Fellay Isabelle, Blanc Pauline, Larionov Alexey, Schlunke Léa, Filgueira Luis, Lannes Nils
Department of Oncology, Microbiology and Immunology, Unit of Anatomy, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
Laboratory of Microbiology and Microtechnology, School of Life Sciences (SV), Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Front Cell Infect Microbiol. 2025 May 2;15:1580958. doi: 10.3389/fcimb.2025.1580958. eCollection 2025.
The neurotropic virus Japanese encephalitis virus invades the human central nervous system, inducing neuroinflammation and further disruption of the blood-brain barrier. JEV interacts with various cell types of the blood-brain barrier including the endothelial cells. The present work aims to investigate impact of receptor-dependent and independent infection of human microvascular endothelial cells by Japanese encephalitis virus.
Receptor-dependent infection was achieved using cell-free virus while receptor-independent infection was by co-culture of microvascular endothelial cells with virus-associated microglia.
While both receptor-dependent and independent infections of human microvascular endothelial cells led to virus propagation, only receptor-independent infection induced cell death of human microvascular endothelial cells. While the CXCR1-CXCL1 axis was inefficient in blocking virus rescue and protecting endothelial cell from cell death, transcriptomics analysis identified Tumour Necrosis Factor-related apoptosis inducing ligand and receptors as potential key player leading to endothelial cell death.
Overall, our findings demonstrate that human microvascular endothelial cells supply virus propagation and Japanese encephalitis virus-associated microglia greatly contribute to endothelial cell death, an important component of the blood brain barrier integrity. Importantly, Tumour Necrosis Factor-related apoptosis inducing ligand and receptors represents a promising therapeutic target preventing microvascular endothelial cell death after neuroinvasion.
嗜神经性病毒日本脑炎病毒侵入人类中枢神经系统，引发神经炎症并进一步破坏血脑屏障。日本脑炎病毒与包括内皮细胞在内的血脑屏障的多种细胞类型相互作用。本研究旨在探讨日本脑炎病毒对人微血管内皮细胞的受体依赖性感染和非受体依赖性感染的影响。
使用无细胞病毒实现受体依赖性感染，而通过微血管内皮细胞与病毒相关小胶质细胞共培养实现非受体依赖性感染。
虽然人微血管内皮细胞的受体依赖性感染和非受体依赖性感染均导致病毒增殖，但只有非受体依赖性感染诱导人微血管内皮细胞死亡。虽然CXCR1-CXCL1轴在阻止病毒拯救和保护内皮细胞免于细胞死亡方面效率低下，但转录组学分析确定肿瘤坏死因子相关凋亡诱导配体及其受体是导致内皮细胞死亡的潜在关键因素。
总体而言，我们的研究结果表明，人微血管内皮细胞支持病毒增殖，而日本脑炎病毒相关小胶质细胞对内皮细胞死亡有很大影响，内皮细胞死亡是血脑屏障完整性的重要组成部分。重要的是，肿瘤坏死因子相关凋亡诱导配体及其受体是预防神经侵袭后微血管内皮细胞死亡的一个有前景的治疗靶点。
