Mechanisms Limiting Neonatal Immunity

项目概要/摘要 巨细胞病毒（CMV）是最常见的先天性感染和出生缺陷的主要原因， 在美国的孩子们。虽然人们普遍认为迫切需要一种针对先天性CMV的疫苗， 导致免疫力低下和维持不足的潜在机制仍然存在， 因此，我们创造有效的预防和治疗方法的能力受到损害。的目标 该建议是使用先天性CMV的小鼠模型来鉴定以下两种机制和后果： 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CD 8 + T细胞，我们 我们的研究重点是了解为什么早期的CD 8 + T细胞不能控制先天性CMV感染。 基于我们已发表的研究和新的初步数据，我们假设新生儿CD 8 + T细胞具有免疫调节作用。 在CMV感染过程中，固有的功能衰竭倾向，导致病毒脱落时间延长 以及CD 8 + T细胞区室的发育改变。在第一个目标中，我们将确定为什么新生儿 CD 8 + T细胞在感染的急性阶段无法控制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CD 8 + T细胞失败 在感染的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脱落 用IL-7疗法增加幼稚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CMV疾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.