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.

项目摘要 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， DNA病毒已经感染了全世界90%以上的人。初次感染会导致水痘， 而病毒在神经系统内的重新激活可能会产生可怕的后果。带状疱疹 （带状疱疹）是最常见的表现，病毒复活，影响一个每一个 在美国有三个人，并引起疱疹后神经痛（PHN），一种严重的，通常是慢性的疼痛 美国每年花费超过10亿美元的综合症。中枢神经系统内的病毒再活化 系统可导致脑炎和脑炎，通常导致死亡或严重的认知和身体 残疾。值得注意的是，VZV继续造成显著的死亡，尽管出现并广泛使用了 抗病毒药物（阿昔洛韦）和疫苗接种，只能提供部分保护， 地址PHN。因此，需要新的治疗方法来限制与糖尿病相关的发病率和死亡率。 神经元感染和再激活。 VZV感染研究的主要局限性是该病毒严格的种特异性， 使得它基本上只感染人类细胞。因此，没有可靠的动物模型 它概括了人类疾病的基本特征。此外，该病毒似乎利用不同的 不同细胞类型中的细胞和分子途径。因此，人类中病毒感染的研究 成纤维细胞或其它皮肤细胞可能不直接影响人神经元内的发病机制。最近， VZV已被证明感染来自人神经干细胞和人多能干细胞的神经元。 干细胞，表明基于干细胞的VZV发病机制的研究方法是可能的 为新疗法的发展带来了巨大的希望。然而，大多数人类神经元 来源于干细胞的培养系统通常由很少的感觉神经元（如果有的话）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 潜伏期和稍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多能干细胞的感觉神经元模型。 VZV感染神经元。这一模型的建立将为研究VZV奠定基础 相关细胞类型中的神经发病机制。我们预计，我们的模型的建立将产生 初步了解VZV如何感染和重新激活人类感觉神经元，并将作为 为VZV再活化和PHN的新治疗方法的开发奠定了基础。

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