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Herpes Simplex Virus Entry Receptors in Immune Memory and Newborn Infection

免疫记忆和新生儿感染中的单纯疱疹病毒进入受体

基本信息

批准号：
8298650
负责人：
William Joseph Muller
金额：
$ 12.91万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8298650
关键词：
Acute Address Adult Advisory Committees Affect American Attenuated Binding CD8B1 gene Cell Surface Receptors Cell membrane Cells Cellular Immunity Child Clinical Congenital herpes simplex Data Development Disease Environment Evaluation Female Glycoproteins Goals Heparitin Sulfate Herpes Simplex Virus Vaccines Herpesviridae Human Human Herpesvirus 2 Human Virus Immune Immune response Immunity Immunologics Individual Infection Investigation Lead Ligands Lymphocyte Lymphocyte Activation Lymphocyte Function Measures Mediating Mediator of activation protein Membrane Fusion Memory Mentors Methods Modeling Molecular Biology Molecular Immunology Mucous Membrane Mus Neonatal Neurologic Newborn Infant Organ Orthologous Gene PVRL1 Pathogenesis Phase Phenotype Population Predisposition Proteins Publishing Recurrence Regulatory T-Lymphocyte Relative (related person)Research Research Design Research Methodology Research Personnel Resistance Route Scientist Severities Signal Transduction Signaling Protein Simplexvirus Site Supervision T cell response T memory cell T-Lymphocyte Testing Therapeutic Tissues Training Translational Research Tumor Necrosis Factor Receptor Vagina Viral Viral Proteins Virus Virus Diseases Virus Receptors base career career development improved lymph nodes member mouse model mutant nectin neonatal exposure pathogen postnatal prevent programs prophylactic public health relevance receptor receptor expression research study response responsible research conduct success therapeutic development therapeutic target therapeutic vaccine therapy development vaccine candidate vaccine development viral DNA

项目摘要

DESCRIPTION (provided by applicant): Objectives: This application defines a program to further the research career of a promising junior investigator within a mentored setting. Successful completion would allow the investigator to initiate a career as an independent clinician-scientist, conducting translational research directed at creating and evaluating therapeutics and vaccine candidates for herpes simplex virus (HSV), with the related goal of improving the understanding of immunity to HSV. The specific project for this application investigates the importance of HSV interactions with its principal entry receptors on neonatal disease and the influence of an interaction between an HSV glycoprotein and an immune signaling protein on memory immunity to HSV. Background: Herpes simplex viruses are common human pathogens, infecting more than 60% of American adults, with newborns particularly susceptible to severe disease. HSV initially infects cells after interacting with one of two principal receptors, HVEM and nectin. Prior published data suggest that neurologic disease is largely related to viral entry using nectin; our preliminary data suggest that the virus may manipulate memory immunity by engagement of HVEM. Research design and methods: In Specific Aim 1 of this project, we will prime immunity to HSV in adult female mice by intravaginal infection with attenuated HSV-2, using either wild-type virus or virus altered to abrogate binding to HVEM. We will then rigorously investigate the memory lymphocyte response after challenge with either wild-type or mutant virus, addressing the hypothesis that regulatory T-cell responses at the mucosa are altered in the memory phase by initial viral interaction with HVEM. In Aim 2, we will test the influence of HVEM engagement on neonatal HSV disease. We will use similar immunologic methods as in Aim 1 to test whether immunity in newborn mice is altered by engagement of HVEM. Routes of infection will be relevant to neonatal disease in humans. In Aim 3, we will investigate in detail our preliminary observation that HVEM is not sufficient to cause HSV disease in newborn mice, looking at spread and pathogenesis of disease in mice lacking one or both principal receptors. We will also measure the relative expression of different receptors in different tissues during early postnatal development. Research environment: The candidate proposes to develop this project within an environment with established success at nurturing the careers of junior investigators. Under the supervision of experts in the field, this project will add new expertise to the candidate's background, including development of murine neonatal infection models, investigation of newborn immune responses, and immunohistochemical methods. Career development activities within the proposal include didactic coursework in molecular biology and immunology, regular evaluations by a career advisory committee, and training in the responsible conduct of research. Public health relevance: The understanding of memory immunity to herpes simplex virus (HSV) has implications for the development of vaccines effective at preventing shedding in chronically infected individuals, and may lead to development of therapeutic methods to minimize or prevent neonatal exposure during delivery. A better understanding of the influence of different HSV receptors on pathogenesis of neonatal disease may lead to improved therapeutics in this population.

描述（由申请人提供）：目标：本申请定义了一个计划，旨在在指导环境中促进有前途的初级研究员的研究生涯。成功完成该课程将使研究者能够开始作为独立临床医生科学家的职业生涯，开展旨在创建和评估单纯疱疹病毒（HSV）候选疗法和疫苗的转化研究，相关目标是提高对 HSV 免疫的了解。该应用的具体项目研究了 HSV 与其主要进入受体相互作用对新生儿疾病的重要性，以及 HSV 糖蛋白和免疫信号蛋白之间的相互作用对 HSV 记忆免疫的影响。背景：单纯疱疹病毒是常见的人类病原体，感染超过 60% 的美国成年人，新生儿特别容易感染严重疾病。 HSV 在与两种主要受体 HVEM 和 nectin 之一相互作用后最初感染细胞。先前发表的数据表明，神经系统疾病在很大程度上与使用连接蛋白的病毒进入有关。我们的初步数据表明，病毒可能通过 HVEM 的参与来操纵记忆免疫。研究设计和方法：在该项目的具体目标 1 中，我们将使用野生型病毒或改变后的病毒来消除与 HVEM 的结合，通过阴道内感染减毒 HSV-2 来增强成年雌性小鼠对 HSV 的免疫力。然后，我们将严格研究野生型或突变病毒攻击后的记忆淋巴细胞反应，解决粘膜调节性 T 细胞反应在记忆阶段因病毒与 HVEM 的初始相互作用而改变的假设。在目标 2 中，我们将测试 HVEM 参与对新生儿 HSV 疾病的影响。我们将使用与目标 1 类似的免疫学方法来测试新生小鼠的免疫力是否因 HVEM 的参与而改变。感染途径与人类新生儿疾病有关。在目标 3 中，我们将详细研究我们的初步观察结果，即 HVEM 不足以在新生小鼠中引起 HSV 疾病，研究缺乏一种或两种主要受体的小鼠中疾病的传播和发病机制。我们还将测量出生后早期发育过程中不同组织中不同受体的相对表达。研究环境：候选人建议在培养初级研究人员职业生涯方面已取得成功的环境中开发该项目。在该领域专家的监督下，该项目将为候选人的背景增添新的专业知识，包括小鼠新生儿感染模型的开发、新生儿免疫反应的研究和免疫组织化学方法。该提案中的职业发展活动包括分子生物学和免疫学的教学课程、职业咨询委员会的定期评估以及负责任的研究行为培训。公共卫生相关性：对单纯疱疹病毒 (HSV) 记忆免疫的了解对于开发有效预防慢性感染者排毒的疫苗具有重要意义，并可能导致开发治疗方法以最大程度地减少或防止新生儿在分娩过程中接触病毒。更好地了解不同 HSV 受体对新生儿疾病发病机制的影响可能会改善该人群的治疗方法。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Longitudinal Characterization of Herpes Simplex Virus (HSV) Isolates Acquired From Different Sites in an Immune-Compromised Child: A New HSV Thymidine Kinase Mutation Associated With Resistance.

DOI：
10.1093/jpids/pis009
发表时间：
2012-06
期刊：
Journal of the Pediatric Infectious Diseases Society
影响因子：
3.2
作者：
Andrew H. Karaba;Laura K Cohen;Taly Glaubach;Sarah J Kopp;J. Reichek;Hawke H. Yoon;Xiaotian Zheng;W. Muller
通讯作者：
Andrew H. Karaba;Laura K Cohen;Taly Glaubach;Sarah J Kopp;J. Reichek;Hawke H. Yoon;Xiaotian Zheng;W. Muller

Herpesvirus entry mediator (HVEM) attenuates signals mediated by the lymphotoxin β receptor (LTβR) in human cells stimulated by the shared ligand LIGHT.