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

项目摘要 小鼠玫瑰状病毒(MRV)是一种与人类玫瑰状病毒高度相关的β疱疹病毒， HHV-6和HHV-7。人类玫瑰病毒与自身免疫性疾病有关，但 玫瑰花环病毒感染的普遍和慢性性质混淆了因果关系的证明。我们有 研究表明，新生儿MRV感染会导致胸腺和外周CD4+T细胞一过性耗尽。有趣的是， 我们发现新生MRV感染会导致成年小鼠自身免疫性胃炎(AIG)的发展，在 没有活动的MRV复制。在我们的初步研究中，我们证明了新生儿MRV感染 导致髓质胸腺上皮细胞(MTECs)一过性减少以及表达减少 AIRE和组织限制了胸腺中的自身抗原。此外，MRV似乎直接感染mTEC， 提示了MRV诱导自身免疫的潜在机制。事实上，新生儿MRV感染会导致 发展自身反应性的CD4+T细胞，这对于MRV诱导的AIG是必要的和充分的。我们的 初步数据表明，玫瑰花样病毒可以通过破坏中枢耐受性来诱导自身免疫。 这项提议的主要目标是确定玫瑰花叶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而发生。我们打算通过以下方式实现这一目标：首先定义人类的影响 和mTECs上的小鼠玫瑰病毒。这将通过描述发生的mTEC转录变化来实现 体内感染MRV后，体外感染MRV和人玫瑰花环病毒。第二，我们将建立 MRV对TCR谱系和新生儿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，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。 我的整个职业目标是了解病毒和免疫系统之间的相互作用， 尤其是在自身免疫力方面。这五年的K08指导临床科学家的研究生涯 发展奖将允许我开始将拟议的研究项目过渡到将 被独立追查。这项研究的总体范围是广泛的，具有多个未来方向，可以 在我的职业生涯中被追逐。通过实现本提案的目标以及职业发展目标， 我将能够确立自己作为一名独立内科科学家的地位，并为 病毒免疫学和自身免疫学领域。

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.