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

基本信息

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
项目类别：
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

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

展开

项目摘要

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.

项目摘要鼠玫瑰洛氏病毒（MRV）是一种β-疱疹病毒，在遗传上与人类玫瑰洛未病毒高度相关， HHV-6和HHV-7。人玫瑰洛未病毒与自身免疫性疾病有关玫瑰细胞病毒感染的无处不在和慢性性质使证明因果关系混淆。我们有表明新生儿MRV感染会导致瞬时胸腺和周围CD4+T细胞耗竭。有趣的是，我们发现，新生儿MRV感染导致成年小鼠中自身免疫性胃炎（AIG）的发展没有主动MRV复制。在我们的初步研究中，我们证明了新生儿MRV感染导致髓质胸腺上皮细胞（MTEC）的短暂降低以及表达降低 Aire和组织限制了胸腺中的自我抗原。此外，MRV似乎直接感染MTEC，提出了MRV引起的自身免疫的潜在机制。实际上，新生儿MRV感染导致自动反应性CD4+ T细胞的开发对于MRV诱导的AIG来说是足够的。我们的初步数据表明，玫瑰果病毒可以通过破坏中心容忍度诱导自身免疫性。该提案的广泛目标是定义玫瑰果病毒诱导自身免疫的机制疾病通过其对中央耐受性的影响。我们打算通过首先定义人的影响来实现这一目标和MTEC上的鼠玫瑰洛氏病毒。这将通过描述发生的MTEC转录组变化来完成 MRV感染在体内以及MRV和人类玫瑰洛氏病毒感染后体外。第二，我们将建立 MRV对TCR曲目和新生儿CD4+ T细胞的影响。我们将评估MRV对TCR的影响随着时间的流逝，曲目通过使用TCR测序，而新生儿CD4+ T细胞研究将使用谱系跟踪作为以及体内和体外功能分析。我的整体职业目标是了解病毒与免疫系统之间的相互作用，特别是自身免疫。这个五年的K08指导了临床科学家研究职业开发奖将使我能够开始对拟议的研究项目的过渡，该项目将独立追求。这项研究的总体范围很广，有多个未来的方向可以在我的职业生涯中被追捕。通过实现该提议的目标以及职业发展目标，我将能够确立自己为独立医师科学家，并为病毒免疫学和自身免疫的领域。