Congenital CMV and CNS Infection Mechanisms of Protective Immunity

项目摘要/摘要 先天性人类巨细胞病毒(HCMV)是最常见的病毒感染 由发育中的胎儿获得。尽管大多数在宫内感染的婴儿不会受到 长期症状，约10%可有长期后遗症。中枢神经 系统(CNS)损害是这些长期后遗症的唯一原因。预防 中枢神经系统感染和疾病是当前抗病毒治疗的靶点，一直以来 提出作为预防性疫苗的一个目标。中枢神经系统疾病的发病机制 先天性感染的人类婴儿仍未确定，到目前为止在动物身上进行的研究 人巨细胞病毒感染中枢神经系统的模型提供的继发性信息很少 这些模型固有的显著局限性。我们最近培育了一只小鼠 相关小鼠巨细胞病毒对发育中中枢神经系统感染模型的建立 人类疾病的许多关键特征，包括听力损失，在 先天性巨细胞病毒感染的婴儿。使用此模型，我们建议定义 保护性抗体限制中枢神经系统感染和疾病的机制。此外，我们 将探索使用经过改造的病毒，这些病毒的能力会减弱，从而导致 中枢神经系统疾病和建立持续感染以诱导保护性抗体反应。 我们预计，这些研究将确定有针对性的发展战略 生物制剂，如抗体和减毒病毒，可以提供免疫 先天性人巨细胞病毒对中枢神经系统感染和损伤的介导性保护 感染。由于巨细胞病毒和巨细胞病毒之间的相关性，这些策略可以 正在迅速过渡到开发类似的生物制品供人类使用。

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.