Evolution of the Immune Response to Cytomegalovirus Transmitted via Breast Milk

对通过母乳传播的巨细胞病毒的免疫反应的演变

• 批准号: 7843546
• 负责人: Lynn Puddington
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7843546
• 关键词: Acute; Advisory Committees; Age; Animal Model; Antibodies; Antigen-Antibody Complex; Antigens; Antiviral Agents; Applications Grants; Arvin; Blood; Breast; Breast Feeding; CD4 Positive T Lymphocytes; CD8B1 gene; Cessation of life; Child; Complex; Conceptions; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Data; Development; Discipline of Nursing; Disease; Effectiveness; Epidemiology; Epithelial Cells; Evolution; Exposure to; Future; Gastrointestinal tract structure; Generations; Goals; Growth; Health; Human; Human Milk; Immune; Immune response; Immunity; Immunization; Individual; Infant; Infection; Interruption; Intestinal Absorption; Intestines; Kinetics; Lactation; Latent Virus; Leukocytes; Life; Longevity; Mammary gland; Maternal antibody; Mediating; Memory; Microcephaly; Milk; Modeling; Morphogenesis; Mothers; Murid herpesvirus 1; Mus; Myeloid Cells; Neonatal; Newborn Infant; Nurses; Organ; Outcome; Pathway interactions; Placenta; Pregnant Women; Process; Public Health; Reporting; Risk; Route; Sensorineural Hearing Loss; T cell response; Testing; Vaccination; Vaccines; Very Low Birth Weight Infant; Viral; Virus; Woman; base; congenital infection; design; immunogenicity; in utero; latent infection; macrophage; monocyte; neonatal Fc receptor; neonate; offspring; oral infection; postnatal; postnatal human; prevent; public health relevance; pup; transmission process; vaccine development

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.

描述(由申请人提供)：对早期感染的免疫反应还不是很清楚，但它们可能导致影响健康的器官发育和功能的深刻变化。例如，人巨细胞病毒(HCMV)在子宫内(先天性)感染可导致生长迟缓、小头畸形、感音神经性听力损失，甚至死亡。巨细胞病毒感染也在新生儿出生后通过母乳病毒传播发生。由于这些婴儿大多没有症状，有人建议这种感染途径可能代表一种自然免疫。通过母乳喂养暴露于病毒对新生儿形成有效的病毒传播和脱落的免疫控制的能力的有效性尚未得到很好的表征。这项探索性研究旨在确定通过母乳传播获得的小鼠巨细胞病毒(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MCMV的新生小鼠CD8+和CD4+T细胞对MCMV的反应的发育进程。对于患有潜伏性巨细胞病毒的母亲的婴儿令人担忧，因为病毒的重新激活可能在哺乳期特定地发生在乳腺内。这可能是由于潜伏感染的单核细胞从血液中重新招募，然后在乳腺的分枝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/巨噬细胞和巨细胞病毒特异性抗体，这些母体抗体可能会通过胃肠道影响出生后的感染。具体地说，母源抗体：MCMV复合体可以通过FcRN途径帮助病毒传播和/或增强病毒的免疫原性。因此，我们推测，将潜伏的MCMV母鼠的母体抗体转移到哺乳仔鼠体内，将增加病毒特异性CD8+和CD4+T细胞的产生，或它们对MCMV免疫控制所需的效应功能。我们的目标是跟踪哺乳前和哺乳期间潜伏的母亲中病毒重新激活的状态。我们还将确定MCMV特异性CD8+和CD4+T细胞反应的动力学和效应功能，并将其与病毒清除相关联。最后，我们将确定FcRN在胃肠道传播传染性病毒方面的影响。为此，我们的目标是：目的1.明确母乳介导的MCMV传播如何影响后代的抗病毒免疫发育；2.确定导致新生儿在母乳喂养期间感染MCMV的因素及其对免疫学结果的影响。公共卫生相关性：该项目与公共卫生的相关性是基于对CMV疫苗的需求，以保护婴儿、儿童和免疫受损的个人(A M Arvin et。Al[2004]，“预防巨细胞病毒疾病的疫苗开发：国家疫苗咨询委员会的报告”，疫苗39：233)。易感人群在接种疫苗方面面临重大挑战，因为他们不具备产生长期保护性免疫的能力。我们的探索性项目旨在开发一种动物模型，以了解通过母乳感染CMV的新生儿的免疫反应性；我们的最终目标是利用该模型来确定增强免疫受损个体免疫中介保护的一般策略。