Nature Neuroscience: 魏滨/王红艳团队揭示脑膜淋巴管系统新功能-传播病毒

2022-05-11 周科 “神经周K”公众号

严重感染会增加血脑屏障的通透性,让病毒通过血脑屏障进入大脑,导致炎症介质释放。病毒也可不需要通过血脑屏障,直接通过嗅神经和三叉神经元进入大脑实质。

脑膜淋巴管位于颅骨下方的背侧和基底侧,可将大脑中的免疫细胞和脑脊液转运到颈部淋巴结。脑膜淋巴管障碍参与神经精神疾病的发病进程:脑膜淋巴系统紊乱后加剧β-淀粉样蛋白在阿尔兹海默症中的沉积;在多发性硬化症动物模型脑淋巴管生成促进抗原回流至淋巴结,促进T细胞增殖。

以往研究表明,严重感染会增加血脑屏障的通透性,让病毒通过血脑屏障进入大脑,导致炎症介质释放。病毒也可不需要通过血脑屏障,直接通过嗅神经和三叉神经元进入大脑实质。

2022年5月6日上海大学生命科学学院魏滨教授、中国科学院分子细胞科学卓越创新中心王红艳 联合研究团队揭示了脑膜淋巴管系统介导嗜神经病毒在大脑中的引流。

小鼠静脉感染日本脑炎病毒后大脑中病毒载量增加,炎症因子白细胞介素-6、肿瘤坏死因子-α 水平升高,对脑膜淋巴管形态进行三维重构发现鼻窦汇合处和横窦脑膜淋巴管生成增多。

图1:小鼠感染嗜神经病毒后淋巴管生成增多

在小鼠感染寨卡病毒、狂犬病病毒 、和水疱性口炎病毒,大脑病毒载量增多后,脑膜淋巴管也增多,这些结果有力证实了大脑病毒感染后促进脑膜淋巴管生成。

图2:小鼠感染嗜神经病毒后淋巴引流功能出现障碍

在未感染病毒小鼠注射伊文思蓝示踪剂后可在深部颈淋巴结检测到,但是在感染日本脑炎病毒后几乎检测不到。通过在体实时荧光成像系统发现在注射荧光蛋白标记的卵清蛋白在正常小鼠颈部区域能够观察到荧光标记物,即便是经过注射2小时后感染日本脑炎病毒的小鼠只能检测到极少量的荧光蛋白。这些结果表明病毒感染大脑后引起淋巴管功能异常。

淋巴管的淋巴管瓣和平滑肌细胞在淋巴液运输中起关键作用。 肌肉细胞提供收缩活动以帮助淋巴液流动,淋巴管瓣调节淋巴液的单向流动以防止液体回流。进一步的研究发现日本脑炎病毒侵入大脑后调控淋巴管瓣和募集平滑肌细胞的分子Prox1, Foxc2 和 Gata2 表达降低。

通过电子显微镜发现小鼠在感染日本脑炎病毒后深部颈淋巴结出现病毒,但在腋窝淋巴结并没发现病毒颗粒。在结扎流入深部颈淋巴结的淋巴管后枕大池感染水疱性口炎病毒后深部颈淋巴结病毒颗粒减少,这就表明病毒可通过脑膜淋巴管排出到颈淋巴结。

图3:破坏脑膜淋巴管加重病毒感染死亡率

破坏脑膜淋巴管或阻断传入深部颈淋巴结的淋巴管后感染日本脑炎病毒后增加小鼠小脑和脑干病毒载量,死亡率也明显增加。分子实验发现在破坏脑膜淋巴管后感染日本脑炎病毒的小鼠大脑中性粒细胞、巨噬细胞、单核细胞、T 细胞和自然杀伤细胞等免疫细胞数量明显增加,表明存在过度炎症反应,或是加重死亡率的原因。

总的来说,本文发现侵入大脑中的病毒科通过脑膜淋巴结排出到颈部淋巴结,揭示了病毒从中枢神经系统传播到外周系统的新途径。

 

原始出处:

Li, X., Qi, L., Yang, D. et al. Meningeal lymphatic vessels mediate neurotropic viral drainage from the central nervous system. Nat Neurosci 25, 577–587 (2022). https://doi.org/10.1038/s41593-022-01063-z.

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    2022-07-11 liye789132251
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    2022-05-11 lsndxfj
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    2022-05-11 jichang
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    2022-05-11 amyloid
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    2022-05-11 12267201m08(暂无昵称)

    学习

    0

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