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：
8450754
负责人：
William Jarvis Britt
金额：
$ 52.21万
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/8450754
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.

描述（由申请人提供）：先天性人类巨细胞病毒（HCMV）代表了发育中的胎儿获得的最常见的病毒感染。尽管大多数感染UTERO的婴儿不会遭受长期症状，但大约10％的婴儿可能具有长期后遗症。中枢神经系统（CNS）损伤是这些长期后遗症的奇异原因。预防中枢神经系统感染和疾病是当前抗病毒治疗的靶标，已被提出是预防性疫苗的目标。先天感染的人类婴儿中CNS疾病的发病机理仍然不确定，迄今为止，HCMV感染中枢神经系统感染的动物模型的研究几乎没有提供有关这些模型固有的显着局限性的信息。我们最近开发了一种与相关的鼠CMV的发育中心感染的鼠模型，该模型概括了人类疾病的许多关键特征，包括某些动物的听力损失。使用此模型，我们建议定义限制CNS感染和疾病的保护性抗体的机制。此外，我们将探索以引起中枢神经系统疾病的能力减弱的工程病毒的使用，并建立持续的感染以诱导保护性抗体反应。我们预计这些研究将确定针对有针对性生物制剂的开发策略，例如抗体和减弱复制病毒，这些病毒可提供免疫学介导的CNS感染的保护和可能遵循先天性HCMV感染的损害。由于MCMV和HCMV之间的相关性，这些策略可以迅速过渡到类似的人类生物制剂的发展。