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

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:本申请定义了一个程序,以进一步指导设置内有前途的初级研究员的研究生涯。成功完成将使研究者开始作为一个独立的临床科学家的职业生涯,进行翻译研究,旨在创造和评估单纯疱疹病毒(HSV)的治疗和疫苗候选人,与提高免疫力的理解HSV的相关目标。本申请的具体项目研究了HSV与其主要进入受体的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。背景资料: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,新生儿特别容易患严重疾病。HSV最初在与两种主要受体HVEM和nectin之一相互作用后感染细胞。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,病毒可能通过参与HVEM来操纵记忆免疫。研究设计和方法:在本项目的具体目标1中,我们将通过阴道内感染减毒HSV-2,使用野生型病毒或改变以消除与HVEM结合的病毒,在成年雌性小鼠中引发对HSV的免疫力。然后,我们将严格调查的记忆淋巴细胞反应后,无论是野生型或突变病毒的挑战,解决的假设,即在粘膜的调节性T细胞反应改变在记忆阶段的初始病毒与HVEM的相互作用。在目标2中,我们将测试HVEM接合对新生儿HSV疾病的影响。我们将使用与目标1相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。感染途径将与人类新生儿疾病相关。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,研究疾病在缺乏一种或两种主要受体的小鼠中的传播和发病机制。我们还将测量产后早期发育期间不同组织中不同受体的相对表达。研究环境:候选人建议在一个成功培养初级调查员职业生涯的环境中发展这一项目。在该领域专家的监督下,该项目将为候选人的背景增加新的专业知识,包括小鼠新生儿感染模型的开发,新生儿免疫反应的调查和免疫组织化学方法。建议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,以及负责任地进行研究的培训。 公共卫生相关性:对单纯疱疹病毒(HSV)记忆免疫的理解对开发有效预防慢性感染个体脱落的疫苗具有意义,并可能导致开发治疗方法以最大限度地减少或预防分娩期间新生儿暴露。更好地了解不同的HSV受体对新生儿疾病发病机制的影响可能会导致在这一人群中改善治疗。

项目成果

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William Joseph Muller其他文献

William Joseph Muller的其他文献

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{{ truncateString('William Joseph Muller', 18)}}的其他基金

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
  • 批准号:
    8298650
  • 财政年份:
    2010
  • 资助金额:
    $ 12.91万
  • 项目类别:
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
  • 批准号:
    8099728
  • 财政年份:
    2010
  • 资助金额:
    $ 12.91万
  • 项目类别:
Keratinocyte innate immune responses after herpes simplex virus infection
单纯疱疹病毒感染后角质形成细胞的先天免疫反应
  • 批准号:
    8488595
  • 财政年份:
  • 资助金额:
    $ 12.91万
  • 项目类别:

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