Cancer Data Science Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
IISc Mathematics Initiative, Indian Institute of Science, Bangalore, India.
Front Immunol. 2022 Jul 1;13:918817. doi: 10.3389/fimmu.2022.918817. eCollection 2022.
Most transcriptomic studies of SARS-CoV-2 infection have focused on differentially expressed genes, which do not necessarily reveal the genes mediating the transcriptomic changes. In contrast, exploiting curated biological network, our PathExt tool identifies central genes from the differentially active paths mediating global transcriptomic response. Here we apply PathExt to multiple cell line infection models of SARS-CoV-2 and other viruses, as well as to COVID-19 patient-derived PBMCs. The central genes mediating SARS-CoV-2 response in cell lines were uniquely enriched for ATP metabolic process, G1/S transition, leukocyte activation and migration. In contrast, PBMC response reveals dysregulated cell-cycle processes. In PBMC, the most frequently central genes are associated with COVID-19 severity. Importantly, relative to differential genes, PathExt-identified genes show greater concordance with several benchmark anti-COVID-19 target gene sets. We propose six novel anti-SARS-CoV-2 targets ADCY2, ADSL, OCRL, TIAM1, PBK, and BUB1, and potential drugs targeting these genes, such as Bemcentinib, Phthalocyanine, and Conivaptan.
大多数关于 SARS-CoV-2 感染的转录组学研究都集中在差异表达基因上，这些基因不一定能揭示介导转录组变化的基因。相比之下，我们的 PathExt 工具利用精心整理的生物网络，从介导全局转录组反应的差异活性路径中识别核心基因。在这里，我们将 PathExt 应用于 SARS-CoV-2 和其他病毒的多种细胞系感染模型，以及 COVID-19 患者来源的 PBMC。在细胞系中介导 SARS-CoV-2 反应的核心基因在 ATP 代谢过程、G1/S 过渡、白细胞激活和迁移方面独特地上调。相比之下，PBMC 反应揭示了失调的细胞周期过程。在 PBMC 中，最常出现的核心基因与 COVID-19 的严重程度有关。重要的是，与差异基因相比，PathExt 鉴定的基因与几个抗 COVID-19 的基准靶基因集具有更高的一致性。我们提出了六个新的抗 SARS-CoV-2 靶标 ADCY2、ADSL、OCRL、TIAM1、PBK 和 BUB1，以及针对这些基因的潜在药物，如 Bemcentinib、酞菁和 Conivaptan。
