T Cell Response to Dengue Virus

描述（由申请人提供）：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），这是全世界最流行的人类节肢动物传播的病毒性疾病。研究表明DHF/DSS是一种免疫致病性疾病，其中T细胞介导的免疫系统可能失调。然而，由于缺乏适当的动物模型来解剖适应性免疫反应，T细胞依赖性免疫在体内对DEN感染的反应中的确切作用尚未完全确定。我们的长期目标是阐明体内免疫系统如何与DEN相互作用，然后建立DHF/DSS小鼠模型。在本提案中，我们将验证T细胞在宿主对DEN的反应中起保护作用的假设。具体来说，我们将通过监测T细胞增殖和分化以及鉴定CD4+和CD8+ T细胞识别的DEN表位来表征T细胞对小鼠原发性DEN感染的反应（目的1）。接下来，我们将使用多种功能丧失和功能获得模型来确定T细胞是否可以保护小鼠免受原发性DEN感染，这些模型将小鼠T细胞与新产生的DEN菌株结合使用，该菌株在100%的T和B细胞缺陷小鼠中引起疾病，并且在野生型小鼠中无毒性（Aim 2）。总的来说，本研究将阐明体内原发性DEN感染免疫应答的细胞机制，并为阐明原发性和继发性DEN感染中免疫系统的保护与致病机制奠定基础。

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.