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.

项目摘要 鼠玫瑰花状病毒（MRV）是一种β-疱疹病毒，其在遗传上与人玫瑰花状病毒高度相关， HHV-6和HHV-7。人类玫瑰病毒与自身免疫性疾病有关， 证明因果关系被玫瑰花状病毒感染的普遍存在和慢性性质所混淆。我们有 显示新生儿MRV感染导致短暂的胸腺和外周CD 4 +T细胞耗竭。有趣的是， 我们发现新生鼠MRV感染可导致成年鼠发生自身免疫性胃炎（AIG）， 没有活跃的MRV复制。在我们的初步研究中，我们证明了新生儿MRV感染 导致胸腺髓质上皮细胞（mTECs）短暂减少， AIRE和组织限制性自身抗原在胸腺中的表达。此外，MRV似乎直接感染mTEC， 提示MRV诱导的自身免疫的潜在机制。事实上，新生儿MRV感染导致 自身反应性CD 4 + T细胞的发展是MRV诱导的AIG所必需和充分的。我们 初步数据表明，玫瑰病毒可通过破坏中枢耐受性诱导自身免疫。 这项提议的主要目标是确定玫瑰病毒诱导自身免疫的机制。 通过对中枢耐受性的影响来控制疾病。我们打算通过以下方式实现这一目标：首先确定人类活动的影响， 和鼠玫瑰花状病毒。这将通过描述发生的mTEC转录组学变化来完成， 在体内MRV感染后以及在体外MRV和人玫瑰花状病毒感染后。第二，我们会设立 MRV对TCR库和新生儿CD 4 + T细胞影响。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，而新生儿CD 4 + T细胞研究将利用谱系追踪， 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， 特别是在自身免疫方面。这个为期五年的K 08指导临床科学家研究生涯 发展奖将使我开始我的过渡，提出的研究项目， 独立追求。这项研究的总体范围是广泛的，有多个未来的方向，可以 在我的职业生涯中，通过实现本提案的宗旨以及职业发展目标， 我将能够建立自己作为一个独立的物理学家，科学家，并作出重大贡献， 病毒免疫学和自身免疫学领域。