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Project 3 - Innate immunity and the HSV lytic/latent balance

项目 3 - 先天免疫和 HSV 裂解/潜伏平衡

基本信息

批准号：
10460512
负责人：
David A Leib
金额：
$ 54.96万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-02 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460512
关键词：
Acute Address Afferent Neurons Antibodies Attenuated Vaccines Autophagocytosis Autophagosome Axon Behavioral Binding Bioenergetics Biological Models Cells Chromatin Collaborations Congenital herpes simplex Data Development Disease Dissection Equilibrium Family Ganglia Gene Expression Gene Expression Profile Genes Herpesviridae Herpesvirus 1 Human Humoral Immunities ISG15 gene Immune Immune Evasion Immune response Immune system Immunity Immunization Immunoglobulin G In Vitro Individual Innate Immune Response Interferons Intervention Link Lytic Lytic Virus Maintenance Measures MicroRNAs Microscopic Microscopy Mitochondria Mitochondrial Proteins Modeling Molecular Morbidity - disease rate Movement Mus Mutate Natural Immunity Nervous system structure Neurons Outcome Pathogenesis Pathology Pathway interactions Pattern Penetrance Physiological Play Population Prevention strategy Property Reactive Oxygen Species Recombinants Refractory Resolution Role Sensory Ganglia Simplexvirus Site Source Structure Structure of trigeminal ganglion System Tadpoles Technology Testing Trigeminal System Viral Viral Genes Viral Proteins Virus Virus Diseases Virus Latency Virus Replication Work acute infection adaptive immunity arm chemotherapeutic agent human pathogen immune clearance in vitro Model in vivo in vivo Model latent gene expression latent infection maternal morbidity maternal vaccination mortality mouse model mutant neonatal infection neonate novel novel strategies pathogen programs reactivation from latency response success vaccine-induced antibodies

项目摘要

Herpesviruses are a major source of morbidity and mortality in humans and their success is due to their ability to establish latent infections, and to modulate the immunity of their hosts. These abilities render the virus refractory to cure by chemotherapeutic agents, and to clearance by the immune system. While latency and immunity to herpesviruses have been intensely studied, the mechanisms that control establishment, maintenance and reactivation of latency remain obscure, especially for herpes simplex virus (HSV). This is due, in part, to the high complexities of in vivo (mostly mouse) models that while highly informative, fail to inform precisely about the unique relationship between HSV and the neuron, its target cell for latency. Recently, our understanding of latency has been significantly enhanced by the development of physiologically relevant in vitro systems employing primary cultured neurons that can be used in combination with more traditional in vivo systems to interrogate the molecular basis of latency and immunity. The over-arching approach of Project 3 is to use and develop relevant in vitro and in vivo models systems to demonstrate roles for intrinsic, innate, and adaptive immunity and viral countermeasures that determine the balance of the latency/reactivation axis. Aim 1, with Projects 1 and 2, examines the structure and function of autophagosomes clusters (intrinsic immunity) that are induced in sensory neurons during the establishment and maintenance of latency. We will probe these newly-discovered structures with high resolution microscopy, and characterize gene expression and chromatin patterns of HSV in cluster-positive neurons. Aim 2 examines the role of viral modulation of reactive oxygen species and mitochondrial movement in cultured neurons on the ability of HSV to establish, and reactivate from latency, and on the genesis of the interferon-dependent innate immune response. With Projects 1 and 2, this aim will also examine the roles of HSV proteins ICP0 and ICP34.5 in the modulation of these responses and their effects on gene expression and chromatin patterns. Aim 3 addresses the hypothesis that antibodies are key immune determinants of HSV-1 replication, pathogenesis, and latency in the nervous system. The activities of antibodies within sensory ganglia will be defined, and their roles in the control of replication, latency, and reactivation, including effects on gene expression and chromatin, will be determined. With Project 1, the ability of an experimental vaccine and antibodies to protect mice not only from mortality following HSV challenge, but also from the long-lived behavioral pathology associated with neonatal infection will be assessed. The general approach then is to continue collaborations with Projects 1 and 2, and, using Core B, to develop and exploit our primary neuron and neonatal infection model systems interfaced with analyses with Core A of gene expression and chromatin patterns, and experimental immunization. These approaches will determine how different branches of immunity control latency, and how HSV counters these responses. This framework will identify novel pathways to help intervene in the lifecycle of this persistent human pathogen.

疱疹病毒是人类发病和死亡的主要来源，其成功归功于其能力建立潜伏感染并调节宿主的免疫力。这些能力使病毒化疗药物难以治愈，也难以被免疫系统清除。虽然延迟和对疱疹病毒的免疫力已得到深入研究，控制建立的机制，潜伏期的维持和重新激活仍然不清楚，特别是对于单纯疱疹病毒（HSV）。这是由于，部分原因是体内（主要是小鼠）模型的高度复杂性，虽然信息丰富，但无法提供信息正是关于 HSV 和神经元（其潜伏期的目标细胞）之间的独特关系。最近，我们的通过生理相关的发展，对潜伏期的理解得到了显着增强。采用原代培养神经元的体外系统，可与更传统的体内系统结合使用系统来探究潜伏期和免疫的分子基础。项目 3 的总体方法是使用和开发相关的体外和体内模型系统来展示内在的、先天的和适应性免疫和病毒对策决定了潜伏/重新激活轴的平衡。目的 1、配合项目1和2，考察自噬体簇的结构和功能（内在免疫）在潜伏期的建立和维持期间在感觉神经元中诱导的。我们将探究这些用高分辨率显微镜观察新发现的结构，并表征基因表达和染色质簇阳性神经元中 HSV 的模式。目标 2 检查病毒调节活性氧的作用培养神经元中的物种和线粒体运动对 HSV 建立和重新激活能力的影响潜伏期，以及干扰素依赖性先天免疫反应的发生。对于项目 1 和 2，这 Target 还将研究 HSV 蛋白 ICP0 和 ICP34.5 在调节这些反应中的作用，它们对基因表达和染色质模式的影响。目标 3 提出了这样的假设：抗体是 HSV-1 复制、发病机制和神经系统潜伏期的关键免疫决定因素。这将定义感觉神经节内抗体的活性，以及它们在控制复制、潜伏期、将确定重新激活，包括对基因表达和染色质的影响。通过项目 1，实验性疫苗和抗体不仅能够保护小鼠免受单纯疱疹病毒感染的死亡挑战，但也来自与新生儿感染相关的长期行为病理学评估。一般方法是继续与项目 1 和 2 合作，并使用核心 B 开发和利用我们的初级神经元和新生儿感染模型系统，并与分析相结合基因表达和染色质模式的核心 A，以及实验免疫。这些方法将确定免疫的不同分支如何控制潜伏期，以及 HSV 如何对抗这些反应。这该框架将确定新的途径来帮助干预这种持久性人类病原体的生命周期。