Characterization of a human-specific positive regulator of flavivirus infection

黄病毒感染的人类特异性正调节因子的表征

基本信息

批准号：
10381448
负责人：
Florian Douam
金额：
$ 10.64万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-12 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381448
关键词：
Acute Affect Angola Area Attenuated Award Binding Binding Sites Blood Brazil Career Transition Award Cell Culture System Cells Clinical Management Collaborations Complex Culicidae Data Dengue Infection Dengue Virus Dependence Development Disease Disease Outbreaks Dose Elements Event Flavivirus Flavivirus Infections Funding Future Genome Goals Hematopoietic Hepatocyte Human Human Cell Line Immune system In Vitro Inbreeding Infection Infectious Agent Integration Host Factors Knowledge Life Cycle Stages Light Mass Vaccinations Medical MicroRNAs Molecular Molecular Virology Mus Mutation Nucleotides Oligonucleotides Pathogenicity Persons Phenotype Physiological Polyproteins Population Positioning Attribute Postdoctoral Fellow Primates Proteins RNA RNA Viruses RNA replication Regulation Research Risk Role Technology Testing Therapeutic Time TimeLine Tissues Training Translations Tropism United States National Institutes of Health Vaccination Vaccines Viral Viral Genome Virulent Virus Virus Replication Work Yellow Fever Yellow Fever Vaccine Yellow Fever Virus Infection Yellow fever virus Zika Virus career cell type detection method effective therapy experimental study genome-wide health economics humanized mouse in vivo in vivo Model inhibitor interest loss of function member mouse model mutant novel novel strategies novel therapeutic intervention overexpression particle pathogen pathogenic virus professor programs therapeutically effective tool transcriptomics unvaccinated viral RNA virus host interaction

项目摘要

Project Summary/Abstract Flaviviruses such as yellow fever virus (YFV), Zika virus (ZIKV) or Dengue virus (DENV) are cause of great health and economic concerns worldwide. YFV is the prototypical member of the flavivirus genus, and one of the first human pathogenic viruses that has been identified. Despite the development of a very potent vaccine in the 1930’s, YFV still represents a real theat. Recent outbreaks in Angola and Brazil, over the past two years, occurred in areas with low vaccination coverage. These resurgence events have exemplified the threat and have highlighted the need for the protection of an estimated 400 to 500 million people worldwide. Facing a significant vaccine shortage, fractional doses of vaccine are now used during vaccination campaigns despite no/limited evidence of long-term protection, hence underscoring the urgent necessity of developing novel strategies to clinically manage future YFV outbreaks. Our knowledge of the YFV infectious cycle in vitro and in vivo is extremely limited which has ultimately hampered the development of specific therapies to treat YFV infection, as none is currently available. I recently identified a novel host regulator of YFV infection in human cells that is required for effective YFV infection and replication in vitro. As it is not expressed in mice, this factor could also contribute to the human/primate-specific tropism of YFV. Building on a robust set of preliminary data, I hypothesize that this factor regulates RNA replication or protein translation through direct binding to viral elements. In Aim 1, I will explore the mechanisms by which this factor regulates the replication of the YFV vaccine strain YFV-17D in vitro as well as the host and virus determinants that govern such regulation. In Aim 2, I will determine the role of this factor on the replication of a virulent YFV strain, YFV-Asibi, as well as of other flaviviruses of interest such as ZIKV and DENV. I will also seek to explore the role of this factor using more relevant cell culture system such as primary human hepatocytes by using specific inhibitor of this factor. In Aim 3, I will use a humanized mouse model I recently developed and that is permissive to YFV infection to evaluate the role of this factor on YFV-Asibi and YFV-17D replication in vivo, by treating mice with specific inhibitor of the identified host factor. Altogether, my strong expertise in studying YFV virus in vitro and in vivo, combined with the different viral tracking tools and in vivo models I have previously developed, position me very well to conduct the proposed research. This research could provide novel avenues for the specific treatment of YFV infection and enhance our understanding of the host-pathogen interactions that define flavivirus pathogenicity. This K22 Career Transition Award will help me achieve my scientific and career goals, which consist of transitioning toward an independent assistant professor position and establishing an independent NIH-funded research program aiming at elucidating the mechanisms of flavivirus pathogenicity.

项目概要/摘要黄热病病毒 (YFV)、寨卡病毒 (ZIKV) 或登革热病毒 (DENV) 等黄病毒是导致重大疾病的原因。 YFV 是黄病毒属的典型成员，也是其中之一。尽管已开发出非常有效的疫苗，但仍发现了第一种人类致病病毒。 1930年代，YFV仍然是最近两年在安哥拉和巴西爆发的真实战场。这些疫情死灰复燃的事件发生在疫苗接种覆盖率较低的地区，这充分体现了这种威胁。强调需要保护全世界估计有 400 至 5 亿人面临着重大挑战。疫苗短缺，尽管没有/有限，但现在在疫苗接种活动中使用了分次剂量的疫苗长期保护的证据，因此强调迫切需要制定新的战略我们对 YFV 体外和体内感染周期的了解是临床管理未来 YFV 爆发的基础。极其有限，最终阻碍了治疗 YFV 感染的特异性疗法的开发，因为我最近发现了一种新的人类细胞中 YFV 感染的宿主调节因子，即由于 YFV 在小鼠体内不表达，因此该因子也可能是有效的 YFV 感染和体外复制所必需的。基于一组可靠的初步数据，我对 YFV 的人类/灵长类特异性趋向做出了贡献。该因子通过直接结合病毒来调节 RNA 复制或蛋白质翻译在目标 1 中，我将探讨该因子调节 YFV 复制的机制。疫苗株 YFV-17D 体外以及控制这种调节的宿主和病毒决定因素。 2，我将确定该因子对 YFV 毒株 YFV-Asibi 以及其他毒株复制的作用我还将尝试更多地探索这一因素的作用。相关细胞培养系统，例如原代人肝细胞，通过使用该因子的特异性抑制剂。 3、我将使用我最近开发的允许YFV感染的人源化小鼠模型来评估通过用特定的抑制剂治疗小鼠，研究该因子对 YFV-Asibi 和 YFV-17D 体内复制的作用总而言之，我在体外和体内研究 YFV 病毒方面的丰富专业知识，加上我之前开发的不同病毒追踪工具和体内模型使我能够很好地进行这项研究可为 YFV 感染的特异性治疗提供新途径。并增强我们对定义黄病毒致病性的宿主-病原体相互作用的理解。职业转型奖将帮助我实现我的科学和职业目标，其中包括向独立助理教授职位并建立独立的 NIH 资助研究项目旨在阐明黄病毒的致病机制。