Congenital CMV and CNS Infection Mechanisms of Protective Immunity

描述(申请人提供)：先天性人类巨细胞病毒(HCMV)是发育中胎儿最常见的病毒感染。虽然大多数宫内感染的婴儿不会出现长期症状，但大约10%的婴儿可能会有长期的后遗症。中枢神经系统(CNS)损伤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目标，并已被提出为预防性疫苗的目标。人类先天性感染的婴儿中枢神经系统疾病的发病机制尚不明确，到目前为止，对巨细胞病毒感染中枢神经系统的动物模型的研究提供的信息很少，这些模型具有明显的局限性。我们最近用相关的小鼠巨细胞病毒建立了发育中的中枢神经系统感染的小鼠模型，该模型概括了人类疾病的许多关键特征，包括在一些动物中进行的听力损失。利用这一模型，我们建议定义保护性抗体的机制，以限制中枢神经系统感染和疾病。此外，我们将探索使用工程病毒，这些病毒的能力已减弱，可导致中枢神经系统疾病并建立持续感染，以诱导保护性抗体反应。我们预计，这些研究将确定开发靶向生物制品的策略，如抗体和减毒复制病毒，这些生物制品可以提供免疫中介保护，防止先天性HCMV感染后的中枢神经系统感染和损害。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生物制剂供人类使用。

DESCRIPTION (provided by applicant): 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 progressive in some animals. 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 replicating 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.