T cell response to Dengue virus serotype 3 in mice and humans

登革病毒(DENV)的四种血清型可引起登革热(DF)和登革热出血 人类的发热/登革热休克综合征(DHF/DSS)。研究表明，DHF/DSS是一种 免疫原性疾病，其T细胞反应可能失调。了解 调节T细胞介导的病理和保护之间的平衡的机制对 开发治疗方法，重要的是，开发一种安全的登革热疫苗。通过交替通过DENV 在老鼠和蚊子细胞之间，我们自然而然地选择了能够诱导强大T细胞的菌株 我们已经证明了CD8+T细胞在限制DENV感染中的关键作用 在老鼠身上。由于CD8+T细胞对DENV2的反应具有广泛的特异性和抗病毒作用，我们 假设小鼠和人CD8+T细胞对DENV3的反应广泛，以大多数病毒为靶点 蛋白质，这些CD8+T细胞保护宿主免受DENV3感染。具体来说，我们将 用小鼠模型研究CD8+T细胞在保护和发病机制中的作用 DENV3感染(目标1和2)，我们将确定人CD8+T细胞的特异性和作用 人类白细胞抗原转基因小鼠和来源的样本对DENV3感染宿主应答的研究 已从原发DENV3感染中康复的人(目标3和4)。这个项目的重点是 DENV3是因为流行病学研究表明某些DENV血清型、基因型别和 DENV感染序列可能与DHF/DSS有关，对DENV3知之甚少 与DENV2相比，虽然DENV3在流行国家与DENV2共同传播， DENV3是最近南亚和拉丁美洲疫情的罪魁祸首。

The four serotypes of Dengue virus (DENV) cause dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) in humans. Studies suggest that DHF/DSS is an immunopathogenic disease in which T cell responses may be dysregulated. Understanding the mechanisms that regulate the balance between T cell mediated pathology versus protection is crucial for developing therapies and, importantly, a safe dengue vaccine. By alternately passaging a DENV between mice and mosquito cells, we have naturally selected for strains that induce robust T cell responses in mice, and we have demonstrated a critical role for CD8+ T cells in limiting DENV infection in mice. Due to the broad specificity and antiviral role of the CD8+ T cell response to DENV2 in mice, we hypothesize that the murine and human CD8+ T cell response to DENV3 is broad, targeting most viral proteins, and these CD8+ T cells protect against DENV3 infection in the host. Specifically, we will examine the contribution of CD8+ T cells to protection versus pathogenesis using a mouse model of DENV3 infection (Aims 1 and 2), and we will define the specificity and role of human CD8+ T cell response in the host response to DENV3 infection using HLA transgenic mice and samples derived from people who have recovered from primary DENV3 infection (Aims 3 and 4). This project focuses on DENV3 because epidemiologic studies suggest that certain DENV serotypes, genotypes, and the sequence of DENV infections may be associated with DHF/DSS, and little is known about DENV3 infection as compared with DENV2, although DENV3 co-circulates with DENV2 in endemic countries, and DENV3 has been responsible for recent epidemics in South Asia and Latin America.