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The transcriptomic landscape of PBMC in SARS-CoV-2 variants-infected Rhesus monkeys via digital RNA-seq analysis

ABSTRACT: The ensuing COVID-19 epidemic and the highly frequent mutations of SARS-CoV-2 have brought an immense social burden to all fields of society worldwide, including public health, socioeconomic development, and school education since 2020. Increasing genome evolution and mutation resulted in the birth of variants of concern (VOC), with the latter presenting differential structural features and gene functions associated with specific clinical symptoms or manifestations. Moreover, SARS-CoV-2-induced inflammation, immune response, and other biological processes involve a mountain of gene molecules and signaling pathways, still requiring further and more effort spent on them. Consequently, in this study, we comprehensively illustrate the transcriptomic landscape of different SARS-CoV-2 strains (Prototype, Beta, Delta, and Omicron) at functional clustering results level (GO and KEGG). Through our deep function analysis, we discovered AGE-RAGE signaling pathway in diabetes complications and its related downstream signaling pathways and gene molecules. Moreover, all Alzheimer disease-related gene identified in our study, such as EPHA4, FYN, CASP4 are almost validated in some authoritative journals. In all, our findings in this study provided quite a few candidate hub genes or potentially therapeutic targets, which could be a significant clue for modern precision medicine in the future.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE246985 | GEO | 2023/12/01

REPOSITORIES: GEO

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Project description:Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.5 that can partially or fully evade (1) many therapeutic monoclonal antibodies in clinical use underlines the need for additional effective treatment strategies. Here, we characterize the antiviral activity of GS-5245, Obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved RNA-dependent viral RNA polymerase (RdRp). Importantly, we show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-related Bat-CoV RsSHC014, Middle East Respiratory Syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant in vitro and highly effective as antiviral therapy in mouse models of SARS-CoV, SARS-CoV-2 (WA/1), MERS-CoV and Bat-CoV RsSHC014 pathogenesis. In all these models of divergent coronaviruses, we observed protection and/or significant reduction of disease metrics such as weight loss, lung viral replication, acute lung injury, and degradation in pulmonary function in GS-5245-treated mice compared to vehicle controls. Finally, we demonstrate that GS-5245 in combination with the main protease (Mpro) inhibitor nirmatrelvir had increased efficacy in vivo against SARS-CoV-2 compared to each single agent. We also evalulate the effect of antiviral therapy on host gene expression using RNAseq and show that therapeutic intervention reduces host inflammatory response as compared to vehicle controls during acute SARS-CoV-2 infection. Altogether, our data supports the continuing clinical evaluation of GS-5245 in humans infected with COVID-19, including as part of a combination antiviral therapy, especially in populations with the most urgent need for more efficacious and durable interventions.

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The transcriptomic landscape of PBMC in SARS-CoV-2 variants-infected Rhesus monkeys via digital RNA-seq analysis

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