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

点击翻译按钮获取中文摘要

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.