A microengineered 3D human neurovascular unit model to probe the neuropathogenesis of herpes simplex encephalitis

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-04-18 DOI:10.1038/s41467-025-59042-4

Min Zhang, Peng Wang, Yunsong Wu, Lin Jin, Jiayue Liu, Pengwei Deng, Rongcan Luo, Xiyue Chen, Mengqian Zhao, Xu Zhang, Yaqiong Guo, Ying Yan, Yingtong Di, Jianhua Qin

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Abstract

Herpes simplex encephalitis (HSE) caused by HSV-1 is the most common non-epidemic viral encephalitis, and the neuropathogenesis of HSE remains elusive. This work describes a 3D human neurovascular unit (NVU) model that allows to explore the neuropathogenesis of HSE in vitro. This model is established by co-culturing human microvascular endothelial cells, astrocytes, microglia and neurons on a multi-compartment chip. Upon HSV-1 infection, this NVU model exhibited HSE-associated pathological changes, including cytopathic effects, blood-brain barrier dysfunction and pro-inflammatory cytokines release. Besides, significant innate immune responses were observed with the infiltration of peripheral immune cells and microglial activation. Transcriptomic analysis revealed broadly inflammatory and chemotactic responses in host cells. Mechanistically, we found HSV-1 could induce severe suppression of autophagic flux in glial cells, especially in microglia. Autophagy activators could effectively inhibit HSV-1 replication and rescue neurovascular injuries, indicating the utility of this unique platform for studying neurological diseases and new therapeutics.

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由HSV-1引起的单纯疱疹性脑炎（HSE）是最常见的非流行性病毒性脑炎，而HSE的神经发病机制至今仍难以捉摸。这项研究介绍了一种三维人类神经血管单元（NVU）模型，可用于体外探索 HSE 的神经发病机制。该模型是通过在多室芯片上共培养人微血管内皮细胞、星形胶质细胞、小胶质细胞和神经元而建立的。感染 HSV-1 后，该 NVU 模型表现出与 HSE 相关的病理变化，包括细胞病理效应、血脑屏障功能障碍和促炎细胞因子释放。此外，还观察到明显的先天性免疫反应，包括外周免疫细胞浸润和小胶质细胞活化。转录组分析显示宿主细胞中存在广泛的炎症和趋化反应。从机理上讲，我们发现 HSV-1 能严重抑制神经胶质细胞，尤其是小胶质细胞的自噬通量。自噬激活剂能有效抑制 HSV-1 复制并挽救神经血管损伤，这表明这一独特平台在研究神经系统疾病和新疗法方面的实用性。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.