Xu Lei, Tao Qian, Zhang Yang, Lee Feng-Qin, Xu Tong, Deng Li-Shuang, Jian Zhi-Jie, Zhao Jun, Lai Si-Yuan, Zhou Yuan-Cheng, Zhu Ling, Xu Zhi-Wen
Key Laboratory of Animal Diseases and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.
Livestock and Poultry Biological Products Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu, China.
Microbiol Spectr. 2024 Oct 22;12(12):e0135124. doi: 10.1128/spectrum.01351-24.
Pseudorabies virus (PRV), a member of the alpha-herpesviruses, can infect both the nervous and reproductive systems of pigs, causing neonatal mortality and reproductive failure in sows, which incurs substantial economic losses. Neurotropism is a common characteristic of various viruses, allowing them to cross the blood-brain barrier and access the central nervous system. However, the precise mechanisms by which PRV affects the blood-brain barrier are not well understood. To investigate the mechanism of PRV's interaction with the blood-brain barrier and its engagement with the PI3K/Akt signaling pathway during infection, an monolayer cell model of the blood-brain barrier was established. Our research found that PRV activates Matrix metallopeptidase 2 (MMP2), which degrades Zonula occludens-1 (ZO-1) and consequently enhances the permeability of the blood-brain barrier. PRV infection elevated the transcriptional levels of tissue inhibitor of metalloproteinases 1 (TIMP1) and inhibited its degradation through the ubiquitin-proteasome pathway, leading to higher intracellular concentrations of TIMP1 protein. TIMP1 regulates apoptosis and inhibits PRV replication in mouse brain microvascular endothelial cells through the PI3K/Akt/mTOR signaling pathway. In summary, our study delineates the mechanism through which PRV compromises the blood-brain barrier and provides insights into the host's antiviral defense mechanisms post-infection.
PRV, known for its neurotropic properties, is capable of inducing severe neuronal damage. Our study discovered that following PRV infection, the expression of MMP2 was upregulated, leading to the degradation of ZO-1. Furthermore, upon PRV infection in the host, the promoter of TIMP1 is significantly activated, resulting in a significant increase in TIMP1 protein levels. This upregulation of TIMP1 inhibits the proliferation of PRV through the PI3K/Akt signaling pathway. This study elucidated the mechanism through which PRV, including the PRV XJ delgE/gI/TK strains, compromises the blood-brain barrier and identifies the antiviral response characterized by the activation of the PI3K/Akt signaling pathway within infected host cells. These findings provide potential therapeutic targets for the clinical management and treatment of PRV.
伪狂犬病病毒（PRV）是α-疱疹病毒的一种，可感染猪的神经和生殖系统，导致新生仔猪死亡和母猪繁殖失败，造成重大经济损失。嗜神经性是各种病毒的共同特征，使它们能够穿过血脑屏障并进入中枢神经系统。然而，PRV影响血脑屏障的确切机制尚不清楚。为了研究PRV在感染过程中与血脑屏障相互作用及其与PI3K/Akt信号通路相互作用的机制，建立了血脑屏障单层细胞模型。我们的研究发现，PRV激活基质金属蛋白酶2（MMP2），MMP2降解紧密连接蛋白1（ZO-1），从而增强血脑屏障的通透性。PRV感染提高了金属蛋白酶组织抑制剂1（TIMP1）的转录水平，并通过泛素-蛋白酶体途径抑制其降解，导致细胞内TIMP1蛋白浓度升高。TIMP1通过PI3K/Akt/mTOR信号通路调节细胞凋亡并抑制PRV在小鼠脑微血管内皮细胞中的复制。总之，我们的研究阐明了PRV破坏血脑屏障的机制，并为感染后宿主的抗病毒防御机制提供了见解。
以嗜神经性著称的PRV能够诱导严重的神经元损伤。我们的研究发现，PRV感染后，MMP2的表达上调，导致ZO-1降解。此外，宿主感染PRV后，TIMP1的启动子被显著激活，导致TIMP1蛋白水平显著增加。TIMP1的这种上调通过PI3K/Akt信号通路抑制PRV的增殖。本研究阐明了PRV（包括PRV XJ delgE/gI/TK株）破坏血脑屏障的机制，并确定了感染宿主细胞内以PI3K/Akt信号通路激活为特征的抗病毒反应。这些发现为PRV的临床管理和治疗提供了潜在的治疗靶点。
