Interferon-mediated control of neuropathogenic Flaviviruses

干扰素介导的神经病性黄病毒的控制

• 批准号: 10326786
• 负责人: Natasha Wyndham Hanners
• 金额: $ 14.88万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-12 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326786
• 关键词: Adult; Advisory Committees; Award; Basic Science; Biochemical; Biological; Biological Assay; Brain; Cell Culture System; Cell Culture Techniques; Cell Death; Cells; Central Nervous System Infections; Clinical; Complement; Data; Development Plans; Disease; Education; Encephalitis; Fetal Development; Flavivirus; Flavivirus Infections; Foundations; Funding; Gene Targeting; Genes; Genome; Goals; Host Defense; Human; IFI6 gene; Immune; Immune response; Immune system; Immunology; In Vitro; Infection; Innate Immune Response; Innate Immune System; Institution; Interferon Type I; Interferons; K-Series Research Career Programs; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Life Cycle Stages; Measures; Mediating; Mentors; Mentorship; Modeling; Molecular; Molecular Virology; Natural Immunity; Neurologic; Neuronal Differentiation; Neurons; Neurosciences; Orthologous Gene; Outcome; Pathologic; Pathway interactions; Physicians; Polymerase; Protein Biosynthesis; Proteins; Publishing; RNA Viruses; RNA replication; Recording of previous events; Research; Research Ethics; Role; Scientist; System; Technical Expertise; Training; Translations; Undifferentiated; Venezuelan Equine Encephalitis Virus; Viral; Viral Pathogenesis; Viral Proteins; Virus; Virus Diseases; Virus Replication; West Nile virus; Work; Yellow Fever; ZIKA; ZIKV infection; Zika Virus; antiviral immunity; base; career; career development; congenital infection; experience; fight against; immune activation; immunopathology; in vivo; inhibitor; interest; meetings; mosquito-borne; mouse model; nerve stem cell; neurotropic; neurotropic virus; novel; overexpression; protein function; response; sound; symposium; viperin; viral RNA; virology; virus host interaction

Title: Interferon-Mediated Control of Neuropathogenic Flaviviruses Abstract: The primary research goals of this Mentored Clinical Scientist Research Career Development Award proposal are to study mechanisms by which antiviral interferons suppress neuropathogenic Flaviviruses. Flaviviruses, including Zika virus (ZIKV) and West Nile virus (WNV), can cause severe neurological complications, including brain disruption sequence and encephalitis. These manifestations are the net result of both virus-induced effects and host immune responses. The type I interferon (IFN) response establishes a cellular antiviral state through the induction of hundreds of IFN-stimulated genes (ISGs), many of which have direct antiviral effects. Through a cell-based screen to identify novel antiviral ISGs, the candidate uncovered C19orf66 as a potent inhibitor of multiple RNA viruses, including WNV, ZIKV, and Venezuelan equine encephalitis virus (VEEV). The candidate has shown that C19orf66 is required for an optimal IFN response and targets the viral life cycle at the stage of genome replication. Additionally, C19orf66 is basally expressed in primary human neural progenitor cells (hNPs), a useful model to study Zika virus-host interaction. Here, the candidate proposes to further characterize the mechanism of C19orf66 inhibition of Flaviviruses. A combination of molecular virological, cell biological, and biochemical approaches will be used to study: 1) the precise viral life cycle step inhibited by C19orf66, 2) the contribution of C19orf66 to antiviral immunity in hNP cell culture models and 3) the in vivo relevance in a mouse model of ZIKV infection. This research plan, complemented by a comprehensive career development plan that capitalizes on the candidate’s strong clinical interest in central nervous system infections, will lead to an independent research career laid on the foundation of strong education and sound technical skills. The research component of this award will be conducted in the laboratory of Dr. John Schoggins at UT Southwestern, who has significant expertise in basic virology and innate immunity, with additional oversight by co-mentor, Dr. Beth Levine, an expert in virus-host interactions with a strong history of successful mentorship. Critical to the candidate’s career development are attendance and presentations at professional conferences, regular meetings with her advisory committee, courses in fundamentals of neuroscience and immunology, mentorship and career development, research ethics, and hands-on training in the neuroscience lab of Dr. Genevieve Konopka. In summary, this training plan will satisfy the candidate’s short-term goals to strengthen her neuroscience and immunology fund of knowledge and expand her experience in basic science, providing for her long-term goal of independent research in the innate immune control of neuropathogenic Flaviviruses.

干扰素介导的神经致病性黄病毒的控制 摘要： 指导临床科学家研究职业发展奖提案的主要研究目标 研究抗病毒干扰素抑制神经致病性黄病毒的机制。黄病毒， 包括寨卡病毒(ZIKV)和西尼罗河病毒(WNV)，可导致严重的神经系统并发症，包括 脑震荡序列和脑炎。这些表现是病毒诱导的两种效应的净结果 和宿主免疫反应。I型干扰素(干扰素)反应通过建立细胞抗病毒状态 诱导数百个干扰素刺激基因(ISGs)，其中许多具有直接的抗病毒作用。穿过 基于细胞的筛选以确定新的抗病毒ISG，候选者发现C19orf66是一种有效的 多种RNA病毒，包括西尼罗河病毒、ZIKV和委内瑞拉马脑炎病毒(VEEV)。候选人 已表明C19orf66是产生最佳干扰素应答所必需的，并以病毒生命周期为靶点 基因组复制。此外，C19orf66在原代人类神经前体细胞(HNPs)中基本表达， 一个研究寨卡病毒与宿主相互作用的有用模型。在这里，候选人提议进一步描述 C19orf66抑制黄病毒的机制。分子病毒学、细胞生物学和 生物化学方法将被用来研究：1)C19orf66抑制病毒生命周期的精确步骤，2) C19orf66在HNP细胞培养模型中对抗病毒免疫的贡献及3)小鼠体内相关性 ZIKV感染模型。这项研究计划，辅以全面的职业发展计划， 利用候选人对中枢神经系统感染的强烈临床兴趣，将导致 独立的研究事业奠定在强大的教育和扎实的技术技能的基础上。这项研究 该奖项的组成部分将在德克萨斯大学西南分校的John Schoggins博士的实验室进行，他 在基础病毒学和先天免疫方面具有重要的专业知识，并由共同导师贝斯博士进行额外监督 Levine博士说，他是病毒-宿主相互作用方面的专家，有很强的成功指导历史。对美国的 应聘者的职业发展是定期参加专业会议和发表演讲 与她的顾问委员会的会议，神经科学和免疫学基础课程，导师 和吉纳维夫博士神经科学实验室的职业发展、研究伦理和动手培训 科诺普卡。总而言之，这个培训计划将满足应聘者的短期目标，以增强她的能力 神经科学和免疫学的知识基金，扩大了她在基础科学方面的经验，为她 神经致病性黄病毒先天免疫控制的独立研究的长期目标。