Dorit Omer1,2, Oren Pleniceanu1,2, Yehudit Gnatek1,2, Michael Namestnikov1,2,3, Osnat Cohen-Zontag1,2, Sanja Goldberg1,2, Yehudit Eden Friedman4, Nehemya Friedman5, Michal Mandelboim5, Einat B Vitner6, Hagit Achdout6, Roy Avraham6, Eran Zahavy7, Tomer Israely6, Haim Mayan8,4, Benjamin Dekel9,2,8,10. 1. Pediatric Stem Cell Research Institute, Edmond and Lily Sara Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel. 2. Pediatric Research Center for Genetics, Development and Environment, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. 3. The Kidney Research Laboratory, The Institute of Nephrology and Hypertension, Sheba Medical Center, Ramat-Gan, Israel. 4. Department of Medicine E, Sheba Medical Center, Ramat-Gan, Israel. 5. Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat-Gan, Israel. 6. Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona, Israel. 7. Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness Ziona, Israel. 8. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. 9. Pediatric Stem Cell Research Institute, Edmond and Lily Sara Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel binyamin.dekel@sheba.health.gov.il. 10. Division of Pediatric Nephrology, Safra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel.
Abstract
BACKGROUND: Although coronavirus disease 2019 (COVID-19) causes significan t morbidity, mainly from pulmonary involvement, extrapulmonary symptoms are also major componen ts of the disease. Kidney disease, usually presenting as AKI, is particularly severe among patients with COVID-19. It is unknown, however, whether such injury results from direct kidney infection with COVID-19's causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or from indirect mechanisms. METHODS: Using ex vivo cell models, we sought to analyze SARS-CoV-2 interactions with kidney tubular cells and assess direct tubular injury. These models comprised primary human kidney epithelial cells (derived from nephrectomies) and grown as either proliferating monolayers or quiescent three-dimensional kidney spheroids. RESULTS: We demonstrated that viral entry molecules and high baseline levels of type 1 IFN-related molecules were present in monolayers and kidney spheroids. Although both models support viral infection and replication, they did not exhibit a cytopathic effect and cell death, outcomes that were strongly present in SARS-CoV-2-infected controls (African green monkey kidney clone E6 [Vero E6] cultures). A comparison of monolayer and spheroid cultures demonstrated higher infectivity and replication of SARS-CoV-2 in actively proliferating monolayers, although the spheroid cultures exhibited high er levels of ACE2. Monolayers exhibited elevation of some tubular injury molecules-including molecules related to fibrosis (COL1A1 and STAT6) and dedifferentiation (SNAI2)-and a loss of cell identity, evident by reduction in megalin (LRP2). The three-dimensional spheroids were less prone to such injury. CONCLUSIONS: SARS-CoV-2 can infect kidney cells without a cytopathic effect. AKI-induced cellular proliferation may potentially intensify infectivity and tubular damage by SARS-CoV-2, suggesting that early intervention in AKI is warranted to help minimize kidney infection.
BACKGROUND: Although coronavirus disease 2019 (COVID-19) causes significan t morbidity, mainly from pulmonary involvement, extrapulmonary symptoms are also major componen ts of the disease. Kidney disease, usually presenting as AKI, is particularly severe among patients with COVID-19. It is unknown, however, whether such injury results from direct kidney infection with COVID-19's causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or from indirect mechanisms. METHODS: Using ex vivo cell models, we sought to analyze SARS-CoV-2 interactions with kidney tubular cells and assess direct tubular injury. These models comprised primary human kidney epithelial cells (derived from nephrectomies) and grown as either proliferating monolayers or quiescent three-dimensional kidney spheroids. RESULTS: We demonstrated that viral entry molecules and high baseline levels of type 1 IFN-related molecules were present in monolayers and kidney spheroids. Although both models support viral infection and replication, they did not exhibit a cytopathic effect and cell death, outcomes that were strongly present in SARS-CoV-2-infected controls (African green monkey kidney clone E6 [Vero E6] cultures). A comparison of monolayer and spheroid cultures demonstrated higher infectivity and replication of SARS-CoV-2 in actively proliferating monolayers, although the spheroid cultures exhibited high er levels of ACE2. Monolayers exhibited elevation of some tubular injury molecules-including molecules related to fibrosis (COL1A1 and STAT6) and dedifferentiation (SNAI2)-and a loss of cell identity, evident by reduction in megalin (LRP2). The three-dimensional spheroids were less prone to such injury. CONCLUSIONS: SARS-CoV-2 can infect kidney cells without a cytopathic effect. AKI-induced cellular proliferation may potentially intensify infectivity and tubular damage by SARS-CoV-2, suggesting that early intervention in AKI is warranted to help minimize kidney infection.
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