T Cell Response to Dengue Virus

描述（由申请人提供）：登革热病毒（DEN）引起登革热（DF）和登革出血热/登革休克综合征（DHF/DSS），这是全球人类最流行的节肢动物传播的病毒性疾病。研究表明DHF/DSS是一种免疫病理性疾病，其中T细胞介导的免疫系统可能失调。然而，由于缺乏足够的动物模型，允许解剖的适应性免疫反应的T细胞依赖性免疫在体内响应DEN感染的确切作用没有完全确定。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，然后建立DHF/DSS的小鼠模型。在这个建议中，我们将测试的假设，T细胞在主机响应DEN发挥保护作用。具体而言，我们将通过监测T细胞增殖和分化以及通过鉴定CD 4+和CD 8 + T细胞识别的DEN表位来表征小鼠中T细胞对原发性DEN感染的应答（目的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菌株来确定T细胞是否可以保护免受原发性DEN感染，所述新产生的DEN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是非毒性的（Aim 2）。总体而言，本研究将阐明在体内的免疫应答的细胞机制，以原发性DEN感染，并建立阐明在原发性和连续DEN感染的免疫系统的保护性与致病性机制的基础。

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.