Mechanisms Limiting Neonatal Immunity

限制新生儿免疫力的机制

基本信息

批准号：
10408128
负责人：
Brian David Rudd
金额：
$ 43.79万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408128
关键词：
Acute Address Adult Age Award Bacteria Brain CD8-Positive T-Lymphocytes Cell Compartmentation Cell physiology Cells Child Chronic Chronic Phase Congenital Abnormality Cytomegalovirus Cytomegalovirus Infections Data Development Disease Experimental Models Failure Generations Gestational Age Goals Grant Hematopoietic stem cells IL7 gene Immune Immune response Immunity Infant Infection Knowledge Life Maintenance Memory Mental Retardation Methods Molecular Morbidity - disease rate Mus Mycobacterium tuberculosis Neonatal Neurological outcome Play Positioning Attribute Prevention Production Proliferating Publishing Research Role Severity of illness Simplexvirus T-Lymphocyte Testing Therapeutic Time Toxoplasma gondii United States Vaccines Viral Virus Virus Diseases Virus Replication Virus Shedding Work acute infection age related base cell behavior chronic infection congenital cytomegalovirus congenital infection disability exhaust hearing impairment immune function improved in utero insight mortality mouse model neonatal immunity neonate novel strategies pathogen receptor response stem stem cell population transmission process treatment strategy

项目摘要

Project Summary / Abstract Cytomegalovirus (CMV) is the most common congenital infection and the leading cause of birth defects in children in the United States. While the urgent need for a vaccine against congenital CMV is widely recognized, the underlying mechanisms responsible for the poor generation and inadequate maintenance of immunity remain undefined, thus compromising our ability to create effective methods for prevention and treatment. The goal of this proposal is to use a murine model of congenital CMV to identify both the mechanisms and consequences of failing to control CMV in early life. Since immune control of CMV is largely dependent upon CD8+ T cells, we have focused our studies on understanding why CD8+ T cells in early life fail to control congenital CMV infection. Based on our published studies and new preliminary data, we hypothesize that neonatal CD8+ T cells have an inherent propensity to become functionally exhausted during CMV infection, leading to prolonged viral shedding and the altered development of the CD8+ T cell compartment. In the first aim, we will determine why neonatal CD8+ T cells fail to control CMV during the acute stage of infection and attempt to revive immune functionality by blocking inhibitory receptors. In the second aim, we will examine why CD8+ T cells made after infection fail to control ongoing viral replication during the latent stage of infection and attempt to limit viral shedding by increasing numbers of naïve T cells with IL-7 therapy. Knowledge from these studies is expected to pave the way for the development of vital preventative and therapeutic strategies against congenital CMV disease.

项目摘要 /摘要巨细胞病毒（CMV）是最常见的先天性感染，也是出生缺陷的主要原因美国的孩子。虽然迫切需要针对先天性CMV进行疫苗，但已得到广泛认可，但导致发电不良和免疫维持不足的基本机制仍然存在因此，未定义，因此损害了我们创造有效方法预防和治疗方法的能力。目标该建议是使用先天性CMV的鼠模型来确定无法控制早期CMV。由于CMV的免疫控制在很大程度上取决于CD8+ T细胞，因此我们的研究集中在理解为什么早期生命中的CD8+ T细胞无法控制先天性CMV感染。根据我们发表的研究和新的初步数据，我们假设新生儿CD8+ T细胞具有 CMV感染期间功能耗尽的固有倾向，导致病毒延长以及CD8+ T细胞室的开发改变。在第一个目标中，我们将确定为什么新生儿 CD8+ T细胞在感染的急性阶段无法控制CMV，并尝试恢复免疫功能通过阻止抑制接收器。在第二个目标中，我们将研究为什么感染后CD8+ T细胞失败控制在感染潜在阶段正在进行的病毒复制，并试图限制通过通过IL-7治疗，幼稚的T细胞数量增加。这些研究的知识预计将铺平开发针对先天性CMV疾病的重要预防和治疗策略的方法。