Regulation of host immunity to impact virus persistence

项目摘要/摘要 慢性病毒感染继续在人类中造成严重的发病率和死亡率。病毒通常会逃避或 抑制宿主免疫力以建立持续性感染。淋巴细胞克隆13株(Cl13) 脉络膜脑膜炎病毒(LCMV)可引起免疫抑制，并持续存在于小鼠体内。LCMV CL 小鼠感染已成为研究宿主病毒调控机制的一个有价值的模型系统。 免疫力和病毒持久性。鞘氨醇激酶(SK)2介导1-磷酸鞘氨醇的合成 (S1P)来自鞘氨醇，控制不同的细胞条件。然而，SK2在宿主免疫中的作用 对病毒感染的反应仍然知之甚少。初步数据表明SK2缺乏 导致小鼠对LCMV Cl13感染的T细胞反应增强，导致致命性免疫病理 与肾脏疾病有关。数据还表明，LCMV Cl13增加了SK2的激活。 CD4T细胞，抑制病毒特异性T细胞的增殖。重要的是，口服给药 SK2特异性抑制剂进入LCMV Cl13感染的小鼠可加速持续感染的清除。 因此，开展以下研究目的是为了揭示SK2在病毒中的调节功能- 诱导免疫抑制、免疫病理和病毒持久性。第一，SK2在CD4T细胞中的作用 将研究持续LCMV Cl13感染期间的抑制以及使用来自 长期感染病毒的患者。第二，SK2抑制病毒的分子机制-- 当LCMV感染时，将确定特异性的CD4T细胞应答和限制性免疫病理。最后， 拟议中的研究将进一步确定SK2特异性抑制剂在持续时间内的治疗效果 并评价SK2抑制对宿主免疫功能的调节作用。总而言之，这是 研究有望阐明SK2调节病毒特异性T细胞反应的机制，以及 为了确定SK2在失衡的免疫机制中的作用，这种失衡可以导致免疫病理 肾脏疾病或持续性病毒感染。该项目可以为开发新的免疫系统提供一个框架 控制慢性病毒感染的治疗干预措施。

Project Summary/Abstract Chronic viral infections continue to cause significant morbidity and mortality in humans. Viruses often evade or suppress the host immunity to establish persistent infections. The clone 13 strain (Cl 13) of lymphocytic choriomeningitis virus (LCMV) induces a profound immune suppression and persists in the mouse. LCMV Cl 13 infection of mice has served as a valuable model system for the mechanistic study of viral regulation of host immunity and virus persistence. Sphingosine kinase (SK) 2 mediates the synthesis of sphingosine 1-phosphate (S1P) from sphingosine and controls diverse cellular conditions. However, the function of SK2 in host immune responses to virus infection remains poorly understood. The preliminary data demonstrate that SK2 deficiency in mice results in heightened T cell responses to LCMV Cl 13 infection, leading to lethal immunopathology associated with kidney disease. The data also indicate that LCMV Cl 13 increases the activation of SK2 in CD4+ T cells, which inhibits the expansion of virus-specific T cells. Importantly, the oral administration of the SK2-specific inhibitor into LCMV Cl 13-infected mice accelerates the clearance of the persistent infection. Therefore, the following research aims are developed to uncover the regulatory function of SK2 in virus- induced immune suppression, immune pathology, and virus persistence. First, the role of SK2 in CD4+ T cell suppression will be investigated during persistent LCMV Cl 13 infection as well as using human T cells from patients chronically infected with viruses. Second, the molecular mechanism by which SK2 suppresses virus- specific CD4+ T cell responses and restricts immune pathology will be determined upon LCMV infection. Lastly, the proposed study will further determine the therapeutic efficacy of the SK2-specific inhibitor during persistent LCMV infection and assess the features of the host immunity regulated by SK2 inhibition. Taken together, this research is expected to elucidate the mechanism by which SK2 regulates virus-specific T cell responses, and to define the function of SK2 in the imbalanced immune mechanism that can cause either immune pathologic kidney disease or persistent viral infection. The project could provide a framework for developing new immune therapeutic interventions for controlling chronic virus infections.