Modeling neurotropic virus infection with functional human neural spheroids as a platform for high-throughput antiviral screening and pathogenesis.

IF 4 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Antiviral research Pub Date : 2025-10-01 Epub Date: 2025-08-05 DOI:10.1016/j.antiviral.2025.106248
Angelica Medina, Yu-Chi Chen, Jiajing Zhang, Sarah C Ogden, Samantha Cotsmire, Harshad D Vishwasrao, Marc Ferrer, Emily M Lee
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引用次数: 0

Abstract

Neurotropic arboviruses pose significant threats to human health due to their ability to infect the central nervous system (CNS). Despite the significant impact on public health, mechanisms underlying neuropathogenesis remains poorly understood, and the development of effective antivirals has been hampered by the lack of predictive, high-throughput (HT) infection platforms that can replicate in vivo disease features to drive early drug discovery. To address this gap, we developed a human-based, HT-compatible, functional viral disease neural spheroid model assembled from human induced pluripotent stem cell (hiPSC)-differentiated neurons and astrocytes as a platform for studying virus infection and the development of HT screening (HTS)-compatible assays for drug discovery. Here, we investigated eight high impact species belonging to either the Bunyaviricetes class or Togaviridae family and evaluated infectability on neural spheroids, followed by characterization of neural activity dysregulation and induced disease. We found that neural spheroids support productive infection, with virus- and time-dependent changes in disease profiles. Transcriptomic changes induced by two representative members, LACV and CHIKV, revealed a highly pro-inflammatory response in LACV infected spheroids whereas CHIKV-infection induced neurodegenerative profiles. Finally, we evaluated antiviral and anti-neural dysfunction activity of interferon-alpha as well as tested the small molecule gemcitabine against CHIKV as a proof-of-concept for HT antiviral compound screening. Together, our data establishes the viral-neural spheroids as a valuable platform that supports productive infection by high impact neurotropic viruses, and this platform can be used to both investigate viral pathogenesis and support therapeutics discovery and development.

用功能性人类神经球模拟嗜神经病毒感染,作为高通量抗病毒药物筛选和发病机制的平台。
嗜神经虫媒病毒具有感染中枢神经系统的能力,对人类健康构成重大威胁。尽管对公共卫生产生了重大影响,但神经发病机制仍然知之甚少,并且由于缺乏可预测的高通量(HT)感染平台,无法复制体内疾病特征以推动早期药物发现,因此阻碍了有效抗病毒药物的开发。为了解决这一空白,我们开发了一种基于人的、HT兼容的、功能性病毒性疾病的神经球体模型,该模型由人诱导多能干细胞(hiPSC)分化的神经元和星形胶质细胞组装而成,作为研究病毒感染和开发HT筛选(HTS)兼容的检测方法的平台,用于药物发现。在这里,我们调查了8种高影响物种,分别属于布尼亚病毒纲和托加病毒科,并评估了神经球体的传染性,随后表征了神经活动失调和诱导疾病。我们发现神经球体支持生产性感染,与病毒和时间依赖的疾病概况的变化。由LACV和CHIKV两种代表性成员诱导的转录组学变化显示,LACV感染的球体具有高度的促炎反应,而CHIKV感染则诱导神经退行性特征。最后,我们评估了干扰素- α的抗病毒和抗神经功能障碍活性,并测试了小分子吉西他滨对CHIKV的作用,作为HT抗病毒化合物筛选的概念证明。总之,我们的数据建立了病毒-神经球体作为一个有价值的平台,支持高影响嗜神经病毒的生产性感染,该平台可用于研究病毒发病机制和支持治疗方法的发现和开发。
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来源期刊
Antiviral research
Antiviral research 医学-病毒学
CiteScore
17.10
自引率
3.90%
发文量
157
审稿时长
34 days
期刊介绍: Antiviral Research is a journal that focuses on various aspects of controlling viral infections in both humans and animals. It is a platform for publishing research reports, short communications, review articles, and commentaries. The journal covers a wide range of topics including antiviral drugs, antibodies, and host-response modifiers. These topics encompass their synthesis, in vitro and in vivo testing, as well as mechanisms of action. Additionally, the journal also publishes studies on the development of new or improved vaccines against viral infections in humans. It delves into assessing the safety of drugs and vaccines, tracking the evolution of drug or vaccine-resistant viruses, and developing effective countermeasures. Another area of interest includes the identification and validation of new drug targets. The journal further explores laboratory animal models of viral diseases, investigates the pathogenesis of viral diseases, and examines the mechanisms by which viruses avoid host immune responses.
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