Abstract
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 S100 family genes (S100A6, S100A8, 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 FDA-approved drug Auranofin mitigated SARS-CoV-2 replication in preclinical hamster model.
Funding: This study was supported by the DBT-IISc partnership program (DBT (IED/4/2020-MED/DBT)), the Infosys Young Investigator award (YI/2019/1106), DBT-BIRAC grant (BT/CS0007/CS/02/20) and the DBT-Wellcome Trust India Alliance Intermediate Fellowship (IA/I/18/1/503613) to ST lab.
Keywords: Auranofin; COVID-19; Meta-analysis; Nasal swab/BALF; Prognostic marker; Proteome; Transcriptome.
【저자키워드】 COVID-19, Meta-analysis, Transcriptome, auranofin, Prognostic marker, proteome, Nasal swab/BALF, 【초록키워드】 Meta-analysis, Transcriptome, Inflammation, severe COVID-19, translation, IL-6, COVID-19 pandemic, India, Intervention, Prognostic markers, host response, in vitro, Prophylactic, COVID-19 disease, Cohort, Viral, viral replication, mRNA, Lungs, Cell culture, therapeutic, Patient, DBT, Factors, auranofin, Prognostic marker, target, targets, Trust, proteome, nasal swab, hamster, respiratory, Respiratory samples, upper respiratory tract, SARS-CoV-2 replication, severe COVID-19 disease, therapeutic targets, thioredoxin, COVID-19 patients, S100A8, administration, Analysis, COVID-19 patient, regimen, oral administration, profile, FDA-approved drug, These data, multitude, overexpression, nasal swabs, S100A9, intermediate, while, COVID-19 cohort, mRNA level, inflammation in the lungs, Host, mitigate, lab, respiratory sample, S100A6, S100P, selected, conducted, reduced, supported, upregulated, individuals, Alliance, TXN, was tested, 【제목키워드】 identification, therapeutic target, nasopharyngeal sample,