Mechanisms Limiting Neonatal Immunity

限制新生儿免疫力的机制

• 批准号: 10623303
• 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
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623303
• 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; Modeling; Molecular; Morbidity - disease rate; Mus; Mycobacterium tuberculosis; Neonatal; Neurological outcome; Play; Positioning Attribute; Predisposition; 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; 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

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.

项目概要/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 尽管人们普遍认识到美国儿童迫切需要一种针对先天性巨细胞病毒的疫苗， 造成免疫力低下和免疫力维持不足的根本机制仍然存在 未定义，从而损害了我们创造有效预防和治疗方法的能力。 该提案是使用先天性巨细胞病毒的小鼠模型来确定先天性巨细胞病毒的机制和后果 由于 CMV 的免疫控制很大程度上依赖于 CD8+ T 细胞，因此我们无法在生命早期控制 CMV。 我们的研究重点是了解生命早期 CD8+ T 细胞为何无法控制先天性 CMV 感染。 根据我们发表的研究和新的初步数据，我们认为新生儿 CD8+ T 细胞具有 CMV 感染期间功能衰竭的固有倾向，导致病毒脱落时间延长 以及 CD8+ T 细胞区室发育的改变 在第一个目标中，我们将确定新生儿的原因。 CD8+ T 细胞在感染急性期无法控制 CMV，并试图恢复免疫功能 通过阻断抑制性受体，我们将研究为什么感染后产生的 CD8+ T 细胞会失败。 在感染潜伏阶段控制持续的病毒复制，并尝试通过以下方式限制病毒脱落 通过 IL-7 疗法增加初始 T 细胞的数量有望为这一研究铺平道路。 开发针对先天性 CMV 疾病的重要预防和治疗策略的方法。

项目成果

Cutting Edge: CCR9 Promotes CD8+ T Cell Recruitment to the Brain during Congenital Cytomegalovirus Infection.

前沿：CCR9 在先天性巨细胞病毒感染期间促进 CD8 T 细胞招募至大脑。

• DOI: 10.4049/jimmunol.2200578
• 发表时间: 2022
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Hilt,ZacharyT;Charles,Wisler;Cheng,KatarinaE;Tabilas,Cybelle;Steinhilber,Megan;Wesnak,SamanthaP;Smith,NorahL;Schaffer,ChrisB;Rudd,BrianD
• 通讯作者: Rudd,BrianD

The Neonatal CD8+ T Cell Repertoire Rapidly Diversifies during Persistent Viral Infection.

• DOI: 10.4049/jimmunol.1501867
• 发表时间: 2016-02-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Venturi V;Nzingha K;Amos TG;Charles WC;Dekhtiarenko I;Cicin-Sain L;Davenport MP;Rudd BD
• 通讯作者: Rudd BD