Cross-validation of SARS-CoV-2 responses in kidney organoids and clinical populations.

Louisa Helms ,Shally Saini ,Charles E Murry ,Jonathan Himmelfarb ,Silvia Marchianò ,Pavan K Bhatraju ,Matthias Kretzler ,Fadhl Alakwaa ,Yan Ting Zhao ,Ian B Stanaway ,Tien-Ying Hsiang ,Rajasree Menon ,Carmen Mikacenic ,Akshita Khanna ,Mark M Wurfel ,Jennifer L Harder ,Michael Gale ,Hannele Ruohola‐Baker ,Eric D Morrell ,Benjamin A Juliar ,Benjamin Freedman

doi:10.1172/jci.insight.154882

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.

Highlights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first detected at the end of 2019 in the Hubei province of China, has spread worldwide, causing the coronavirus disease COVID-19 [1]
Using a fluorescent SARS-CoV-2 reporter virus with infectious properties comparable to those of native SARS-CoV-2, we directly demonstrate that the proximal tubules are uniquely infected in these cultures [30]
polycystic kidney disease (PKD) cysts, which feature a more squamous epithelium, contain cells expressing Angiotensin-converting enzyme 2 (ACE2) and LTL that are susceptible to SARS-CoV-2 infection, which likely derive from proximal tubules [37]

Summary

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first detected at the end of 2019 in the Hubei province of China, has spread worldwide, causing the coronavirus disease COVID-19 [1]. Because human pluripotent stem cells are immortal, they are readily amenable to genome editing to produce isogenic pairs of mutant and control cell lines, enabling reconstitution of hereditary disease phenotypes such as polycystic kidney disease (PKD) cystogenesis in derived organoids [28] Such cell lines cannot be readily established from primary cultures, which typically senesce rapidly and have a much more limited proliferative potential [24]. We cross-validate SARS-CoV-2’s impact on kidney organoids and clinical data to investigate tropism, mechanism, and therapeutics These findings provide clear evidence of SARS-CoV-2’s kidney tropism, acute cytopathic effects, systemic and kidney-specific proteomic responses, and efficacy of COVID-19 therapeutics

Results

Discussion

Methods

Data availability and material transfer agreements