Li Cong, Zhang Weijian, Chang Xiaodan, Di Xiaohua, Xie Qi, Lin Bihua, Zhang Hui, Ye Ziyu, Lan Minsheng, Lian Jiachun, Zhang Hailiang, Qiu Xianxiu, Zeng Jincheng, Huang Mingyuan
Department of Stomatology, Dongguan Maternal and Child Health Care Hospital, Dongguan, China.
Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China.
Transl Pediatr. 2023 Feb 28;12(2):194-207. doi: 10.21037/tp-23-41. Epub 2023 Feb 24.
Hand, foot, and mouth disease (HFMD) is a common viral childhood illness caused most commonly by enterovirus 71 (EV71) and coxsackievirus A16. The pathogenesis of EV71 has been extensively studied, and the regulation of the host immune response is suspected to aggravate the serious complications induced by EV71. Our previous research showed that EV71 infection significantly increased the release of circulating interleukin (IL)-6, IL-10, IL-13, and IL-27. Notably, these cytokines are related to the EV71 infection risk and clinical stage. Polyamines are compounds that are ubiquitous in mammalian cells and play a key role in various cellular processes. Several studies have shown that targeting polyamine metabolic pathways can reduce infections caused by viruses. However, the significance of polyamine metabolism in EV71 infection remains largely unknown.
Serum samples from 82 children with HFMD and 70 healthy volunteers (HVs) were collected to determine the polyamine metabolites spermidine (SPD) and spermine (SPM), and IL-6 levels. In addition, peripheral blood mononuclear cells (PBMCs) were treated with EV71 viral protein 1 (VP1) and EV71 VP4, and the cells and supernatant were then collected to analyze the expression of polyamine metabolism-related enzymes by western blot. The data were analyzed using GraphPad Prism 7.0 software (USA).
The serum polyamine metabolites SPD and SPM were elevated in the HFMD patients, especially in the EV71-infected children. Further, a positive correlation was found between serum SPD and IL-6 levels in the EV71-infected children. We also found that the upregulation of peripheral blood polyamine metabolites in the EV71-infected HFMD children was related to EV71 capsid protein VP1, but not VP4. VP1 may promote the expression of polyamine metabolism-related enzymes and promote the production of polyamine metabolites, thereby upregulating the SPD/nuclear factor kappa B/IL-6 signaling pathway. However, VP4 has the opposite effect in this process.
Our results suggest that EV71 capsid protein may regulate the polyamine metabolic pathways of infected cells in a variety of ways. This study provides insights into the mechanism of EV71 infection and polyamine metabolism and has good reference value for the development of EV71 vaccine.
手足口病（HFMD）是一种常见的儿童病毒性疾病，最常见的病因是肠道病毒71型（EV71）和柯萨奇病毒A16型。EV71的发病机制已得到广泛研究，宿主免疫反应的调节被怀疑会加重EV71引起的严重并发症。我们之前的研究表明，EV71感染显著增加了循环白细胞介素（IL）-6、IL-10、IL-13和IL-27的释放。值得注意的是，这些细胞因子与EV71感染风险和临床阶段相关。多胺是在哺乳动物细胞中普遍存在的化合物，在各种细胞过程中起关键作用。多项研究表明，靶向多胺代谢途径可以减少病毒引起的感染。然而，多胺代谢在EV71感染中的意义仍 largely未知。
收集82例手足口病患儿和70例健康志愿者（HV）的血清样本，以测定多胺代谢产物亚精胺（SPD）和精胺（SPM）以及IL-6水平。此外，用EV71病毒蛋白1（VP1）和EV71 VP4处理外周血单个核细胞（PBMC），然后收集细胞和上清液，通过蛋白质印迹法分析多胺代谢相关酶的表达。使用GraphPad Prism 7.0软件（美国）对数据进行分析。
手足口病患者血清多胺代谢产物SPD和SPM升高，尤其是在EV71感染的儿童中。此外，在EV71感染的儿童中，血清SPD与IL-6水平之间存在正相关。我们还发现，EV71感染的手足口病儿童外周血多胺代谢产物的上调与EV71衣壳蛋白VP1有关，而与VP4无关。VP1可能促进多胺代谢相关酶的表达并促进多胺代谢产物的产生，从而上调SPD/核因子κB/IL-6信号通路。然而，VP4在此过程中具有相反的作用。
我们的结果表明，EV71衣壳蛋白可能以多种方式调节感染细胞的多胺代谢途径。本研究为EV71感染和多胺代谢的机制提供了见解，对EV71疫苗的开发具有良好的参考价值。
