Congenital CMV and CNS Infection Mechanisms of Protective Immunity

先天性巨细胞病毒和中枢神经系统感染的保护性免疫机制

基本信息

批准号：
8263366
负责人：
William Jarvis Britt
金额：
$ 55.84万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-13 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8263366
关键词：
Animal Model Animals Antibodies Antibody Formation Antibody-mediated protection Antiviral Agents Attenuated Biologic Characteristic Biological Biological Models Birth Brain Brain Diseases Case Study Cells Central Nervous System Diseases Central Nervous System Infections Characteristics Cytomegalovirus Cytomegalovirus Infections Defective Viruses Development Disease Dose Empiricism Encephalitis Endothelium Engineering Evaluation Exhibits Fetus Frequencies Future Goals Hepatic Human Immune response Immunity Immunocompromised Host Infant Infection Infection prevention Inflammation Investigation Lead Live Birth Mediating Modeling Morbidity - disease rate Murid herpesvirus 1 Mus Natural History Neonatal Nervous System Trauma Neuraxis Neuroglia Neurologic Neurons Newborn Animals Newborn Infant Passive Immunity Pathogenesis Prevention Role Safety Secondary to Sensorineural Hearing Loss Specimen Symptoms Therapeutic Time Tissues Translating Translations Vaccines Viral Viral Antibodies Viral Vaccines Viremia Virus Virus Diseases Virus Replication acquired immunity cell type congenital cytomegalovirus design hearing impairment human disease in utero in vitro Model in vivo mouse model neurovirulence peripheral blood prevent prophylactic public health relevance research study vaccine development

项目摘要

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. PUBLIC HEALTH RELEVANCE: Using a mouse model of congenital human cytomegalovirus (HCMV), we will carry out studies to define HCMV infection of the brain of the developing fetus. These studies will serve as an important starting point for our experiments to identify biological molecules such as antibody and/or viral vaccines attenuated in their capacity to infect the brain or cause brain disease that can limit infection and disease associated with HCMV infection. These studies will serve as a platform for the rationale design of effective and safe therapies for use in humans.

描述（由申请人提供）：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。尽管大多数在子宫内感染的婴儿不会出现长期症状，但大约 10% 的婴儿可能会出现长期后遗症。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，并且已被提议作为预防性疫苗的目标。先天性感染的人类婴儿中枢神经系统疾病的发病机制仍不清楚，迄今为止，HCMV 感染中枢神经系统动物模型的研究提供的信息很少，因为这些模型固有的显着局限性。我们最近开发了一种用相关的小鼠 CMV 感染正在发育的中枢神经系统的小鼠模型，该模型概括了人类疾病的许多关键特征，包括某些动物中进行性的听力损失。我们建议使用该模型来定义限制中枢神经系统感染和疾病的保护性抗体的机制。此外，我们将探索使用工程病毒，其引起中枢神经系统疾病的能力减弱，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剂的策略，例如抗体和减毒复制病毒，这些生物制剂可以提供免疫介导的保护，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，这些策略可以迅速转化为人类使用的类似生物制剂的开发。公共卫生相关性：我们将使用先天性人类巨细胞病毒 (HCMV) 小鼠模型进行研究，以确定发育中胎儿大脑的 HCMV 感染。这些研究将作为我们实验的重要起点，以鉴定生物分子，例如抗体和/或病毒疫苗，其感染大脑或引起脑部疾病的能力减弱，从而限制感染和与 HCMV 感染相关的疾病。这些研究将作为用于人类的有效且安全的疗法的基本原理设计的平台。