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Cross-validation of SARS-CoV-2 responses in kidney organoids and clinical populations
Louisa Helms1,2,3,4,5, Silvia Marchiano1,4,5,6,7, Ian B Stanaway1,2,3
1Department of Medicine.
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.
Insights
This study reveals that the kidneys are susceptible to SARS-CoV-2 infection, particularly in proximal tubules. Kidney organoids and patient data show similar responses, aiding the development of COVID-19 therapies.
Area of Science:
- Nephrology
- Virology
- Genetics
Background:
- Kidneys are identified as key targets in COVID-19.
- Understanding kidney cell susceptibility and response to SARS-CoV-2 infection is crucial but limited.
- Investigating the mechanisms and potential treatments for kidney involvement in COVID-19 is essential.
Purpose of the Study:
- To investigate the tropism, mechanism, and therapeutic strategies for SARS-CoV-2 infection in kidney organoids.
- To correlate findings from kidney organoids with clinical data from COVID-19 patients.
- To assess the impact of different SARS-CoV-2 variants on kidney organoids.
Main Methods:
- Utilized genome-edited kidney organoids and SARS-CoV-2 variants.
- Analyzed viral tropism, cellular responses (apoptosis, morphology), and gene expression patterns.
- Cross-validated organoid data with proteomic signatures from critically ill COVID-19 patients' urine.
- Tested therapeutic interventions including ACE2 knockout and spike binder peptides.
Main Results:
- SARS-CoV-2 demonstrated specific tropism for proximal tubules in kidney organoids.
- Infection led to viral replication, apoptosis, and altered cell morphology, mirroring features seen in polycystic kidney disease.
- Gene expression patterns in organoids correlated with interferon pathway upregulation observed in COVID-19 patients.
- Viral variants (alpha, beta, gamma, kappa, delta) showed similar infection levels.
- ACE2 deficiency reduced infection, and spike binder peptides effectively blocked viral entry.
Conclusions:
- Kidney organoids serve as a valuable model to understand SARS-CoV-2 kidney tropism and infection mechanisms.
- Findings highlight the role of the interferon pathway in COVID-19 kidney pathology.
- The study validates potential therapeutic targets and strategies for mitigating kidney damage in COVID-19.
