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

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.-.; Triana, S.H.; Alexandrov, T.; Timm, M.-.; van den Berge, B.T.; van den Broek, M.; Nlandu, Q.; Heijnert, J.; Bindels, E.M.J.; Hoogenboezem, R.M.; Mooren, F.; Kuppe, C.; Miesen, P.; Grunberg, K.; Ijzermans, T.; Steenbergen, E.J.; Czogalla, J.; Schreuder, M.F.; Sommerdijk, N.; Akiva, A.; Boor, P.; Puelles, V.G.; Floege, J.; Huber, T.B.; Achdout, H.; Aimon, A.; Bar-David, E.; Barr, H.; Ben-Shmuel, A.; Bennett, J.; Boby, M.L.; Borden, B.; Bowman, G.R.; Brun, J.; Bvnbs, S.; Calmiano, M.; Carbery, A.; Cattermole, E.; Chernychenko, E.; Choder, J.D.; Clyde, A.; Coffland, J.E.; Cohen, G.; Cole, J.; Contini, A.; Cox, L.; Cvitkovic, M.; Dias, A.; Donckers, K.; Dotson, D.L.; Douangamath, A.; Duberstein, S.; Dudgeon, T.; Dunnett, L.; Eastman, P.K.; Erez, N.; Eyermann, C.J.; Fairhead, M.; Fate, G.; Fearon, D.; Federov, O.; Ferla, M.; Fernandes, R.S.; Ferrins, L.; Foster, R.; Foster, H.; Gabizon, R.; Garcia-Sastre, A.; Gawriljuk, V.O.; Gehrtz, P.; Gileadi, C.; Giroud, C.; Glass, W.G.; Glen, R.; Glinert, I.; Godoy, A.S.; Gorichko, M.; Gorrie-Stone, T.; Griffen, E.J.; Hart, S.H.; Heer, J.; Henry, M.; Hill, M.; Horrell, S.; Hurley, M.F.D.; Israely, T.; Jajack, A.; Jnoff, E.; Jochmans, D.; John, T.; De Jonghe, S.; Kantsadi, A.L.; Kenny, P.W.; Kiappes, J.L.; Koekemoer, L.; Kovar, B.; Krojer, T.; Lee, A.A.; Lefker, B.A.; Levy, H.; London, N.; Lukacik, P.; Macdonald, H.B.; Maclean, B.; Malla, T.R.; Matviiuk, T.; Mccorkindale, W.; Mcgovern, B.L.; Melamed, S.; Michurin, O.; Mikolajek, H.; Milne, B.F.; Morris, A.; Morris, G.M.; Morwitzer, M.J.; Moustakas, D.; Nakamura, A.M.; Neto, J.B.; Neyts, J.; Nguyen, L.; Noske, G.D.; 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, V.L.; Reddi, R.N.; Reid, S.P.; Resnick, E.; Ripka, E.G.; Robinson, M.C.; Robinson, R.P.; 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, M.D.; Solmesky, L.J.; Spencer, J.; Strain-Damarell, C.; Swamy, V.; Tamir, H.; Tennant, R.; Thompson, W.; Thompson, A.; Tomasia, S.; Tumber, A.; Vakonakis, I.; van Rij, R.P.; van Geel, L.; Vaschetto, M.; Vitner, E.B.; Voelz, V.; Volkamer, A.; von Delft, F.; von Delft, A.; Walsh, M.; Ward, W.; Weatherall, C.; Weiss, S.; White, K.M.; Wild, C.F.; Wittmann, M.; Wright, N.; Yahalom-Ronen, Y.; Zaidmann, D.; Zidane, H.; Zitzmann, N.; Costa, I.G.; Schneider, R.K.; Smeets, B.; Kramann, R.

doi:10.1016/j.stem.2021.12.010

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.

SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids / J. Jansen, K.C. Reimer, J.S. Nagai, F.S. Varghese, G.J. Overheul, M. de Beer, R. Roverts, D. Daviran, L.A.S. Fermin, B. Willemsen, M. Beukenboom, S. Djudjaj, S. von Stillfried, L.E. van Eijk, M. Mastik, M. Bulthuis, W.D. Dunnen, H. van Goor, J.-. Hillebrands, S.H. Triana, T. Alexandrov, M.-. Timm, B.T. van den Berge, M. van den Broek, Q. Nlandu, J. Heijnert, E.M.J. Bindels, R.M. Hoogenboezem, F. Mooren, C. Kuppe, P. Miesen, K. Grunberg, T. Ijzermans, E.J. Steenbergen, J. Czogalla, M.F. Schreuder, N. Sommerdijk, A. Akiva, P. Boor, V.G. Puelles, J. Floege, T.B. Huber, H. Achdout, A. Aimon, E. Bar-David, H. Barr, A. Ben-Shmuel, J. Bennett, M.L. Boby, B. Borden, G.R. Bowman, J. Brun, S. Bvnbs, M. Calmiano, A. Carbery, E. Cattermole, E. Chernychenko, J.D. Choder, A. Clyde, J.E. Coffland, G. Cohen, J. Cole, A. Contini, L. Cox, M. Cvitkovic, A. Dias, K. Donckers, D.L. Dotson, A. Douangamath, S. Duberstein, T. Dudgeon, L. Dunnett, P.K. Eastman, N. Erez, C.J. Eyermann, M. Fairhead, G. Fate, D. Fearon, O. Federov, M. Ferla, R.S. Fernandes, L. Ferrins, R. Foster, H. Foster, R. Gabizon, A. Garcia-Sastre, V.O. Gawriljuk, P. Gehrtz, C. Gileadi, C. Giroud, W.G. Glass, R. Glen, G. Itai, A.S. Godoy, M. Gorichko, T. Gorrie-Stone, E.J. Griffen, S.H. Hart, J. Heer, M. Henry, M. Hill, S. Horrell, M.F.D. Hurley, T. Israely, A. Jajack, E. Jnoff, D. Jochmans, T. John, S. De Jonghe, A.L. Kantsadi, P.W. Kenny, J.L. Kiappes, L. Koekemoer, B. Kovar, T. Krojer, A.A. Lee, B.A. Lefker, H. Levy, N. London, P. Lukacik, H.B. Macdonald, B. Maclean, T.R. Malla, T. Matviiuk, W. McCorkindale, B.L. McGovern, S. Melamed, O. Michurin, H. Mikolajek, B.F. Milne, A. Morris, G.M. Morris, M.J. Morwitzer, D. Moustakas, A.M. Nakamura, J.B. Neto, J. Neyts, L. Nguyen, G.D. Noske, V. Oleinikovas, G. Oliva, D. Owen, V. Psenak, R. Pai, J. Pan, N. Paran, B. Perry, M. Pingle, J. Pinjari, B. Politi, A. Powell, R. Puni, V.L. Rangel, R.N. Reddi, S.P. Reid, E. Resnick, E.G. Ripka, M.C. Robinson, R.P. Robinson, J. Rodriguez-Guerra, R. Rosales, D. Rufa, C. Schofield, M. Shafeev, A. Shaikh, J. Shi, K. Shurrush, S. Sing, A. Sittner, R. Skyner, A. Smalley, M.D. Smilova, L.J. Solmesky, J. Spencer, C. Strain-Damarell, V. Swamy, H. Tamir, R. Tennant, W. Thompson, A. Thompson, S. Tomasia, A. Tumber, I. Vakonakis, R.P. van Rij, L. van Geel, M. Vaschetto, E.B. Vitner, V. Voelz, A. Volkamer, F. von Delft, A. von Delft, M. Walsh, W. Ward, C. Weatherall, S. Weiss, K.M. White, C.F. Wild, M. Wittmann, N. Wright, Y. Yahalom-Ronen, D. Zaidmann, H. Zidane, N. Zitzmann, I.G. Costa, R.K. Schneider, B. Smeets, R. Kramann. - In: CELL STEM CELL. - ISSN 1934-5909. - 29:2(2022 Feb 03), pp. 217-231.e8. [10.1016/j.stem.2021.12.010]

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

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.;Triana S. H.;Alexandrov T.;Timm M. -C.;van den Berge B. T.;van den Broek M.;Nlandu Q.;Heijnert J.;Bindels E. M. J.;Hoogenboezem R. M.;Mooren F.;Kuppe C.;Miesen P.;Grunberg K.;Ijzermans T.;Steenbergen E. J.;Czogalla J.;Schreuder M. F.;Sommerdijk N.;Akiva A.;Boor P.;Puelles V. G.;Floege J.;Huber T. B.;Achdout H.;Aimon A.;Bar-David E.;Barr H.;Ben-Shmuel A.;Bennett J.;Boby M. L.;Borden B.;Bowman G. R.;Brun J.;BVNBS S.;Calmiano M.;Carbery A.;Cattermole E.;Chernychenko E.;Choder J. D.;Clyde A.;Coffland J. E.;Cohen G.;Cole J.;A. Contini;Cox L.;Cvitkovic M.;Dias A.;Donckers K.;Dotson D. L.;Douangamath A.;Duberstein S.;Dudgeon T.;Dunnett L.;Eastman P. K.;Erez N.;Eyermann C. J.;Fairhead M.;Fate G.;Fearon D.;Federov O.;Ferla M.;Fernandes R. S.;Ferrins L.;Foster R.;Foster H.;Gabizon R.;Garcia-Sastre A.;Gawriljuk V. O.;Gehrtz P.;Gileadi C.;Giroud C.;Glass W. G.;Glen R.;Itai glinert;Godoy A. S.;Gorichko M.;Gorrie-Stone T.;Griffen E. J.;Hart S. H.;Heer J.;Henry M.;Hill M.;Horrell S.;Hurley M. F. D.;Israely T.;Jajack A.;Jnoff E.;Jochmans D.;John T.;De Jonghe S.;Kantsadi A. L.;Kenny P. W.;Kiappes J. L.;Koekemoer L.;Kovar B.;Krojer T.;Lee A. A.;Lefker B. A.;Levy H.;London N.;Lukacik P.;Macdonald H. B.;Maclean B.;Malla T. R.;Matviiuk T.;McCorkindale W.;McGovern B. L.;Melamed S.;Michurin O.;Mikolajek H.;Milne B. F.;Morris A.;Morris G. M.;Morwitzer M. J.;Moustakas D.;Nakamura A. M.;Neto J. B.;Neyts J.;Nguyen L.;Noske G. D.;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 V. L.;Reddi R. N.;Reid S. P.;Resnick E.;Ripka E. G.;Robinson M. C.;Robinson R. P.;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 M. D.;Solmesky L. J.;Spencer J.;Strain-Damarell C.;Swamy V.;Tamir H.;Tennant R.;Thompson W.;Thompson A.;Tomasia S.;Tumber A.;Vakonakis I.;van Rij R. P.;van Geel L.;Vaschetto M.;Vitner E. B.;Voelz V.;Volkamer A.;von Delft F.;von Delft A.;Walsh M.;Ward W.;Weatherall C.;Weiss S.;White K. M.;Wild C. F.;Wittmann M.;Wright N.;Yahalom-Ronen Y.;Zaidmann D.;Zidane H.;Zitzmann N.;Costa I. G.;Schneider R. K.;Smeets B.;Kramann R.

2022

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.

Scheda breve

Scheda completa

Scheda completa (DC)

	Parole chiave
	
			chronic kidney disease; COVID-19; fibrosis; human iPSC kidney organoids; kidney injury; protease blocker; SARS-CoV-2; Fibrosis; Humans; Kidney; Organoids; COVID-19; SARS-CoV-2
		
	Settori scientifico-disciplinari dell'articolo
	
			Settore CHIM/06 - Chimica Organica
Settore MED/04 - Patologia Generale
		
	Data di pubblicazione
	
			3-feb-2022
		
	Rivista in ANCE
	
			CELL STEM CELL
		
	DOI
	
			https://dx.doi.org/10.1016/j.stem.2021.12.010
		
	Tipologia
	
			Article (author)
		
	Appare nelle tipologie:
	
			01 - Articolo su periodico

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