Neuroimmunology Section, Laboratory of Persistent Viral Disease, Rocky Mountain Laboratories, NIAID, NIH, 903 S. 4th Street, MT, 59840, Hamilton, USA.
Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 4 Memorial Drive, Bethesda, MD, 20892, USA.
Nat Commun. 2023 May 18;14(1):2836. doi: 10.1038/s41467-023-37833-x.
One of the key events in viral encephalitis is the ability of virus to enter the central nervous system (CNS). Several encephalitic viruses, including La Crosse Virus (LACV), primarily induce encephalitis in children, but not adults. This phenomenon is also observed in LACV mouse models, where the virus gains access to the CNS of weanling animals through vascular leakage of brain microvessels, likely through brain capillary endothelial cells (BCECs). To examine age and region-specific regulatory factors of vascular leakage, we used genome-wide transcriptomics and targeted siRNA screening to identify genes whose suppression affected viral pathogenesis in BCECs. Further analysis of two of these gene products, Connexin43 (Cx43/Gja1) and EphrinA2 (Efna2), showed a substantial effect on LACV pathogenesis. Induction of Cx43 by 4-phenylbutyric acid (4-PBA) inhibited neurological disease in weanling mice, while Efna2 deficiency increased disease in adult mice. Thus, we show that Efna2 and Cx43 expressed by BCECs are key mediators of LACV-induced neuroinvasion and neurological disease.
病毒进入中枢神经系统（CNS）是病毒性脑炎的关键事件之一。包括拉科罗病毒（LACV）在内的几种脑炎病毒主要在儿童中引起脑炎，但不在成人中引起。这种现象也在 LACV 小鼠模型中观察到，病毒通过脑微血管的血管渗漏进入幼小动物的中枢神经系统，可能通过脑毛细血管内皮细胞（BCEC）。为了研究血管渗漏的年龄和区域特异性调节因子，我们使用全基因组转录组学和靶向 siRNA 筛选来鉴定抑制这些基因会影响 BCEC 中病毒发病机制的基因。对这两种基因产物之一的连接蛋白 43（Cx43/Gja1）和 EphrinA2（Efna2）的进一步分析表明，它们对 LACV 发病机制有重大影响。4-苯丁酸（4-PBA）诱导的 Cx43 抑制了幼鼠的神经疾病，而 Efna2 缺乏则增加了成年鼠的疾病。因此，我们表明，BCEC 表达的 Efna2 和 Cx43 是 LACV 诱导的神经入侵和神经疾病的关键介质。
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