Pushparaj Peter Natesan, Abdulkareem Angham Abdulrahman, Naseer Muhammad Imran
Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
Front Pharmacol. 2021 Aug 31;12:688227. doi: 10.3389/fphar.2021.688227. eCollection 2021.
SARS-CoV-2 is the causative agent for coronavirus disease-19 (COVID-19) and belongs to the family Coronaviridae that causes sickness varying from the common cold to more severe illnesses such as severe acute respiratory syndrome, sudden stroke, neurological complications (Neuro-COVID), multiple organ failure, and mortality in some patients. The gene expression profiles of COVID-19 infection models can be used to decipher potential therapeutics for COVID-19 and related pathologies, such as Neuro-COVID. Here, we used the raw RNA-seq reads (Single-End) in quadruplicates derived using Illumina Next Seq 500 from SARS-CoV-infected primary human bronchial epithelium (NHBE) and mock-treated NHBE cells obtained from the Gene Expression Omnibus (GEO) (GSE147507), and the quality control (QC) was evaluated using the CLC Genomics Workbench 20.0 (Qiagen, United States) before the RNA-seq analysis using BioJupies web tool and iPathwayGuide for gene ontologies (GO), pathways, upstream regulator genes, small molecules, and natural products. Additionally, single-cell transcriptomics data (GSE163005) of meta clusters of immune cells from the cerebrospinal fluid (CSF), such as T-cells/natural killer cells (NK) (TcMeta), dendritic cells (DCMeta), and monocytes/granulocyte (monoMeta) cell types for comparison, namely, Neuro-COVID versus idiopathic intracranial hypertension (IIH), were analyzed using iPathwayGuide. L1000 fireworks display (L1000FWD) and L1000 characteristic direction signature search engine (L1000 CDS) web tools were used to uncover the small molecules that could potentially reverse the COVID-19 and Neuro-COVID-associated gene signatures. We uncovered small molecules such as camptothecin, importazole, and withaferin A, which can potentially reverse COVID-19 associated gene signatures. In addition, withaferin A, trichostatin A, narciclasine, camptothecin, and JQ1 have the potential to reverse Neuro-COVID gene signatures. Furthermore, the gene set enrichment analysis (GSEA) preranked method and Metascape web tool were used to decipher and annotate the gene signatures that were potentially reversed by these small molecules. In conclusion, our study unravels a rapid approach for applying next-generation knowledge discovery (NGKD) platforms to discover small molecules with therapeutic potential against COVID-19 and its related disease pathologies.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是冠状病毒病19（COVID-19）的病原体，属于冠状病毒科，可导致从普通感冒到更严重疾病的各种病症，如严重急性呼吸综合征、突发性中风、神经并发症（神经型COVID）、多器官衰竭，以及部分患者死亡。COVID-19感染模型的基因表达谱可用于解读针对COVID-19及其相关病症（如神经型COVID）的潜在治疗方法。在此，我们使用了从基因表达综合数据库（GEO）（GSE147507）获取的、通过Illumina Next Seq 500以一式四份获得的SARS-CoV感染的原代人支气管上皮细胞（NHBE）和模拟处理的NHBE细胞的原始RNA测序读数（单端），并在使用BioJupies网络工具和iPathwayGuide进行RNA测序分析之前，使用CLC基因组学工作台20.0（美国Qiagen公司）对质量控制（QC）进行评估，以分析基因本体（GO）、通路、上游调节基因、小分子和天然产物。此外，使用iPathwayGuide分析了来自脑脊液（CSF）的免疫细胞元簇的单细胞转录组学数据（GSE163005），例如T细胞/自然杀伤细胞（NK）（TcMeta）、树突状细胞（DCMeta）和单核细胞/粒细胞（monoMeta）细胞类型，用于比较神经型COVID与特发性颅内高压（IIH）。使用L1000烟花展示（L1000FWD）和L1000特征方向特征搜索引擎（L1000 CDS）网络工具来发现可能逆转COVID-19和神经型COVID相关基因特征的小分子。我们发现了喜树碱、咪唑、白果酸等小分子，它们可能逆转COVID-19相关基因特征。此外，白果酸、曲古抑菌素A、水仙环素、喜树碱和JQ1有潜力逆转神经型COVID基因特征。此外，使用基因集富集分析（GSEA）预排名方法和Metascape网络工具来解读和注释这些小分子可能逆转的基因特征。总之，我们的研究揭示了一种快速方法，可应用下一代知识发现（NGKD）平台来发现具有治疗COVID-19及其相关疾病病理潜力的小分子。
