Retrovirology Research Laboratory, Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, Honolulu, HI 96813, USA.
Virology. 2010 Feb 5;397(1):130-8. doi: 10.1016/j.virol.2009.10.036. Epub 2009 Nov 18.
Though compromised blood-brain barrier (BBB) is a pathological hallmark of WNV-associated neurological sequelae, underlying mechanisms are unclear. We characterized the expression of matrix metalloproteinases (MMP) in WNV-infected human brain microvascular endothelial cells (HBMVE) and human brain cortical astrocytes (HBCA), components of BBB and their role in BBB disruption. Expression of multiple MMPs was significantly induced in WNV-infected HBCA cells. Naïve HBMVE cells incubated with the supernatant from WNV-infected HBCA cells demonstrated loss of tight junction proteins, which were rescued in the presence of MMP inhibitor, GM6001. Further, supernatant from WNV-infected HBCA cells compromised the in vitro BBB model integrity. Our data suggest astrocytes as one of the sources of MMP in the brain, which mediates BBB disruption allowing unrestricted entry of immune cells into the brain, thereby contributing to WNV neuropathogenesis. Because of the unavailability of WNV antivirals and vaccines, use of MMP inhibitors as an adjunct therapy to ameliorate WNV disease progression is warranted.
虽然受损的血脑屏障（BBB）是 WNV 相关神经后遗症的病理标志，但潜在的机制尚不清楚。我们描述了基质金属蛋白酶（MMP）在 WNV 感染的人脑微血管内皮细胞（HBMVE）和人脑皮质星形胶质细胞（HBCA）中的表达，这两种细胞是 BBB 的组成部分，以及它们在 BBB 破坏中的作用。在 WNV 感染的 HBCA 细胞中，多种 MMP 的表达显著诱导。在 MMP 抑制剂 GM6001 的存在下，与来自 WNV 感染的 HBCA 细胞的上清液孵育的原始 HBMVE 细胞显示出紧密连接蛋白的丢失，这在上清液中得到了恢复。此外，来自 WNV 感染的 HBCA 细胞的上清液损害了体外 BBB 模型的完整性。我们的数据表明星形胶质细胞是大脑中 MMP 的来源之一，它介导 BBB 破坏，允许免疫细胞不受限制地进入大脑，从而导致 WNV 神经发病机制。由于缺乏 WNV 抗病毒药物和疫苗，使用 MMP 抑制剂作为辅助治疗来改善 WNV 疾病进展是有必要的。
