Establishing the impact of roseolovirues on development of autoimmunity due to loss of central tolerance

确定玫瑰病毒由于中枢耐受性丧失而对自身免疫发展的影响

• 批准号: 10591246
• 负责人: Tarin M Bigley
• 金额: $ 19.86万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591246
• 关键词: Address; Adult; Age; Antigens; Atrophic; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Award; Biological Assay; Bystander Effect; CD4 Positive T Lymphocytes; Cell Count; Cell Culture Techniques; Cell physiology; Childhood; Chronic; Clinical; Comparative Study; Data; Development; Etiology; Exanthema; Exanthema Subitum; Fever; Flow Cytometry; Funding; Future; Gastric Parietal Cells; Gene Expression; Genes; Goals; Herpesviridae; High Prevalence; Human; Human Characteristics; Human Herpesvirus 6; Human Herpesvirus 7; Immune Tolerance; Immune system; Immunology; In Vitro; Infection; Inflammation; K ATPase; K-Series Research Career Programs; Kinetics; Knowledge; Laboratories; Life; Link; Mediating; Mentors; Modeling; Molecular Mimicry; Mouse Strains; Mus; Nature; Neonatal; Organ; Periodicals; Peripheral; Persons; Physicians; Process; Production; Proteins; Regulatory T-Lymphocyte; Research; Research Project Grants; Resolution; Rheumatology; Role; Roseolovirus; Roseolovirus Infections; Scientist; Seroprevalences; Sorting; Stomach; T cell receptor repertoire sequencing; T-Cell Depletion; T-Cell Development; T-Lymphocyte; T-cell receptor repertoire; Thymic epithelial cell; Thymus Gland; Time; Tissues; Viral; Virus; Virus Diseases; Virus Replication; Wild Type Mouse; acute infection; autoimmune gastritis; autoreactive T cell; autoreactivity; career; career development; central tolerance; experimental study; in vivo; insight; latent infection; neonatal infection; novel; pathogen; single-cell RNA sequencing; thymocyte; time use; transcriptome; transcriptome sequencing; transcriptomics

Project Summary Murine roseolovirus (MRV) is a beta-herpesvirus that is genetically highly related to the human roseoloviruses, HHV-6 and HHV-7. The human roseoloviruses have been associated with autoimmune disease but demonstrating causality is confounded by the ubiquitous and chronic nature of roseolovirus infections. We have shown that neonatal MRV infection results in transient thymic and peripheral CD4+T cell depletion. Interestingly, we found that neonatal MRV infection leads to development of autoimmune gastritis (AIG) in adult mice, in the absence of active MRV replication. In our preliminary studies, we demonstrated that neonatal MRV infection resulted in a transient decrease in medullary thymic epithelial cells (mTECs) as well as reduced expression of AIRE and tissue restricted self-antigens in the thymus. Moreover, MRV appears to directly infect mTECs, suggesting a potential mechanism for MRV-induced autoimmunity. Indeed, neonatal MRV infection results in development of autoreactive CD4+ T cells that are necessary and sufficient for MRV-induced AIG. Our preliminary data suggest that roseoloviruses can induce autoimmunity by disrupting central tolerance. The broad goal of this proposal is to define the mechanism by which roseoloviruses induces autoimmune disease through its impact on central tolerance. We intend to meet this goal by, first defining the impact of human and murine roseolovirus on mTECs. This will be done by delineating mTEC transcriptomic changes that occur after MRV infection in vivo and by MRV and human roseolovirus infection in vitro. Second, we will establish the impact of MRV on TCR repertoire and neonatal CD4+ T cells. We will evaluate the impact of MRV on TCR repertoire over time by using TCR sequencing, while neonatal CD4+ T cell studies will utilize lineage tracing as well as in vivo and in vitro functional assays. My overall career goal is to understand the interaction between viruses and the immune system, especially in regard to autoimmunity. This five-year K08 Mentored Clinical Scientist Research Career Development Award will allow me to begin my transition of the proposed research project toward one that will be pursued independently. The overall scope of this research is broad, with multiple future directions that can be pursued during my career. By carrying out the Aims of this proposal as well as the career development goals, I will be able to establish myself as an independent physician-scientist and make significant contributions to the fields of viral immunology and autoimmunity.

项目概要 鼠玫瑰疹病毒 (MRV) 是一种 β-疱疹病毒，与人类玫瑰疹病毒在遗传上高度相关， HHV-6 和 HHV-7。人类玫瑰病毒与自身免疫性疾病有关，但 玫瑰病毒感染的普遍性和慢性性混淆了因果关系的证明。我们有 研究表明，新生儿 MRV 感染会导致短暂的胸腺和外周 CD4+T 细胞耗竭。有趣的是， 我们发现，新生小鼠 MRV 感染会导致成年小鼠患上自身免疫性胃炎 (AIG)。 缺乏活跃的 MRV 复制。在我们的初步研究中，我们证明新生儿 MRV 感染 导致胸腺髓质上皮细胞 (mTEC) 短暂减少以及表达减少 胸腺中的 AIRE 和组织限制性自身抗原。此外，MRV 似乎直接感染 mTEC， 提示 MRV 诱导自身免疫的潜在机制。事实上，新生儿 MRV 感染会导致 自身反应性 CD4+ T 细胞的发育对于 MRV 诱导的 AIG 是必要且充分的。我们的 初步数据表明，玫瑰病毒可以通过破坏中枢耐受性来诱导自身免疫。 该提案的总体目标是确定玫瑰病毒诱导自身免疫的机制 疾病通过其对中枢耐受性的影响。我们打算通过首先定义人类的影响来实现这一目标 和 mTEC 上的鼠玫瑰病毒。这将通过描绘发生的 mTEC 转录组变化来完成 体内MRV感染后以及体外MRV和人玫瑰病毒感染后。其次，我们将建立 MRV 对 TCR 库和新生儿 CD4+ T 细胞的影响。我们将评估MRV对TCR的影响 随着时间的推移，通过使用 TCR 测序来研究所有库，而新生儿 CD4+ T 细胞研究将利用谱系追踪作为 以及体内和体外功能测定。 我的总体职业目标是了解病毒和免疫系统之间的相互作用， 尤其是在自身免疫方面。为期五年的 K08 指导临床科学家研究生涯 发展奖将使我能够开始将拟议的研究项目转变为能够 独立追求。这项研究的总体范围很广泛，有多个未来方向可以 在我的职业生涯中受到追求。通过实现本提案的目的以及职业发展目标， 我将能够使自己成为一名独立的医师科学家，并为医学界做出重大贡献 病毒免疫学和自身免疫学领域。