Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
Cell Rep. 2019 Feb 5;26(6):1598-1613.e8. doi: 10.1016/j.celrep.2019.01.036.
Flaviviruses cause systemic or neurotropic-encephalitic pathology in humans. The flavivirus nonstructural protein 1 (NS1) is a secreted glycoprotein involved in viral replication, immune evasion, and vascular leakage during dengue virus infection. However, the contribution of secreted NS1 from related flaviviruses to viral pathogenesis remains unknown. Here, we demonstrate that NS1 from dengue, Zika, West Nile, Japanese encephalitis, and yellow fever viruses selectively binds to and alters permeability of human endothelial cells from lung, dermis, umbilical vein, brain, and liver in vitro and causes tissue-specific vascular leakage in mice, reflecting the pathophysiology of each flavivirus. Mechanistically, each flavivirus NS1 leads to differential disruption of endothelial glycocalyx components, resulting in endothelial hyperpermeability. Our findings reveal the capacity of a secreted viral protein to modulate endothelial barrier function in a tissue-specific manner both in vitro and in vivo, potentially influencing virus dissemination and pathogenesis and providing targets for antiviral therapies and vaccine development.
黄病毒可引起人类全身性或神经嗜性病理。黄病毒非结构蛋白 1（NS1）是一种分泌型糖蛋白，参与登革热病毒感染期间的病毒复制、免疫逃逸和血管渗漏。然而，相关黄病毒的分泌型 NS1 对病毒发病机制的贡献尚不清楚。在这里，我们证明了登革热、寨卡、西尼罗河、乙型脑炎和黄热病病毒的 NS1 选择性地结合并改变了来自肺、真皮、脐静脉、脑和肝的人内皮细胞的通透性，并在小鼠中引起组织特异性血管渗漏，反映了每种黄病毒的病理生理学。从机制上讲，每种黄病毒 NS1 导致内皮糖萼成分的差异破坏，导致内皮通透性增加。我们的发现揭示了一种分泌型病毒蛋白在体外和体内以组织特异性方式调节内皮屏障功能的能力，这可能影响病毒的传播和发病机制，并为抗病毒治疗和疫苗开发提供了靶点。
