MOE Key Laboratory for Cellular Dynamics and Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
Department of Physics, University of Science and Technology of China, Hefei, Anhui, China.
Front Immunol. 2024 Sep 26;15:1435170. doi: 10.3389/fimmu.2024.1435170. eCollection 2024.
The term "Long-COVID" (LC) is characterized by the aftereffects of COVID-19 infection. Various studies have suggested that Epstein-Barr virus (EBV) reactivation is among the significant reported causes of LC. However, there is a lack of in-depth research that could largely explore the pathogenic mechanism and pinpoint the key genes in the EBV and LC context. This study mainly aimed to predict the potential disease-associated common genes between EBV reactivation and LC condition using next-generation sequencing (NGS) data and reported naturally occurring biomolecules as inhibitors. We applied the bulk RNA-Seq from LC and EBV-infected peripheral blood mononuclear cells (PBMCs), identified the differentially expressed genes (DEGs) and the Protein-Protein interaction (PPI) network using the STRING database, identified hub genes using the cytoscape plugins CytoHubba and MCODE, and performed enrichment analysis using ClueGO. The interaction analysis of a hub gene was performed against naturally occurring bioflavonoid molecules using molecular docking and the molecular dynamics (MD) simulation method. Out of 357 common genes, 22 genes (CCL2, CCL20, CDCA2, CEP55, CHI3L1, CKAP2L, DEPDC1, DIAPH3, DLGAP5, E2F8, FGF1, NEK2, PBK, TOP2A, CCL3, CXCL8, DEPDC1, IL6, RETN, MMP2, LCN2, and OLR1) were classified as hub genes, and the remaining ones were classified as neighboring genes. Enrichment analysis showed the role of hub genes in various pathways such as immune-signaling pathways, including JAK-STAT signaling, interleukin signaling, protein kinase signaling, and toll-like receptor pathways associated with the symptoms reported in the LC condition. ZNF and MYBL TF-family were predicted as abundant TFs controlling hub genes' transcriptional machinery. Furthermore, OLR1 (PDB: 7XMP) showed stable interactions with the five shortlisted refined naturally occurring bioflavonoids, i.e., apigenin, amentoflavone, ilexgenin A, myricetin, and orientin compounds. The total binding energy pattern was observed, with amentoflavone being the top docked molecule (with a binding affinity of -8.3 kcal/mol) with the lowest total binding energy of -18.48 kcal/mol. In conclusion, our research has predicted the hub genes, their molecular pathways, and the potential inhibitors between EBV and LC potential pathogenic association. The or experimental methods could be utilized to functionally validate our findings, which would be helpful to cure LC or to prevent EBV reactivation.
“长新冠”（LC）一词的特征是新冠病毒感染后的后遗症。各种研究表明，爱泼斯坦-巴尔病毒（EBV）再激活是报告的 LC 主要原因之一。然而，缺乏深入研究可以在很大程度上探索 EBV 再激活和 LC 情况下的致病机制，并确定 EBV 和 LC 相关的关键基因。本研究主要旨在使用下一代测序（NGS）数据和报告的天然生物分子作为抑制剂，预测 EBV 再激活和 LC 条件之间潜在的疾病相关共同基因。我们应用 LC 和 EBV 感染外周血单个核细胞（PBMC）的批量 RNA-Seq，使用 STRING 数据库识别差异表达基因（DEGs）和蛋白-蛋白相互作用（PPI）网络，使用 cytoscape 插件 CytoHubba 和 MCODE 识别枢纽基因，并使用 ClueGO 进行富集分析。使用分子对接和分子动力学（MD）模拟方法，对一个枢纽基因与天然生物类黄酮分子的相互作用进行分析。在 357 个共同基因中，有 22 个基因（CCL2、CCL20、CDCA2、CEP55、CHI3L1、CKAP2L、DEPDC1、DIAPH3、DLGAP5、E2F8、FGF1、NEK2、PBK、TOP2A、CCL3、CXCL8、DEPDC1、IL6、RETN、MMP2、LCN2 和 OLR1）被归类为枢纽基因，其余的被归类为邻接基因。富集分析表明，枢纽基因在各种途径中发挥作用，包括 JAK-STAT 信号通路、白细胞介素信号通路、蛋白激酶信号通路和与 LC 症状相关的 Toll 样受体途径。ZNF 和 MYBL TF 家族被预测为控制枢纽基因转录机制的丰富 TF。此外，OLR1（PDB：7XMP）与五种精选的天然生物类黄酮（芹菜素、amentoflavone、Ilexgenin A、杨梅素和orientin 化合物）表现出稳定的相互作用。观察到总结合能模式，amentoflavone 是与靶结合的最佳对接分子（结合亲和力为-8.3 kcal/mol），总结合能最低为-18.48 kcal/mol。总之，我们的研究预测了 EBV 和 LC 潜在致病关联中的枢纽基因、它们的分子途径和潜在抑制剂。可以使用 或 实验方法来验证我们的发现，这将有助于治疗 LC 或预防 EBV 再激活。
