A Human Sensory Neuron Model of VZV Infection

VZV 感染的人类感觉神经元模型

• 批准号: 9766418
• 负责人: ARUN VENKATESAN
• 金额: $ 20.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766418
• 关键词: Acyclovir; Address; Affect; Afferent Neurons; Animal Model; Antiviral Agents; Apoptosis; Autopsy; Biological Assay; Biology; Brain; Cells; Cessation of life; Chickenpox; DNA Viruses; Data; Development; Encephalitis; Event; Experimental Models; Expression Profiling; Fibroblasts; Gene Expression Profiling; Genetic Transcription; Herpes zoster disease; Herpesvirus Type 3; Human; In Vitro; Individual; Infection; Latent Virus; Lytic Phase; MAPK8 gene; Modeling; Molecular; Morbidity - disease rate; Myelitis; Nervous system structure; Neuraxis; Neurologic; Neurons; Neuropathogenesis; Pain; Pathogenesis; Pathway interactions; Physically Handicapped; Physiological; Population; Positioning Attribute; Postherpetic neuralgia; Primary Infection; Role; Sensory; Skin; Species Specificity; Specimen; Spinal Ganglia; Stem cells; Syndrome; System; Tissues; Transcript; Ursidae Family; Vaccination; Viral; Viral Pathogenesis; Virus; Virus Diseases; Virus Latency; Virus Replication; Xenograft procedure; base; cell type; chronic pain; cognitive disability; cost; fetal; human disease; human embryonic stem cell; human model; human pluripotent stem cell; in vitro Model; in vivo; induced pluripotent stem cell; insight; latency associated transcript; mortality; nerve stem cell; novel therapeutics; permissiveness; prospective

Project Summary New experimental models are needed to develop treatments for varicella zoster virus (VZV), a DNA virus that has infected over 90% of individuals worldwide. Primary infection causes chickenpox, while reactivation of the virus within the nervous system can have dire consequences. Shingles (herpes zoster) is the most common manifestation of viral reactivation, affecting one out of every three people in the U.S. and causing post-herpetic neuralgia (PHN), a severe, often chronic, pain syndrome with annual U.S. costs of over $1 billion. Viral reactivation within the central nervous system can result in encephalitis and myelitis, often leading to death or severe cognitive and physical disability. Notably, VZV continues to exact a marked toll despite the advent and widespread use of antiviral agents (acyclovir) and vaccination, which only afford partial protection and do not specifically address PHN. Thus, new therapies are needed to limit the morbidity and mortality associated with neuronal infection and reactivation. The major limitation in the study of VZV infection is the strict species-specificity of the virus, such that it essentially exclusively infects human cells. As a result, there are no robust animal models that recapitulate essential features of human disease. Moreover, the virus appears to utilize distinct cellular and molecular pathways in different cell types. Thus, studies of viral infection in human fibroblasts or other skin cells may not directly bear on pathogenesis within human neurons. Recently, VZV has been shown to infect neurons derived from human neural stem cells and human pluripotent stem cells, suggesting that stem-cell based approaches for the study of VZV pathogenesis are likely to hold great promise for the development of new treatments. However, most human neuronal cultures systems derived from stem cells are typically comprised of few, if any, sensory neurons. This is a great limitation since sensory neurons are the main cell type in which the virus establishes latency and later re-emerges during reactivation. Here, we propose to develop a model of human pluripotent stem cell based model of sensory neuron infection by VZV. The establishment of such a model will result in the ability to study VZV neuropathogenesis in a relevant cell type. We anticipate that establishment of our model will yield initial insights into how VZV infects and reactivates in human sensory neurons and will serve as the basis for a system to develop new treatments for VZV reactivation and PHN.

项目概要 需要新的实验模型来开发水痘带状疱疹病毒（VZV）的治疗方法，水痘带状疱疹病毒是一种 DNA病毒已经感染了全世界90%以上的人。原发感染引起水痘， 而神经系统内病毒的重新激活可能会产生可怕的后果。带状疱疹 （带状疱疹）是病毒再激活的最常见表现，影响着十分之一的人 美国有 3 人患有带状疱疹后神经痛 (PHN)，这是一种严重且通常是慢性的疼痛 美国每年为此付出的代价超过 10 亿美元。中枢神经内的病毒重新激活 系统可导致脑炎和脊髓炎，通常导致死亡或严重的认知和身体障碍 残疾。值得注意的是，尽管 VZV 已经出现并广泛使用，但它仍然造成了显着的损失。 抗病毒药物（阿昔洛韦）和疫苗接种，仅提供部分保护，并不具体 地址 PHN。因此，需要新的疗法来限制与相关的发病率和死亡率 神经元感染和重新激活。 VZV 感染研究的主要限制是病毒严格的物种特异性， 因此它基本上只感染人类细胞。因此，目前还没有稳健的动物模型 概括了人类疾病的基本特征。此外，该病毒似乎利用了独特的 不同细胞类型中的细胞和分子途径。因此，对人类病毒感染的研究 成纤维细胞或其他皮肤细胞可能不会直接影响人类神经元的发病机制。最近， VZV 已被证明可以感染源自人类神经干细胞和人类多能细胞的神经元 干细胞，表明基于干细胞的方法可能用于研究 VZV 发病机制 为新疗法的开发带来巨大希望。然而，大多数人类神经元 源自干细胞的培养系统通常由很少（如果有的话）的感觉神经元组成。 这是一个很大的限制，因为感觉神经元是病毒建立的主要细胞类型 潜伏期并随后在重新激活期间重新出现。 在这里，我们建议开发一种基于人类多能干细胞的感觉模型 VZV 神经元感染。这样一个模型的建立将带来研究VZV的能力 相关细胞类型的神经发病机制。我们预计模型的建立将产生 初步了解 VZV 如何感染人类感觉神经元并重新激活，并将作为 为开发 VZV 重新激活和 PHN 新疗法的系统奠定了基础。

项目成果

Nectin-1 Is an Entry Mediator for Varicella-Zoster Virus Infection of Human Neurons

Nectin-1 是人类神经元水痘带状疱疹病毒感染的进入介质

• DOI: 10.1128/jvi.01227-21
• 发表时间: 2021
• 期刊: Journal of Virology
• 影响因子: 5.4
• 作者: Rajbhandari Labchan;Shukla Priya;Jagdish Balaji;Mandalla Abby;Li Qingxue;Ali Mir A.;Lee Hojae;Lee Gabsang;Sadaoka Tomohiko;Cohen Jeffrey I.;Venkatesan Arun
• 通讯作者: Venkatesan Arun