Mechanisms Limiting Neonatal Immunity

项目摘要/摘要 巨细胞病毒(CMV)是最常见的先天性感染，也是导致出生缺陷的主要原因。 美国的儿童。虽然人们普遍认识到对先天性巨细胞病毒疫苗的迫切需求， 造成免疫力低下和维持不充分的根本机制仍然存在 不明确，从而影响我们创造有效的预防和治疗方法的能力。的目标是 这项建议是利用先天性巨细胞病毒的小鼠模型来确定 在生命早期未能控制CMV。由于CMV的免疫控制在很大程度上依赖于CD8 T细胞，我们 我们的研究重点是了解为什么早期的CD8T细胞无法控制先天性CMV感染。 根据我们已发表的研究和新的初步数据，我们假设新生儿CD8 T细胞具有 在感染CMV期间，固有的功能耗尽倾向，导致病毒长时间脱落 以及CD8 T细胞室发育的改变。在第一个目标中，我们将确定为什么新生儿 CD8 T细胞在感染急性期未能控制CMV并试图恢复免疫功能 通过阻断抑制性受体。在第二个目标中，我们将研究为什么感染后产生的CD8 T细胞失败 在感染潜伏期控制正在进行的病毒复制，并试图通过以下方式限制病毒的传播 IL-7治疗可增加幼稚T细胞的数量。从这些研究中获得的知识有望为 为开发针对先天性巨细胞病毒病的重要预防和治疗策略提供了途径。

Project Summary / Abstract Cytomegalovirus (CMV) is the most common congenital infection and the leading cause of birth defects in children in the United States. While the urgent need for a vaccine against congenital CMV is widely recognized, the underlying mechanisms responsible for the poor generation and inadequate maintenance of immunity remain undefined, thus compromising our ability to create effective methods for prevention and treatment. The goal of this proposal is to use a murine model of congenital CMV to identify both the mechanisms and consequences of failing to control CMV in early life. Since immune control of CMV is largely dependent upon CD8+ T cells, we have focused our studies on understanding why CD8+ T cells in early life fail to control congenital CMV infection. Based on our published studies and new preliminary data, we hypothesize that neonatal CD8+ T cells have an inherent propensity to become functionally exhausted during CMV infection, leading to prolonged viral shedding and the altered development of the CD8+ T cell compartment. In the first aim, we will determine why neonatal CD8+ T cells fail to control CMV during the acute stage of infection and attempt to revive immune functionality by blocking inhibitory receptors. In the second aim, we will examine why CD8+ T cells made after infection fail to control ongoing viral replication during the latent stage of infection and attempt to limit viral shedding by increasing numbers of naïve T cells with IL-7 therapy. Knowledge from these studies is expected to pave the way for the development of vital preventative and therapeutic strategies against congenital CMV disease.