LSUHSC COBRE: ROLE OF INNATE IMMUNITY IN YELLOW FEVER VIRUS PATHOGENESIS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 由蚊媒黄热病病毒（YFV）引起的高致死性、泛系统性出血热是非洲、欧洲和美洲最令人恐惧的疾病之一，直到1930年开发出17 D减毒活疫苗。S. 为了获得17 D疫苗株，将YFV的天然野生型Asibi分离株在原代培养细胞上凭经验传代176次。 尽管17 D被认为是一种原型减毒活病毒疫苗，但黄病毒领域最大的谜团之一是控制这种减毒活疫苗减毒和免疫原性的分子机制。我们的长期目标是揭示17 D基因组中积累的哪些突变在体内是减毒的，并确定它们对病毒发病机制的影响，并确定减毒感染如何差异地影响早期病毒-宿主相互作用，在用17 D免疫后引发YFV特异性保护性免疫应答。我们正在检验以下假设：由于在树突状细胞、单核细胞和/或巨噬细胞中复制的能力不同，17 D减毒活疫苗株的早期病毒血症传播与强毒亲本Asibi病毒相比显著受损，减毒表型与诱导适于刺激局部淋巴组织适应性免疫的趋化因子/细胞因子相关。预期我们的发现将促进其他减毒活病毒疫苗的合理设计，特别是针对其他致病性黄病毒（例如，西尼罗河病毒和登革热病毒）和密切相关的甲病毒（例如，东部马脑炎病毒），其中大多数是新出现的传染病和生物恐怖主义/生物战的病原体。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The highly-lethal, pan-systemic hemorrhagic fever caused by the mosquito-borne yellow fever virus (YFV) was one of the most feared diseases in Africa, Europe and the Americas until the live-attenuated 17D vaccine was developed in the 1930s. To derive the 17D vaccine strain, the natural wild-type Asibi isolate of YFV was empirically passaged 176 times on primary cultured cells. Although 17D is considered a prototypic live-attenuated virus vaccine, one of the greatest mysteries in the flavivirus field is the molecular mechanism that controls the attenuation and immunogenicity of this live-attenuated vaccine. Our long-term goals are to reveal which of the mutations accumulated in the 17D genome are attenuating in vivo and determine their effect(s) on viral pathogenesis, and to determine how the attenuated infection differentially affects early virus-host interactions, eliciting YFV-specific protective immune responses after immunization with 17D. We are testing the hypothesis that early viremic dissemination of the live-attenuated 17D vaccine strain is significantly impaired in comparison with the virulent parental Asibi virus as a result of a differential ability to replicate in dendritic cells, monocytes and/or macrophages and that the attenuated phenotype will correlate with induction of chemokine/cytokines appropriate for stimulation of adaptive immunity in regional lymphoid tissues. It is anticipated that our findings will facilitate the rational design of other live-attenuated virus vaccines, particularly against other pathogenic flaviviruses (e.g., West Nile and dengue viruses) and the closely-related alphaviruses (e.g., eastern equine encephalitis virus), most of which are agents of both emerging infectious disease and bioterrorism/biowarfare.