1. Cross-validation of SARS-CoV-2 responses in kidney organoids and clinical populations.
- Author
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Helms L, Marchiano S, Stanaway IB, Hsiang TY, Juliar BA, Saini S, Zhao YT, Khanna A, Menon R, Alakwaa F, Mikacenic C, Morrell ED, Wurfel MM, Kretzler M, Harder JL, Murry CE, Himmelfarb J, Ruohola-Baker H, Bhatraju PK, Gale M Jr, and Freedman BS
- Subjects
- Acute Kidney Injury etiology, Adult, Aged, Angiotensin-Converting Enzyme 2 genetics, Animals, Apoptosis, Bowman Capsule cytology, Bowman Capsule virology, COVID-19 complications, Chlorocebus aethiops, Female, Gene Knockout Techniques, Hospital Mortality, Hospitalization, Humans, Kidney metabolism, Kidney pathology, Kidney Tubules, Proximal metabolism, Kidney Tubules, Proximal pathology, Male, Middle Aged, Organoids metabolism, Podocytes virology, Polycystic Kidney Diseases, Protein Kinase D2 genetics, Proteome, Receptors, Coronavirus genetics, Reproducibility of Results, Transcriptome, Vero Cells, Viral Tropism, Virus Replication, Acute Kidney Injury urine, COVID-19 urine, Kidney virology, Kidney Tubules, Proximal virology, Organoids virology, SARS-CoV-2 pathogenicity
- Abstract
Kidneys are critical target organs of COVID-19, but susceptibility and responses to infection remain poorly understood. Here, we combine SARS-CoV-2 variants with genome-edited kidney organoids and clinical data to investigate tropism, mechanism, and therapeutics. SARS-CoV-2 specifically infects organoid proximal tubules among diverse cell types. Infections produce replicating virus, apoptosis, and disrupted cell morphology, features of which are revealed in the context of polycystic kidney disease. Cross-validation of gene expression patterns in organoids reflects proteomic signatures of COVID-19 in the urine of critically ill patients indicating interferon pathway upregulation. SARS-CoV-2 viral variants alpha, beta, gamma, kappa, and delta exhibit comparable levels of infection in organoids. Infection is ameliorated in ACE2-/- organoids and blocked via treatment with de novo-designed spike binder peptides. Collectively, these studies clarify the impact of kidney infection in COVID-19 as reflected in organoids and clinical populations, enabling assessment of viral fitness and emerging therapies.
- Published
- 2021
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