Report
Integrative analysis of functional genomic screening and clinical data identifies a protective role for spironolactone in severe COVID-19

https://doi.org/10.1016/j.crmeth.2023.100503Get rights and content
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Highlights

  • RxGRID is a method for network-based drug prioritization using CRISPR screening data

  • RxGRID identifies spironolactone as a potential modulator of SARS-CoV-2 entry

  • Spironolactone is associated with improved COVID-19 outcomes in a retrospective study

Motivation

The emergence of SARS-CoV-2 variants with resistance to existing COVID-19 treatments and evasion from prior vaccination reinforces the need for drugs targeting host entry factors. Nonetheless, there is a lack of methods that systematically and rapidly prioritize host-targeting drugs for viral infection. High-throughput functional screens provide an unbiased and broadly accessible means of identifying genes that influence the infection of host cells. However, it remains challenging to infer pharmacologic signatures from functional screening data.

Summary

We demonstrate that integrative analysis of CRISPR screening datasets enables network-based prioritization of prescription drugs modulating viral entry in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by developing a network-based approach called Rapid proXimity Guidance for Repurposing Investigational Drugs (RxGRID). We use our results to guide a propensity-score-matched, retrospective cohort study of 64,349 COVID-19 patients, showing that a top candidate drug, spironolactone, is associated with improved clinical prognosis, measured by intensive care unit (ICU) admission and mechanical ventilation rates. Finally, we show that spironolactone exerts a dose-dependent inhibitory effect on viral entry in human lung epithelial cells. Our RxGRID method presents a computational framework, implemented as an open-source software package, enabling genomics researchers to identify drugs likely to modulate a molecular phenotype of interest based on high-throughput screening data. Our results, derived from this method and supported by experimental and clinical analysis, add additional supporting evidence for a potential protective role of the potassium-sparing diuretic spironolactone in severe COVID-19.

Research topic(s)

CP: Microbiology
CP: Systems biology

Data and code availability

All CRISPR screening data analyzed are publicly available from their respective source publications as listed in the key resources table. Patient medical record data is not publicly available due to patient privacy regulations. Pseudoviral inhibition assay data will be shared by the lead contact upon request.

All original code has been deposited at https://github.com/henrycousins/RxGRID and archived on Zenodo (https://doi.org/10.5281/zenodo.7789897) and is publicly available as of the date of publication.

Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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