Congenital CMV and CNS Infection Mechanisms of Protective Immunity

项目总结/摘要 先天性人巨细胞病毒（HCMV）是最常见的病毒感染 由发育中的胎儿获得。虽然大多数在子宫内感染的婴儿不会遭受 长期症状，约10%可有长期后遗症。中枢神经 中枢神经系统（CNS）损伤是这些长期后遗症的唯一原因。预防 CNS感染和疾病是目前抗病毒治疗的目标， 作为预防性疫苗的目标。中枢神经系统疾病的发病机制 先天性感染的人类婴儿仍然不确定，迄今为止在动物中的研究 HCMV的CNS感染模型提供的继发于 这些模型中固有的重大局限性。我们最近培育了一种 发育中CNS感染相关鼠CMV的模型， 人类疾病的许多关键特征，包括听力损失， 先天性CMV感染的婴儿。使用这个模型，我们建议定义 限制CNS感染和疾病的保护性抗体机制。另外我们 将探索使用基因工程病毒， CNS疾病和建立持续感染以诱导保护性抗体应答。 我们预计，这些研究将确定发展有针对性的战略， 生物制剂，如抗体和减毒病毒，可以提供免疫 介导的保护免受先天性HCMV引起的CNS感染和损伤 感染由于MCMV和HCMV之间的相关性，这些策略可以 迅速过渡到开发类似的人类生物制剂。

Project Summary/Abstract Congenital human cytomegalovirus (HCMV) represents the most common viral infection acquired by the developing fetus. Although most infants infected in-utero do not suffer long term symptoms, approximately 10% can have long term sequelae. Central nervous system (CNS) damage is the singular cause of these long term sequelae. Prevention of CNS infection and disease is the target of current antiviral treatment and has been proposed as a goal of prophylactic vaccines. The pathogenesis of CNS disease in congenitally infected human infants remains undefined and to date studies in animal models of CNS infection by HCMV have provided little information secondary to significant limitations inherent in these models. We have recently developed a murine model of infection of the developing CNS with the related murine CMV that recapitulates many key characteristics of the human disease, including hearing loss that is common in infants with congenital CMV infections. Using this model we propose to define mechanisms of protective antibodies that limit CNS infection and disease. In addition, we will explore the use of engineered viruses that are attenuated in their capacity to cause CNS disease and establish persistent infection to induce protective antibody responses. We anticipate that these studies will identify strategies for development of targeted biologics such as antibodies and attenuated viruses that can provide immunologically mediated protection from CNS infection and damage that can follow congenital HCMV infection. Because of the relatedness between MCMV and HCMV, these strategies could be rapidly transitioned into development of similar biologics for human use.