Virus induced immunopathology

描述（由申请人提供）：我们在动物模型中表明，由于不相关病原体之间的T细胞交叉反应而产生的异源免疫有助于增强或减少病毒载量，并显著改变对牛痘病毒、沙粒病毒、流感病毒和巨细胞病毒的免疫病理。这种异源免疫的例子现已在人类感染eb病毒、登革热病毒和丙型肝炎病毒中得到报道。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细胞的频率、功能和功能在宿主经历连续的急性或持续的非相同病毒感染时是如何变化的，就像在人类身上发生的那样。了解这些问题对于智能设计有效且无不良副作用的现代疫苗是必要的，因为意外的T细胞交叉反应有时会导致破坏性病理。异源免疫的许多问题仍未得到探讨。我们对改变的交叉反应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T细胞受体（TCR）库在衰老宿主或因感染、癌症或免疫抑制药物治疗导致淋巴细胞减少的宿主中变窄的异源免疫的影响知之甚少。我们也不清楚为什么不同病原体之间的异源免疫不一定是相互的。为了澄清这些问题，我们建议在连续和持续病毒感染的情况下检查TCR库的变化和交叉反应T细胞的亲和力，检查异种免疫的MHC基础，以确认它是由TCR-MHC相互作用介导的，检查由于年龄或淋巴细胞减少导致的TCR库有限的情况下的异种免疫，以确定感染如何影响幼稚旁观者T细胞的频率和功能。并对病原菌间保护性异源免疫缺乏互易性进行了探讨。公共卫生相关性：现代疫苗策略旨在产生强烈的记忆T细胞反应来控制病毒感染，但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”对正常和老年宿主的影响，将有助于提高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.