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

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. TrianaTheodore 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, 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, 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, Susana Tomasia, Anthony Tumber, Ioannis Vakonakis, Ronald P. van Rij, Laura van Geel, 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, Ivan G. Costa, Rebekka K. Schneider, Bart Smeets, Rafael Kramann^* (Corresponding Author)

^*Corresponding author for this work

Chemistry

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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
Number of pages	24
Journal	Cell Stem Cell
Volume	29
Issue number	2
Early online date	25 Dec 2021
DOIs	https://doi.org/10.1016/j.stem.2021.12.010
Publication status	Published - 3 Feb 2022

Bibliographical note

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 (Charite´ Universitatsmedizin 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.

Data Availability Statement

Supplementary Information
Supplemental information can be found online at https://doi.org/10.1016/j.stem.2021.12.010.

Data and code availability
Single cell RNA sequencing data generated for this study is available from Gene Expression Omnibus (GEO): https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE167747. The scripts used for pathway analyses (PROGENy and DoRothEA), ligand-receptor analysis, virus read detection (viral track), as well as the Fiji macro for fibrosis quantification in Masson’s trichrome staining are available on Zenodo: https://zenodo.org/record/5776147. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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Jansen, J., Reimer, K. C., 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., Hillebrands, J.-L., ... 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

Jansen, J, Reimer, KC, 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, J-L, Triana, SH, Alexandrov, T, Timm, M-C, 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, Boby, ML, Borden, B, Bowman, GR, Brun, J, BVNBS, S, Calmiano, M, Carbery, A, Cattermole, E, Chernychenko, E, Choder, JD, Clyde, A, Coffland, JE, Cohen, G, Cole, J, Contini, A, Cox, L, Cvitkovic, M, Dias, A, Donckers, K, Dotson, DL, Douangamath, A, Duberstein, S, Dudgeon, T, Dunnett, L, Eastman, PK, Erez, N, Eyermann, CJ, Fairhead, M, Fate, G, Fearon, D, Federov, O, Ferla, M, Fernandes, RS, Ferrins, L, Foster, R, Foster, H, Gabizon, R, Garcia-Sastre, A, Gawriljuk, VO, Gehrtz, P, Gileadi, C, Giroud, C, Glass, WG, Glen, R, glinert, I, Godoy, AS, Gorichko, M, Gorrie-Stone, T, Griffen, EJ, Hart, SH, Heer, J, Henry, M, Hill, M, Horrell, S, Hurley, MFD, Israely, T, Jajack, A, Jnoff, E, Jochmans, D, John, T, De Jonghe, S, Kantsadi, AL, Kenny, PW, Kiappes, JL, Koekemoer, L, Kovar, B, Krojer, T, Lee, AA, Lefker, BA, Levy, H, London, N, Lukacik, P, Macdonald, HB, Maclean, B, Malla, TR, Matviiuk, T, McCorkindale, W, McGovern, BL, Melamed, S, Michurin, O, Mikolajek, H, Milne, BF, Morris, A, Morris, GM, Morwitzer, MJ, Moustakas, D, Nakamura, AM, Neto, JB, Neyts, J, Nguyen, L, Noske, GD, Oleinikovas, V, Oliva, G, Owen, D, Psenak, V, Pai, R, Pan, J, Paran, N, Perry, B, Pingle, M, Pinjari, J, Politi, B, Powell, A, Puni, R, Rangel, VL, Reddi, RN, Reid, SP, Resnick, E, Ripka, EG, Robinson, MC, Robinson, RP, Rodriguez-Guerra, J, Rosales, R, Rufa, D, Schofield, C, Shafeev, M, Shaikh, A, Shi, J, Shurrush, K, Sing, S, Sittner, A, Skyner, R, Smalley, A, Smilova, MD, Solmesky, LJ, Spencer, J, Strain-Damarell, C, Swamy, V, Tamir, H, Tennant, R, Thompson, W, Thompson, A, Tomasia, S, Tumber, A, Vakonakis, I, van Rij, RP, van Geel, L, Vaschetto, M, Vitner, EB, Voelz, V, Volkamer, A, von Delft, F, von Delft, A, Walsh, M, Ward, W, Weatherall, C, Weiss, S, White, KM, Wild, CF, Wittmann, M, Wright, N, Yahalom-Ronen, Y, Zaidmann, D, Zidane, H, Zitzmann, N, Costa, IG, Schneider, RK, Smeets, B & 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

@article{e176afb5e01d45baba11f5e31d9e65c3,

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

note = "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 (Charite´ Universitatsmedizin 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.",

year = "2022",

month = feb,

day = "3",

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

language = "English",

volume = "29",

pages = "217--231.e8",

journal = "Cell Stem Cell",

issn = "1934-5909",

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TY - JOUR

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

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

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N1 - 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 (Charite´ Universitatsmedizin 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.

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.

U2 - 10.1016/j.stem.2021.12.010

DO - 10.1016/j.stem.2021.12.010

M3 - Article

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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