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

• 批准号: 10843473
• 负责人: Florian Douam
• 金额: $ 7.56万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 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/10843473
• 关键词: Acute; Affect; Angola; Area; Attenuated; Award; Binding; Binding Sites; Biotinylation; 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; Economics; Elements; Engraftment; Event; Flavivirus; Flavivirus Infections; Funding; Future; Genome; Goals; Health; Hematopoietic; Hepatocyte; Human; Human Cell Line; Immune system; In Vitro; Inbreeding; Infection; Infectious Agent; Integration Host Factors; Knowledge; Life Cycle Stages; 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; 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; 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; permissiveness; professor; programs; therapeutically effective; timeline; tool; transcriptomics; transmission process; unvaccinated; viral RNA; virus host interaction

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.

项目摘要/摘要 黄热病病毒（YFV），寨卡病毒（ZIKV）或登革热病毒（DENV）等黄热病病毒是很大的原因 全球健康和经济问题。 YFV是黄病毒属的典型成员，是其中之一 已鉴定出的第一个人类病毒病毒。尽管开发了一种潜在的疫苗 1930年代，YFV仍然代表着真正的蛋白。在过去的两年中，最近在安哥拉和巴西的爆发， 发生在疫苗覆盖范围低的地区。这些复兴事件已经举例说明了威胁，并 强调需要保护全球估计有400至5亿人。面对重要的 疫苗短缺，分数剂量的疫苗现在在疫苗活动中使用/有限 长期保护的证据，因此强调了制定新型策略的迫切必要性 临床管理未来的YFV暴发。我们对体外和体内YFV感染周期的了解是 极其有限的，最终阻碍了治疗YFV感染的特定疗法的发展， 当前没有一个可用。我最近确定了人类细胞中YFV感染的新型宿主调节剂 有效的YFV感染和体外复制所必需的。由于它在小鼠中没有表达，因此这个因素也可能 有助于YFV的人类/灵长类动物特异性的潮流。建立在强大的初步数据的基础上 假设该因子通过直接结合病毒来调节RNA复制或蛋白质翻译 元素。在AIM 1中，我将探讨该因素调节YFV复制的机制 疫苗菌株YFV-17D体外以及宿主和病毒决定了这种调节。目标 2，我将确定该因素在重复YFV菌株YFV-ASIBI以及其他其他因素中的作用 ZIKV和DENV等感兴趣的黄病毒。我还将寻求使用更多 相关的细胞培养系统，例如使用该因素的特定抑制剂，例如原代人肝细胞。目标 3，我将使用我最近开发的人源化鼠标模型，这对YFV感染允许评估 该因素在体内的YFV-ASIBI和YFV-17D复制中的作用，通过用特定的抑制剂治疗小鼠 确定的宿主因子。总的来说，我在体外和体内研究YFV病毒方面的强大专业知识，结合 我以前开发过的不同病毒跟踪工具和体内模型 拟议的研究。这项研究可以为YFV感染的特定治疗提供新的途径 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。这个K22 职业过渡奖将帮助我实现我的科学和职业目标，包括向过渡到 独立助理教授职位并建立一项独立的NIH资助研究计划 旨在阐明黄素病毒致病性的机制。