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

• 批准号: 9791978
• 负责人: David A Leib
• 金额: $ 60.78万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 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/9791978
• 关键词: Acute; Address; Afferent Neurons; Antibodies; Attenuated Live Virus Vaccine; 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; Latent Virus; 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; Vaccines; 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 infection; maternal morbidity; maternal vaccination; mortality; mouse model; mutant; neonatal infection; neonate; novel; novel strategies; pathogen; programs; reactivation from latency; response; success; virology

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率和死亡率的主要来源，其成功是由于它们的能力 建立潜在的感染并调节宿主的免疫力。这些能力使病毒 难以通过化学治疗剂治愈，并通过免疫系统清除。而延迟和 对疱疹病毒的免疫力进行了深入研究，控制机制的机制， 潜伏期的维持和重新激活仍然晦涩难懂，特别是对于单纯疱疹病毒（HSV）。这是到的， 在某种程度上，虽然非常有用的信息，但虽然很有意义 正是关于HSV与神经元之间的独特关系，即其潜伏期的目标细胞。最近，我们的 通过在生理上相关的发展，对潜伏期的理解显着增强了 采用原发性培养神经元的体外系统可以与更传统的体内结合使用 询问潜伏期和免疫力的分子基础的系统。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，以展示内在，先天和 自适应免疫和病毒对策决定了潜伏期/重新激活轴的平衡。目的 1，通过项目1和2，研究自噬体簇的结构和功能（内在免疫） 在建立和维持潜伏期期间，感官神经元引起的。我们将调查这些 具有高分辨率显微镜的新发现结构，并表征基因表达和染色质 集群阳性神经元中的HSV模式。 AIM 2检查活性氧的病毒调节的作用 培养神经元中的物种和线粒体运动在HSV的能力上建立并重新激活 潜伏期，以及依赖干扰素的先天免疫反应的起源。通过项目1和2， AIM还将检查HSV蛋白ICP0和ICP34.5在调节这些响应中的作用 它们对基因表达和染色质模式的影响。 AIM 3解决了抗体是 神经系统中HSV-1复制，发病机理和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动，并在控制复制，延迟，延迟， 将确定重新激活，包括对基因表达和染色质的影响。与项目1一起 实验疫苗和抗体的能力，不仅保护小鼠免受HSV的死亡率 挑战，但也来自与新生儿感染相关的长期行为病理学 评估。然后，一般方法是继续与项目1和2的合作，并使用核心B进行 开发和利用我们的主要神经元和新生儿感染模型系统与与分析相关的 基因表达和染色质模式的核心A以及实验免疫。这些方法会 确定免疫力的不同分支如何控制潜伏期，以及HSV如何反驳这些反应。这 框架将确定新的途径，以帮助干预这种持续的人类病原体的生命周期。