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.

项目总结/摘要 黄病毒如黄热病病毒（YFV）、寨卡病毒（ZIKV）或登革病毒（DENV）是引起严重的登革热的原因。 健康和经济问题。YFV是黄病毒属的典型成员， 第一个被确认的人类致病病毒。尽管已经开发出了一种非常有效的疫苗， 在20世纪30年代，YFV仍然代表着一个真实的剧院。最近在安哥拉和巴西爆发的疫情，在过去两年中， 发生在疫苗接种覆盖率低的地区。这些死灰复燃的事件证明了这种威胁， 强调需要保护全世界约4亿至5亿人。面临巨大的 疫苗短缺，尽管没有/有限的疫苗接种， 长期保护的证据，因此强调迫切需要制定新的战略， 临床管理未来的YFV爆发。我们对YFV体外和体内感染周期的了解是 这最终阻碍了治疗YFV感染的特异性疗法的开发， 目前没有。我最近在人类细胞中发现了一种新的YFV感染宿主调节因子， 所需的有效YFV感染和体外复制。由于它在小鼠中不表达，该因子也可能 有助于YFV的人/灵长类特异性向性。基于一组可靠的初步数据， 假设该因子通过直接与病毒结合来调节RNA复制或蛋白质翻译， 元素在目标1中，我将探索该因子调节YFV复制的机制 疫苗株YFV-17 D在体外以及宿主和病毒的决定因素，支配这种调节。在Aim中 2、确定该因子对YFV强毒株YFV-Asibi以及其他毒株复制的作用。 在一些实施方案中，所述病毒是感兴趣的黄病毒，例如ZIKV和DENV。我还将寻求探索这个因素的作用，使用更多的 相关的细胞培养系统如原代人肝细胞。在Aim中 3.我将使用我最近开发的人源化小鼠模型，该模型允许YFV感染，以评估 该因子对YFV-Asibi和YFV-17 D体内复制的作用，通过用特异性抑制剂处理小鼠， 确定的主机因素。总之，我在体外和体内研究YFV病毒方面的专业知识， 我以前开发的不同病毒跟踪工具和体内模型，使我能够很好地进行 拟议的研究。本研究为YFV感染的特异性治疗提供了新的途径 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。K22 职业过渡奖将帮助我实现我的科学和职业目标，其中包括过渡到 一个独立的助理教授职位，并建立一个独立的NIH资助的研究项目 旨在阐明黄病毒的致病机制。