Regulation of host immunity to impact virus persistence

项目概要/摘要 慢性病毒感染继续在人类中引起显著的发病率和死亡率。病毒通常会逃避或 抑制宿主免疫力以建立持续感染。克隆13株（C113）淋巴细胞 脉络丛脑膜炎病毒（LCMV）诱导了深刻的免疫抑制，并持续在小鼠。LCMV Cl 13感染的小鼠已成为研究病毒对宿主的调节机制的有价值的模型系统 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)神经鞘氨醇和控制不同的细胞条件。然而，SK 2在宿主免疫中的功能 对病毒感染的反应仍然知之甚少。初步数据表明，SK2缺乏 导致对LCMV C113感染的T细胞应答增强，导致致命的免疫病理学 与肾脏疾病有关。数据还表明，LCMV C113增加SK2的活化， CD 4 + T细胞，其抑制病毒特异性T细胞的扩增。重要的是，口服施用本发明的组合物。 SK2特异性抑制剂进入LCMV C113感染的小鼠加速了持续感染的清除。 因此，以下研究目的是揭示SK 2在病毒中的调节功能- 诱导的免疫抑制、免疫病理学和病毒持久性。第一，SK2在CD 4 + T细胞中的作用 将在持续LCMV C113感染期间以及使用来自 长期感染病毒的病人。其次，SK2抑制病毒的分子机制- 将在LCMV感染后确定特异性CD 4 + T细胞应答和限制性免疫病理学。最后， 拟议的研究将进一步确定SK2特异性抑制剂在持续性 LCMV感染，并评估由SK 2抑制调节的宿主免疫的特征。总的来说，这 研究有望阐明SK2调节病毒特异性T细胞应答的机制， 确定SK 2在不平衡免疫机制中的功能，该免疫机制可导致免疫病理性 肾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框架。 控制慢性病毒感染的治疗干预。

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.