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

登革病毒（DENV）的四种血清型引起登革热（DF）和出血性登革 登革热/登革热休克综合征（DHF/DSS）。研究表明DHF/DSS是一种 T细胞应答可能失调的免疫病原性疾病。了解 调节T细胞介导的病理与保护之间的平衡的机制对于 开发治疗方法，更重要的是，开发安全的登革热疫苗。通过交替传代DENV 在小鼠和蚊子细胞之间，我们自然地选择了诱导强大T细胞的菌株， 我们已经证明了CD 8 + T细胞在限制DENV感染中的关键作用， 对小鼠由于小鼠中CD 8 + T细胞对DENV 2应答的广泛特异性和抗病毒作用，我们 假设鼠和人CD 8 + T细胞对DENV 3的应答是广泛的，靶向大多数病毒， 这些CD 8 + T细胞保护宿主免受DENV 3感染。具体来说，我们将 使用小鼠模型检查CD 8 + T细胞对保护作用与发病机制的贡献。 DENV 3感染（目的1和2），我们将确定人CD 8 + T细胞的特异性和作用， 使用HLA转基因小鼠和来源于DENV 3感染的样品， 已从原发性DENV 3感染中康复的人（目标3和4）。该项目的重点是 DENV 3，因为流行病学研究表明，某些DENV血清型，基因型， 登革病毒感染顺序可能与DHF/DSS有关，而登革病毒3型（DENV 3）的感染顺序尚不清楚 感染与DENV 2相比，尽管DENV 3与DENV 2在流行国家共传播， DENV 3是南亚和拉丁美洲最近流行的原因。

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.