Identification of COVID-19 prognostic markers and therapeutic targets through meta-analysis and validation of Omics data from nasopharyngeal samples

Background: While our battle with the COVID-19 pandemic continues, a multitude of Omics data have been generated from patient samples in various studies. Translation of these data into clinical interventions against COVID-19 remains to be accomplished. Exploring host response to COVID-19 in the upper respiratory tract can unveil prognostic markers and therapeutic targets. Methods: We conducted a meta-analysis of published transcriptome and proteome profiles of respiratory samples of COVID-19 patients to shortlist high confidence upregulated host factors. Subsequently, mRNA overexpression of selected genes was validated in nasal swabs from a cohort of COVID-19 positive/negative, symptomatic/asymptomatic individuals. Guided by this analysis, we sought to check for potential drug targets. An FDA-approved drug, Auranofin, was tested against SARS-CoV-2 replication in cell culture and Syrian hamster challenge model. Findings: The meta-analysis and validation in the COVID-19 cohort revealed 5100 family genes (S100A6, S100AB, S100A9, and S100P) as prognostic markers of severe COVID-19. Furthermore, Thioredoxin (TXN) was found to be consistently upregulated. Auranofin, which targets Thioredoxin reductase, was found to mitigate SARS-CoV-2 replication in vitro. Furthermore, oral administration of Auranofin in Syrian hamsters in therapeutic as well as prophylactic regimen reduced viral replication, IL-6 production, and inflammation in the lungs. Interpretation: Elevated mRNA level of S100s in the nasal swabs indicate severe COVID-19 disease, and FDAapproved drug Auranofin mitigated SARS-CoV-2 replication in preclinical hamster model. (C) 2021 The Author( s). Published by Elsevier B.V.

Automated summary

Analysis and validation revealed S100 family genes (S100A6, S100AB, S100A9, and S100P) as prognostic markers of severe COVID-19. Thioredoxin (TXN) was consistently upregulated. Auranofin, targeting Thioredoxin reductase, reduced SARS-CoV-2 replication in vitro and in a preclinical hamster model.