Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China.
J Virol. 2024 Oct 22;98(10):e0104824. doi: 10.1128/jvi.01048-24. Epub 2024 Aug 30.
Pseudorabies virus (PRV) utilizes multiple strategies to inhibit type I interferon (IFN-I) production and signaling to achieve innate immune evasion. Among several other functions, mitochondria serve as a crucial immune hub in the initiation of innate antiviral responses. It is currently unknown whether PRV inhibits innate immune responses by manipulating mitochondria. In this study, we found that PRV infection damages mitochondrial structure and function, as shown by mitochondrial membrane potential depolarization, reduction in mitochondrial numbers, and an imbalance in mitochondrial dynamics. In addition, PRV infection triggered PINK1-Parkin-mediated mitophagy to eliminate the impaired mitochondria, which resulted in a suppression of IFN-I production, thereby promoting viral replication. Furthermore, we found that mitophagy resulted in the degradation of the mitochondrial antiviral signaling protein, which is located on the mitochondrial outer membrane. In conclusion, the data of the current study indicate that PRV-induced mitophagy represents a previously uncharacterized PRV evasion mechanism of the IFN-I response, thereby promoting virus replication.IMPORTANCEPseudorabies virus (PRV), a pathogen that induces different disease symptoms and is often fatal in domestic animals and wildlife, has caused great economic losses to the swine industry. Since 2011, different PRV variant strains have emerged in Asia, against which current commercial vaccines may not always provide optimal protection in pigs. In addition, there are indications that some of these PRV variant strains may sporadically infect people. In the current study, we found that PRV infection causes mitochondria injury. This is associated with the induction of mitophagy to eliminate the damaged mitochondria, which results in suppressed antiviral interferon production and signaling. Hence, our study reveals a novel mechanism that is used by PRV to antagonize the antiviral host immune response, providing a theoretical basis that may contribute to the research toward and development of new vaccines and antiviral drugs.
伪狂犬病毒（PRV）利用多种策略来抑制 I 型干扰素（IFN-I）的产生和信号转导，从而实现先天免疫逃避。在线粒体等几个其他功能中，线粒体作为先天抗病毒反应起始的关键免疫中心。目前尚不清楚 PRV 是否通过操纵线粒体来抑制先天免疫反应。在这项研究中，我们发现 PRV 感染会破坏线粒体的结构和功能，表现为线粒体膜电位去极化、线粒体数量减少以及线粒体动力学失衡。此外，PRV 感染触发 PINK1-Parkin 介导的线粒体自噬来清除受损的线粒体，从而抑制 IFN-I 的产生，进而促进病毒复制。此外，我们发现线粒体自噬导致位于线粒体外膜上的抗病毒信号蛋白的降解。总之，本研究的数据表明，PRV 诱导的线粒体自噬代表了一种以前未被描述的 PRV 逃避 IFN-I 反应的机制，从而促进了病毒的复制。
伪狂犬病毒（PRV）是一种病原体，在家畜和野生动物中会引起不同的疾病症状，并且经常是致命的，给养猪业造成了巨大的经济损失。自 2011 年以来，亚洲出现了不同的 PRV 变异株，目前的商业疫苗在猪身上可能并不总是能提供最佳的保护。此外，有迹象表明，其中一些 PRV 变异株可能会偶尔感染人类。在当前的研究中，我们发现 PRV 感染会导致线粒体损伤。这与诱导线粒体自噬以消除受损的线粒体有关，从而导致抗病毒干扰素的产生和信号转导受到抑制。因此，我们的研究揭示了 PRV 拮抗抗病毒宿主免疫反应的一种新机制，为研究和开发新的疫苗和抗病毒药物提供了理论依据。
