Evolution of the Immune Response to Cytomegalovirus Transmitted via Breast Milk

描述（由申请人提供）：生命早期对感染的免疫反应尚不清楚；然而，它们会导致影响健康的器官发育和功能的深刻变化。例如，子宫内（先天性）感染人类巨细胞病毒（HCMV）可导致生长迟缓、小头畸形、感音神经性听力丧失，甚至死亡。HCMV感染也发生在出生后的新生儿中，通过母乳中的病毒传播。由于这些婴儿大多数是无症状的，因此有人提出这种感染途径可能代表一种自然免疫。通过母乳喂养接触病毒对新生儿发展有效的免疫控制病毒传播和脱落的能力的有效性尚未得到很好的表征。本探索性研究旨在确定哺乳期间母体传播的小鼠巨细胞病毒（MCMV）感染后免疫反应的演变。我们的目标是确定通过这种自然途径感染的新生小鼠中CD8+和CD4+ T细胞对MCMV反应的发育进展。潜伏HCMV母亲的婴儿值得关注，因为病毒的再激活可在哺乳期特异性地发生在乳腺内。这可能是潜伏感染的单核细胞从血液中募集，随后在乳腺分支形态发生过程中分化为巨噬细胞的结果。由于母乳中富含单核/巨噬细胞和hcmv特异性抗体，这些母体抗体可能通过胃肠道影响产后感染。具体来说，母源抗体：MCMV复合物可以帮助病毒利用FcRn途径运输和/或增强病毒的免疫原性。因此，我们假设来自潜伏MCMV母亲的母源抗体转移到哺乳幼崽中会增加病毒特异性CD8+和CD4+ T细胞的产生或它们在幼崽中免疫控制MCMV所必需的效应功能。我们的目标是跟踪潜伏母亲在哺乳期之前和期间的病毒再激活状态。我们还将确定潜伏感染母鼠的幼崽中mcmv特异性CD8+和CD4+ T细胞反应的动力学和效应功能，并将其与病毒清除联系起来。最后，我们将确定FcRn对感染性病毒在胃肠道中的传递的影响。为此，我们的目标是：确定母乳介导的MCMV传播如何影响子代和AIM 2抗病毒免疫的发展。确定导致母乳喂养期间新生儿获得MCMV的因素及其对免疫结果的影响。公共卫生相关性：该项目与公共卫生的相关性是基于需要一种巨细胞病毒疫苗来保护婴儿、儿童和免疫功能受损的个体（a M Arvin等[2004]，“预防巨细胞病毒病的疫苗开发：国家疫苗咨询委员会的报告”，《疫苗》39:233）。易感个体在疫苗接种方面面临重大挑战，因为他们产生长期保护性免疫的能力较弱。我们的探索性项目旨在建立一种动物模型来了解通过母乳感染巨细胞病毒的新生儿的免疫反应性；我们的最终目标是利用这个模型来确定一般策略，以增强免疫受损个体的免疫介导保护。

DESCRIPTION (provided by applicant): Immune responses to infections in early life are not well understood; however, they can result in profound changes in development and function of organs impacting health. For example, human cytomegalovirus (HCMV) infection in utero (congenital) can result in growth retardation, microcephaly, sensorineural hearing loss, and even death. HCMV infection also occurs postnatally in newborns via viral transmission in breast milk. As most of these infants are asymptomatic, it has been proposed that this route of infection could represent a type of natural immunization. The effectiveness of exposure to the virus through breastfeeding in the ability of the neonate to develop effective immune control of viral dissemination and shedding is not well characterized. This exploratory study is designed to define the evolution of the immune response following murine CMV (MCMV) infection acquired by maternal transmission during breastfeeding. Our goals are to determine the developmental progression of the CD8+ and CD4+ T cell response to MCMV in neonatal mice following infection acquired via this natural route. There is concern for infants of mothers with latent HCMV, as reactivation of the virus can occur specifically within the mammary gland during lactation. This could be the consequence of latently infected monocyte recruitment from the blood followed by differentiation to macrophages in the breast during branching morphogenesis in the mammary gland. As breast milk is enriched with monocytes/macrophages and HCMV-specific antibodies, it is possible that these maternal antibodies can influence postnatal infection through the gastrointestinal tract. Specifically, maternal antibody:MCMV complexes could either aid in virus transport utilizing the FcRn pathway and/or enhance viral immunogenicity. Therefore, we hypothesize that maternal antibodies from latent MCMV moms transferred to nursing pups will augment the generation of virus specific CD8+ and CD4+ T cells or their effector functions necessary for immune control of MCMV in the pups. Our goals are to track the state of viral reactivation in Latent Moms prior to and during lactation. We will also determine the kinetics and effector function of MCMV-specific CD8+ and CD4+ T cell responses in pups from mothers with latent infection and correlate this with viral clearance. Finally, we will determine the impact of FcRn in delivery of infectious virus in the gastrointestinal tract. To this end, our aims are: AIM 1. Define how breast milk-mediated transmission of MCMV impacts the development of antiviral immunity in offspring and AIM 2. Identify factors contributing to neonatal acquisition of MCMV during breastfeeding and their impact on immunological outcomes. PUBLIC HEALTH RELEVANCE: The relevance of this project to public health is based on the need for a CMV vaccine to protect infants, children and immune compromised individuals (A M Arvin et. al [2004], "Vaccine development to prevent cytomegalovirus disease: report from the national vaccine advisory committee", Vaccines 39:233). Susceptible individuals share significant challenges for vaccination, as they are less competent to generate long-term protective immunity. Our exploratory project aims to develop an animal model to understand immune responsiveness in neonates acquiring CMV infection via breast milk; our ultimate goal being to exploit this model to identify general strategies to enhance immune-mediated protection in immune compromised individuals.