Virus induced immunopathology

描述（由申请人提供）：我们在动物模型中已经证明，由于不相关病原体之间的T细胞交叉反应性而发生的异源免疫有助于增强或降低病毒载量，并显著改变针对牛痘病毒、沙粒病毒、流感病毒和巨细胞病毒的免疫病理学。这种异源免疫的例子现在已经在人类感染EB病毒（由我们），登革热和丙型肝炎病毒中报道。这项资助的总体目标是利用我们开发的小鼠模型来确定T细胞频率，功能和库如何随着宿主经历连续的急性或持续感染不同的病毒而变化，就像在人类中发生的那样。对这些问题的深入了解对于有效且无不良副作用的现代疫苗的智能设计是必要的，因为意外的T细胞交叉反应有时会导致破坏性病理。异种免疫的许多问题仍未被探索。我们对改变的交叉反应性库是如何形成的以及它如何有助于免疫病理学知之甚少。我们对异源免疫的影响知之甚少，因为T细胞受体（TCR）库在衰老的宿主或因感染、癌症或免疫抑制药物治疗而导致淋巴细胞减少的宿主中变窄。我们也缺乏洞察力，为什么不同病原体之间的异源免疫不一定是互惠的。为了阐明这些问题，我们建议检查在连续和持续病毒感染的条件下交叉反应性T细胞的TCR库和亲和力的变化，检查异源免疫的MHC基础以确认它是由TCR-MHC相互作用介导的，检查在由年龄或淋巴细胞减少引起的有限TCR库条件下的异源免疫，以确定初始旁观者T细胞的频率和功能如何受到感染的影响，并揭示病原体之间保护性异源免疫缺乏互惠性。公共卫生相关性：现代疫苗策略旨在产生强大的记忆T细胞反应以控制病毒感染，但对一种病毒特异性的记忆T细胞可能与另一种病毒交叉反应并改变其发病机制。了解这种“异源免疫”在正常和老年宿主中的含义，将增强我们对病毒发病机制的认识，并有助于设计更好的疫苗。

DESCRIPTION (provided by applicant): Heterologous immunity occurring as a consequence of T cell cross-reactivity between unrelated pathogens has been shown by us in animal models to contribute to either enhanced or reduced viral loads and remarkably altered immunopathology against vaccinia virus, arenaviruses, influenza virus, and cytomegalovirus. Examples of such heterologous immunity have now been reported in human infections with Epstein-Barr (by us), dengue and hepatitis C viruses. The overall objective of this grant is to exploit our developed mouse models to determine how T cell frequencies, functions, and repertoires change as the host undergoes successive acute or persistent infections with non-identical viruses, much like that which occurs in humans. Insights on these issues are necessary for the intelligent design of modern vaccines that are effective and without unwanted side effects, as unanticipated T cell cross-reactivity can sometimes lead to damaging pathology. Many issues of heterologous immunity are still unexplored. We know little about how the altered cross-reactive repertoire is formed and how it contributes to immunopathology. We know little about the impact of heterologous immunity as the T cell receptor (TCR) repertoire narrows in the aging host or in hosts rendered lymphopenic by infection, cancer, or immunosuppressive drug treatment. We also lack insight on why heterologous immunity between different pathogens is not necessarily reciprocal. To clarify these issues we propose to examine changes in the TCR repertoire and affinities of cross-reactive T cells under conditions of sequential and persistent viral infections, to examine the MHC basis of heterologous immunity to confirm that it is mediated by TCR-MHC interactions, to examine heterologous immunity under conditions of limited TCR repertoires caused by age or lymphopenia, to determine how frequencies and functions of naive bystander T cells are influenced by infection, and to shed insight on the lack of reciprocity in protective heterologous immunity between pathogens. PUBLIC HEALTH RELEVANCE: Modern vaccine strategies are directed at generating strong memory T cell responses to control viral infections, but memory T cells specific to one virus may cross-react with another and alter its pathogenesis. Understanding the implications of this "heterologous immunity" in normal and aged hosts should enhance our knowledge of viral pathogenesis and contribute to the design of better vaccines.