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.

项目总结

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