Zhang Jing, Li Miao, Cheng Jing, Wang Yutong, Ma Cuiqing, Yin Lizheng, Wang Jiachao, Gao Xue, Liang Wenzhang, Wei Lin
Department of Immunology, Hebei Medical University, Shijiazhuang, Hebei, China.
Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang, Hebei, China.
J Virol. 2025 Jul 22;99(7):e0007425. doi: 10.1128/jvi.00074-25. Epub 2025 Jun 24.
The "Warburg effect," a type of metabolic reprogramming characterized by enhanced glycolysis even in the presence of oxygen, is frequently observed in tumor cells and has also been detected in cells infected with viruses. Our study demonstrated that respiratory syncytial virus (RSV) infection induced aerobic glycolysis both and . By utilizing the glycolysis agonist PS48 or inhibitor 2-DG, we ascertained that RSV can utilize glycolysis to promote its replication. Mechanistically, glycolysis may facilitate RSV replication by negatively regulating the IFNβ response. Additionally, we discovered a host molecule, namely CypA, that could downregulate glycolysis to combat RSV infection. CypA interacted with PKM2, a key enzyme of glycolysis, and reduced its expression. By overexpressing or knocking down CypA, we verified that CypA could inhibit aerobic glycolysis, enhance IFNβ production, and reduce RSV replication. Inhibiting the PPIase activity of CypA resulted in the disappearance of its function, indicating that CypA exerted its effects dependent on PPIase activity. Furthermore, we found that CypA has a synergistic effect with 2-DG and an antagonistic effect with PS48 on the IFNβ response, supporting the notion that CypA regulates IFNβ by inhibiting glycolysis. These results indicate that CypA may serve as a novel host factor in the regulation of glycolysis, the interferon response, and ultimately in resisting RSV infection.
Viruses utilize the host's resources and energy to carry out essential life processes and achieve self-replication. In response, hosts have evolved a range of antagonistic mechanisms. Our study investigates how RSV employs glycolysis to benefit its replication, with a particular focus on the interaction between glycolysis and IFNβ regulation. Additionally, we explore how the host employs CypA to antagonize the virus's utilization of glycolysis, thereby inhibiting RSV replication. Our findings will contribute to the development of effective antiviral therapies targeting CypA.
“瓦伯格效应”是一种代谢重编程类型，其特征是即使在有氧存在的情况下糖酵解也会增强，在肿瘤细胞中经常观察到，在感染病毒的细胞中也已检测到。我们的研究表明，呼吸道合胞病毒（RSV）感染在[具体情况1]和[具体情况2]中均诱导有氧糖酵解。通过使用糖酵解激动剂PS48或抑制剂2-DG，我们确定RSV可以利用糖酵解来促进其复制。从机制上讲，糖酵解可能通过负调节IFNβ反应来促进RSV复制。此外，我们发现了一种宿主分子，即环孢素A（CypA），它可以下调糖酵解以对抗RSV感染。CypA与糖酵解的关键酶丙酮酸激酶M2（PKM2）相互作用，并降低其表达。通过过表达或敲低CypA，我们验证了CypA可以抑制有氧糖酵解，增强IFNβ产生，并减少RSV复制。抑制CypA的肽基脯氨酰异构酶（PPIase）活性导致其功能消失，表明CypA依赖于PPIase活性发挥其作用。此外，我们发现CypA在IFNβ反应方面与2-DG具有协同作用，与PS48具有拮抗作用，支持CypA通过抑制糖酵解来调节IFNβ的观点。这些结果表明，CypA可能作为一种新型宿主因子参与糖酵解、干扰素反应的调节，并最终抵抗RSV感染。
病毒利用宿主的资源和能量来进行基本生命过程并实现自我复制。作为回应，宿主进化出了一系列拮抗机制。我们的研究调查了RSV如何利用糖酵解来促进其复制，特别关注糖酵解与IFNβ调节之间的相互作用。此外，我们探讨了宿主如何利用CypA来拮抗病毒对糖酵解的利用，从而抑制RSV复制。我们的发现将有助于开发针对CypA的有效抗病毒疗法。
