Angelica Medina, Yu-Chi Chen, Jiajing Zhang, Sarah C Ogden, Samantha Cotsmire, Harshad D Vishwasrao, Marc Ferrer, Emily M Lee
{"title":"Modeling neurotropic virus infection with functional human neural spheroids as a platform for high-throughput antiviral screening and pathogenesis.","authors":"Angelica Medina, Yu-Chi Chen, Jiajing Zhang, Sarah C Ogden, Samantha Cotsmire, Harshad D Vishwasrao, Marc Ferrer, Emily M Lee","doi":"10.1016/j.antiviral.2025.106248","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106248"},"PeriodicalIF":4.0000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Antiviral research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.antiviral.2025.106248","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/5 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
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.
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.