T Cell Response to Dengue Virus

描述(申请人提供)：登革病毒(DEN)引起登革热(DF)和登革出血热/登革休克综合征(DHF/DSS)，这是全球最流行的节肢动物传播的病毒疾病。研究表明，DHF/DSS是一种免疫原性疾病，其T细胞介导的免疫系统可能处于失调状态。然而，由于缺乏足够的动物模型来分析获得性免疫反应，T细胞依赖免疫在体内对DEN感染的反应中的确切作用还没有完全确定。我们的长期目标是阐明免疫系统如何在体内与DEN相互作用，然后开发出DHF/DSS的小鼠模型。在这项提议中，我们将检验T细胞在宿主对DEN的反应中发挥保护作用的假设。具体地说，我们将通过监测T细胞的增殖和分化，并通过识别CD4+和CD8+T细胞识别的DEN表位来表征小鼠对初次DEN感染的T细胞反应(目标1)。接下来，我们将使用小鼠T细胞的各种功能丧失和功能获得模型，结合新产生的DEN菌株，确定T细胞是否能够预防原发DEN感染。新产生的DEN菌株在T细胞和B细胞缺陷小鼠中会导致100%的疾病，而在野生型小鼠中是无毒的(目标2)。总之，这项研究将阐明体内对原发DEN感染的免疫反应的细胞机制，并为阐明初发和继发的DEN感染时免疫系统的保护和致病机制奠定基础。

DESCRIPTION (provided by applicant): Dengue virus (DEN) causes dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), the most prevalent arthropod-borne viral illnesses in humans worldwide. Studies suggest that DHF/DSS is an immunopathogenic disease in which the T cell-mediated immune system may be dysregulated. However, the precise role of the T cell-dependent immunity in response to DEN infection in vivo is not fully defined due to the lack of an adequate animal model that allows dissection of the adaptive immune response. Our long-term goal is to elucidate how the immune system interacts with DEN in vivo and then develop a mouse model of DHF/DSS. In this proposal, we will test the hypothesis that T cells play a protective role in the host response to DEN. Specifically, we will characterize the T cell response to primary DEN infection in mice by monitoring T cell proliferation and differentiation and by identifying the DEN epitopes recognized by CD4+ and CD8+ T cells (Aim 1). Next, we will determine whether T cells can protect against primary DEN infection using a variety of loss-of-function and gain-of-function models for mouse T cells in combination with newly generated DEN strains that cause disease in 100% of T and B cell-deficient mice, and are nonvirulent in wild-type mice (Aim 2). Overall, this research will elucidate the cellular mechanisms of the immune response to primary DEN infection in vivo and establish the foundation for elucidating the protective versus pathogenic mechanisms of the immune system in primary and sequential DEN infections.