A Nonhuman Primate Model of Infant CMV Infection

婴儿 CMV 感染的非人灵长类动物模型

基本信息

  • 批准号:
    7907251
  • 负责人:
  • 金额:
    $ 9.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-04-01 至 2011-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) is the most common congenital infection worldwide and the primary infectious cause of serious birth defects in newborns. HCMV has long been recognized as an infectious threat to the fetus, particularly in women without HCMV immunity and who have a primary HCMV infection during pregnancy. The major source of infection for pregnant women are children with subclincal HCMV infection. Children that become infected congenitally or perinatally shed virus for longer periods of time and at higher titers than people that acquire HCMV later in life. The mechanism(s), why children who acquire the virus early in prenatal or post-natal life shed the virus longer and in higher titers are not known. Considering the severe health risks associated with congenital HCMV infection, breaking the chain of transmission from subclinically infected children to pregnant women to fetuses would have important benefits for human health. This requires a better understanding of virus-host interactions in very young children as compared to adults. For ethical reasons, studies in newborns are very limited. Thus, we propose to develop a nonhuman primate model of infant HCMV infection by orally infecting infant macaques with rhesus CMV (RhCMV) (Aim 1). A model of HCMV pathogenesis in adult macaques has been developed and closely mimics HCMV infection in humans. The establishment of an infant model of RhCMV infection will provide us with the opportunity to define differences in specific immune responses to RhCMV infection between infants and adults while keeping the virus inoculum, the dose, and the route of transmission constant. The underlying assumption is that long-term virological outcome in HCMV infected patients depends on the earliest virus-host interactions. As the infant immune system is less mature, the overall HCMV response is less likely to control virus replication. HCMV-specific CD4+T cells have been implicated to play an essential role in the control of virus replication. Thus, we present the hypothesis that a limited functional capacity of infant CD4+T cells, as assessed by reduced IFN-g production, combined with higher frequencies of regulatory T cells in infants interfere with the development of effective HCMV-specific CD4+T cells (Aim 2). This hypothesis will be tested in the infant macaque model of RhCMV infection established in Aim 1. The results of the proposed studies should be of broader importance for understanding infant immune responses to other infectious agents and how to prevent a pathogenic outcome in children. Thus, a nonhuman primate model of infant HCMV infection would be a unique resource to test the efficacy and safety of pediatric antiviral therapies and HCMV vaccines. PUBLIC HEALTH RELEVANCE: Human cytomegalovirus (HCMV) is the most common congenital infection worldwide and is the primary infectious cause of serious birth defects in newborns. Children with sublinical HCMV infection are the major source for HCMV infection in pregnant women because HCMV infected children shed virus for a longer time and at higher titers that people that acquire HCMV later in life. We propose to develop a nonhuman primate model of infant HCMV infection to advance our understanding of the age-related differences in HCMV pathogenesis in infants and adults with the longterm goal of breaking the chain of transmission from subclinically infected children to pregnant women to fetuses.
描述(由申请人提供):人类巨细胞病毒(HCMV)是世界范围内最常见的先天性感染,也是新生儿严重出生缺陷的主要原因。长期以来,HCMV 一直被认为对胎儿具有传染性威胁,特别是对于没有 HCMV 免疫力且在怀孕期间原发性 HCMV 感染的女性。孕妇的主要感染源是亚临床HCMV感染的儿童。先天性或围产期感染的儿童比晚年感染 HCMV 的儿童传播病毒的时间更长、滴度更高。为什么在产前或产后早期感染病毒的儿童传播病毒的时间更长且滴度更高的机制尚不清楚。考虑到与先天性 HCMV 感染相关的严重健康风险,打破从亚临床感染儿童到孕妇再到胎儿的传播链将对人类健康产生重要益处。与成人相比,这需要更好地了解幼儿的病毒与宿主的相互作用。出于伦理原因,对新生儿的研究非常有限。因此,我们建议通过用恒河猴 CMV (RhCMV) 口服感染婴儿猕猴来开发婴儿 HCMV 感染的非人灵长类动物模型(目标 1)。已经开发出成年猕猴 HCMV 发病机制的模型,该模型非常模拟人类的 HCMV 感染。 RhCMV感染婴儿模型的建立将为我们提供机会,在保持病毒接种量、剂量和传播途径不变的情况下,明确婴儿和成人之间对RhCMV感染的特异性免疫反应的差异。基本假设是 HCMV 感染患者的长期病毒学结果取决于最早的病毒与宿主的相互作用。由于婴儿免疫系统不太成熟,总体 HCMV 反应不太可能控制病毒复制。 HCMV 特异性 CD4+T 细胞在病毒复制的控制中发挥重要作用。因此,我们提出这样的假设:婴儿 CD4+T 细胞的功能能力有限(通过 IFN-g 产生减少来评估),加上婴儿中调节性 T 细胞频率较高,会干扰有效 HCMV 特异性 CD4+T 细胞的发育(目标 2)。这一假设将在目标 1 中建立的 RhCMV 感染的婴儿猕猴模型中得到检验。拟议研究的结果对于了解婴儿对其他传染源的免疫反应以及如何预防儿童的致病结果具有更广泛的重要性。因此,婴儿 HCMV 感染的非人灵长类动物模型将是测试儿科抗病毒疗法和 HCMV 疫苗的功效和安全性的独特资源。 公共卫生相关性:人类巨细胞病毒 (HCMV) 是全世界最常见的先天性感染,也是新生儿严重出生缺陷的主要原因。患有亚临床HCMV感染的儿童是孕妇HCMV感染的主要来源,因为与晚年感染HCMV的人相比,感染HCMV的儿童传播病毒的时间更长且滴度更高。我们建议开发一种婴儿 HCMV 感染的非人灵长类动物模型,以加深我们对婴儿和成人 HCMV 发病机制与年龄相关的差异的理解,长期目标是打破从亚临床感染儿童到孕妇再到胎儿的传播链。

项目成果

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Kristina De Paris其他文献

Kristina De Paris的其他文献

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{{ truncateString('Kristina De Paris', 18)}}的其他基金

Core C: B Cell Core
核心C:B细胞核心
  • 批准号:
    10731279
  • 财政年份:
    2023
  • 资助金额:
    $ 9.55万
  • 项目类别:
Core A: Administrative Core
核心A:行政核心
  • 批准号:
    10731277
  • 财政年份:
    2023
  • 资助金额:
    $ 9.55万
  • 项目类别:
Project 1: The impact of innate immune responses on the development of broadly neutralizing antibodies by vaccination
项目 1:先天免疫反应对通过疫苗接种产生广泛中和抗体的影响
  • 批准号:
    10731281
  • 财政年份:
    2023
  • 资助金额:
    $ 9.55万
  • 项目类别:
Project 2: Microbial determinants of HIV broadly-neutralizing antibody precursor induction in infants
项目2:婴儿中HIV广泛中和抗体前体诱导的微生物决定因素
  • 批准号:
    10731282
  • 财政年份:
    2023
  • 资助金额:
    $ 9.55万
  • 项目类别:
Core B: Non-human Primate Core
核心B:非人类灵长类核心
  • 批准号:
    10731278
  • 财政年份:
    2023
  • 资助金额:
    $ 9.55万
  • 项目类别:
Determinants of HIV broadly-neutralizing antibody precursor induction in infants
婴儿中 HIV 广泛中和抗体前体诱导的决定因素
  • 批准号:
    10731276
  • 财政年份:
    2023
  • 资助金额:
    $ 9.55万
  • 项目类别:
Vaccine-induced SARS-CoV-2-specific T cell responses in patients with X-linked Agammaglobulinemia
X 连锁无丙种球蛋白血症患者中疫苗诱导的 SARS-CoV-2 特异性 T 细胞反应
  • 批准号:
    10593523
  • 财政年份:
    2023
  • 资助金额:
    $ 9.55万
  • 项目类别:
Immunogenicity and Efficacy of SARS-CoV-2 stabilized prefusion Spike protein vaccines in infant rhesus macaques
SARS-CoV-2 稳定预灌注 Spike 蛋白疫苗在幼年恒河猴中的免疫原性和功效
  • 批准号:
    10223634
  • 财政年份:
    2020
  • 资助金额:
    $ 9.55万
  • 项目类别:
Subingual-parenteral Vaccination to Prevent Oral HIV Transmission in Infants
舌下注射疫苗预防婴儿经口艾滋病毒传播
  • 批准号:
    10172886
  • 财政年份:
    2018
  • 资助金额:
    $ 9.55万
  • 项目类别:
Subingual-parenteral Vaccination to Prevent Oral HIV Transmission in Infants
舌下注射疫苗预防婴儿经口艾滋病毒传播
  • 批准号:
    10425465
  • 财政年份:
    2018
  • 资助金额:
    $ 9.55万
  • 项目类别:

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