Flaviviruses: Yin-yang of Heterologous Immunity

黄病毒科包括60多种人类病原体，包括出血热 病毒[例如登革热、黄热病（YF）]和脑炎病毒[例如西尼罗河病毒、日本脑炎病毒 脑炎病毒（JE）]。这些病毒具有高度的同源性和免疫交叉反应性。 该项目的长期目标是确定黄病毒特异性 原发性黄病毒感染诱导的CD 4+和CD 8 + T细胞应答对免疫应答的影响 随后感染其他黄病毒。连续性黄病毒感染在自然界中发生， 在继发性黄病毒中有交叉保护和增强疾病的例子 感染.在目标1中，我们计划鉴定新的黄病毒特异性CD 4+和CD 8 + T细胞表位。我们 然后将表征对同源的和非同源的细胞因子的效应器应答（细胞因子产生、增殖）， 异源病毒在目标2中，我们将使用两种密切相关的病毒来模拟免疫系统。 黄病毒连续感染”黄热病（YF）17 D“和日本候选人的影响 脑炎病毒（JE）疫苗，其包含活的减毒嵌合YF，所述嵌合YF含有前膜 (prM)和异源黄病毒JE的包膜（E）区。我们将量化 表位特异性T细胞反应在原发性和继发性黄病毒感染，并确定 继发性感染是否改变了T细胞表位层次，以记忆/回忆（非结构性）或 新的/幼稚的（结构）抗原。在目标3中，我们将研究小学和高中阶段的关联， YF 17 D和嵌合YF/JE在黄病毒特异性T细胞之间二次免疫 病毒血症和抗体反应。这些研究将有助于阐明有益的和 有害方面的异源病毒免疫，并将有助于开发新的 针对这些生物威胁的疫苗

The family Flaviviridae includes over 60 human pathogens, including hemorrhagic fever viruses [e.g. dengue, yellow fever (YF)] and encephalitis viruses [e.g. West Nile virus, Japanese encephalitis virus (JE)]. These viruses have a high degree of homology and immunologic crossreactivity. The long-term objective of this project is to determine the effect of flavivirus-specific CD4+ and CD8+ T cell responses induced by primary flavivirus infection on the immune response to subsequent infection with other flaviviruses. Sequential flavivirus infections occur in nature and there are examples of cross-protection as well as enhanced disease in secondary flavivirus infections. In Aim 1, we plan to identify novel flavivirus-specific CD4+ and CD8+ T cell epitopes. We will then characterize effector responses (cytokine production, proliferation) to homologous and heterologous viruses. In Aim 2, we will use two closely related viruses to model the immunologic effects of sequential flavivirus infection" yellow fever (YF)17D and a candidate Japanese encephalitis virus (JE) vaccine comprised of a live attenuated chimeric YF that contains the premembrane (prM) and envelope (E) regions of a heterologous flavivirus, JE. We will quantitate the epitope-specific T cell responses in primary and secondary flavivirus infection, and determine whether secondary infections alter the T cell epitope hierarchy to memory/recall (nonstructural) or novel/na'fve (structural) antigens. In Aim 3, we will examine associations during primary and secondary immunization with YF17D and chimeric YF/JE between flavivirus-specific T cell responses and viremia and antibody responses. These studies will help to elucidate beneficial and detrimental aspects of heterologous viral immunity and will help in the development of novel vaccines against these biological threats.