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

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.

An in silico analysis identifies drugs potentially modulating the cytokine storm triggered by SARS-CoV-2 infection

“…First, S100 calcium-binding proteins and LRRK2 are known to promote inflammation and cytokine production [40][41][42][43][44] . In fact, an increase of S100 calcium-binding proteins has been reported in severe or critically ill COVID-19 patients 45,46 . Furthermore, treatment with paquinimod, a selective inhibitor of S100A8/ A9, prevented death in a lethal model of mouse coronavirus infections 47 .…”

A natural broad-spectrum inhibitor of enveloped virus entry, effective against SARS-CoV-2 and Influenza A Virus in preclinical animal models

“…With encouraging results of in vivo efficacy against IAV, we next tested the same against SARS-CoV-2. For this, we used the Syrian Golden hamster model and an optimized protocol for testing antivirals against SARS-CoV-2 developed by our group (Fig 3A) (Biji et al, 2021). We observed that IP administration of 20 mg/kg PA prophylactically and therapeutically, resulted in a reduction of lung vRNA load on D3 post-infection by ∼3 and ∼1 order of magnitude respectively (Fig 3B).…”

Circulating Calprotectin as a Predictive and Severity Biomarker in Patients with COVID-19

“…Despite progress in understanding the pathogenesis of COVID-19, the development of vaccines, and increasing experience in managing patients, COVID-19 remains a critical healthcare problem worldwide. While intense efforts to understand and predict the differential impact of SARS-CoV-2 infection on individuals have resulted in an expanding trove of data on gene, protein, and cellular processes in patients with COVID-19, front-line care of patients still focuses on the use of practical, well-understood, and easily automated routine laboratory tests [ 8 , 14 , 15 , 16 ]. The strong inflammatory component of COVID-19 has led to interest in measuring cytokines such as IL-6, as well as other differentially expressed biomarkers, but these assays are not routinely available in clinical laboratories [ 17 ].…”