Japanese encephalitis virus NS1 and NS1′ protein disrupts the blood-brain barrier through macrophage migration inhibitory factor-mediated autophagy

作者：Luping Zhang, Xiaowei Nan, Dengyuan Zhou, Xugang Wang, Shuo Zhu, Qiuyan Li, Fan Jia, Bibo Zhu, Youhui Si, Shengbo Cao, Jing Ye · 发表于：Journal of Virology · 年份：2024 · DOI：10.1128/jvi.00116-24 · 被引用次数：25 · 研究领域：Macrophage Migration Inhibitory Factor、Parasites and Host Interactions、Nuclear Receptors and Signaling

ABSTRACT Flaviviruses in the Japanese encephalitis virus (JEV) serogroup, such as JEV, West Nile virus, and St. Louis encephalitis virus, can cause severe neurological diseases. The nonstructural protein 1 (NS1) is a multifunctional protein of flavivirus that can be secreted by infected cells and circulate in the host bloodstream. NS1′ is an additional form of NS1 protein with 52 amino acids extension at its carboxy-terminal and is produced exclusively by flaviviruses in the JEV serogroup. In this study, we demonstrated that the secreted form of both NS1 and NS1′ can disrupt the blood-brain barrier (BBB) of mice, with NS1′ exhibiting a stronger effect. Using the in vitro BBB model, we found that treatment of soluble recombinant JEV NS1 or NS1′ protein increases the permeability of human brain microvascular endothelial cells (hBMECs) and leads to the degradation of tight junction proteins through the autophagy-lysosomal pathway. Consistently, NS1′ protein exhibited a more pronounced effect compared to NS1 in these cellular processes. Further research revealed that the increased expression of macrophage migration inhibitory factor (MIF) is responsible for triggering autophagy after NS1 or NS1′ treatment in hBMECs. In addition, TLR4 and NF-κB signaling was found to be involved in the activation of MIF transcription. Moreover, administering the MIF inhibitor has been shown to decrease viral loads and mitigate inflammation in the brains of mice infected with JEV. This research off...