Immune correlates of protection from Rift Valley fever virus

预防裂谷热病毒的免疫相关性

• 批准号: 9109849
• 负责人: Anita K McElroy
• 金额: $ 17.51万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109849
• 关键词: Acute; Address; Advisory Committees; Affect; Africa; Animals; Antibodies; Antibody Response; Antibody Therapy; Antiviral Response; Appointment; Area; Attenuated Live Virus Vaccine; Award; B-Lymphocytes; Blood; Brain; CD4 Positive T Lymphocytes; Cells; Centers for Disease Control and Prevention (U.S.); Childhood; Clinical; Communicable Diseases; Culicidae; Data; Detection; Development; Disease; Doctor of Philosophy; Encephalitis; Environment; Excision; Faculty; Failure; Frequencies; Funding; Future; Generations; Goals; HIV Infections; HIV Seropositivity; Histocompatibility Antigens Class II; Human; Immune; Immune response; Immune system; Immunity; Immunologist; Immunology; Individual; Infection; Inflammatory; Instruction; Interferon Type I; Interferons; Junior Physician; Kinetics; Knowledge; Lead; Life; Livestock; Location; MS4A1 gene; Measures; Mediating; Mentors; Mentorship; Middle East; Modification; Monitor; Mus; Passive Transfer of Immunity; Peptides; Pharmaceutical Preparations; Phenotype; Physicians; Play; Population; Prevention; Prevention strategy; Proteins; Public Health; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Research Project Grants; Research Training; Resources; Rift Valley fever virus; Role; Science; Scientist; Secondary to; T-Cell Activation; T-Lymphocyte Subsets; Tanzania; Time; Training Programs; United States National Institutes of Health; Universities; Vaccinated; Vaccination; Vaccines; Viral; Viral Antigens; Viral Nonstructural Proteins; Virulence Factors; Virus; Virus Diseases; Wild Type Mouse; Work; adaptive immunity; analytical tool; attenuation; base; career; career development; cell type; cytokine; design; diphtheria toxin receptor; disorder prevention; human disease; lymph nodes; medical schools; meetings; mouse development; mouse model; mutant; neuroinflammation; pathogen; pediatric department; prevent; programs; public health relevance; research and development; research study; response; skills; vaccine candidate; viral RNA

 DESCRIPTION (provided by applicant): Candidate: I hold an MD/PhD and am a pediatric infectious disease physician and basic scientist. Every step in my career journey has been focused towards the goal of becoming a physician scientist. I am at the beginning of my first faculty appointment, and find that this time is a unique one in which I have the opportunity to broaden my skills in the area of immunology. My main goal during the time of the K08 award is to develop expertise in state of the art experimental immunology. I will achieve this via didactic instruction, accompanied by mentorship from several virologists and immunologists in the context of the proposed research project examining the role of CD4 T cells in preventing Rift Valley fever virus encephalitis. My primary mentor, Paul Spearman, MD, is a viral immunologist as well as a physician scientist and my division director. As a career and science mentor, he will guide my research progress over the time of the award, facilitate advisory committee meetings, and provide career development assistance including R01 proposal development and review. In the next 5 years I plan to capitalize on these newly gained skills to establish myself as an expert in studies of the interaction between host immune responses and emerging viruses. Environment: My appointment is in the Division of Pediatric Infectious Disease, Department of Pediatrics in the Emory University School of Medicine. The Department of Pediatrics at Emory is ranked ninth in the 2014 NIH rankings for Departments of Pediatrics for NIH based funding. This Department has an established track record of supporting junior physician scientists. There are numerous resources available to me at Emory for both research and career development. The experiments will be performed in the BSL-3E space at the US Centers for Disease Control and Prevention, where I hold a guest researcher appointment in the Viral Special Pathogens Branch and will have the expert mentorship and support from Christina Spiropoulou, PhD, team lead. Research: Rift Valley fever virus (RVFV) is a mosquito borne virus that causes disease in people and animals in Africa and the Middle East. In the past few years several new live attenuated vaccines have become available for use in livestock. The basis of attenuation for all of these vaccines is the deletion/modification of the viral virulence factor, NSs. These Del NSs viruses generate a protective immune response in animals, in that vaccinated animals are protected from challenge with wild-type virus. However, until recently, little was known about which specific components of the immune response were important for this protection. We reported that mice that were depleted of their CD4 T cells developed encephalitis following infection with the Del NSs virus, suggesting that some function of the CD4 T cell was important for providing protection from this virus. In this proposal, we will first determine the mechanism (viral vs. immune mediated) of Del NSs encephalitis in the CD4 depleted mice. Then, since there are at least 5 different types of CD4 T cells with various roles, we will characterize the CD4 T cell subsets that are activated and functional during Del NSs infection and begin to examine each subset individually to determine how they contribute to protection from encephalitis. Finally the role of B cells and antibodies in protection from encephalitis will be defined. These experiments will establish correlates of immunity against RVFV in the mouse model. These data will be used to design future studies targeted at examining immune correlates of protection in humans.

 描述（由申请人提供）： 候选人：我拥有医学博士/博士学位，是一名儿科传染病医师和基础科学家。我职业生涯中的每一步都集中在成为一名医学科学家的目标上。我正处于第一次教职任命的开始，并发现这次是一次独特的机会，我有机会拓宽我在免疫学领域的技能。在获得 K08 奖期间，我的主要目标是发展最先进的实验免疫学方面的专业知识。我将通过教学指导，并在几位病毒学家和免疫学家的指导下，在拟议的研究项目中实现这一目标，该研究项目旨在检查 CD4 T 细胞在预防裂谷热病毒脑炎中的作用。我的主要导师保罗·斯皮尔曼（Paul Spearman）医学博士是一位病毒免疫学家、医学科学家和我的部门主管。作为一名职业和科学导师，他将在获奖期间指导我的研究进展，促进顾问委员会会议，并提供职业发展援助，包括 R01 提案的制定和审查。在接下来的 5 年内，我计划利用这些新获得的技能来使自己成为一名专家 研究宿主免疫反应和新出现的病毒之间的相互作用。环境：我的任命在埃默里大学医学院儿科小儿传染病科。埃默里大学儿科在 2014 年 NIH 儿科排名中获得 NIH 资助，排名第九。该部门在支持初级医师科学家方面有着良好的记录。埃默里大学为我提供了大量的研究和职业发展资源。这些实验将在美国疾病控制与预防中心的 BSL-3E 空间进行，我在那里担任病毒特殊病原体部门的客座研究员，并将得到团队负责人 Christina Spiropoulou 博士的专家指导和支持。研究：裂谷热病毒（RVFV）是一种蚊媒病毒，会导致非洲和中东的人和动物患病。在过去几年中，几种新的减毒活疫苗已可用于牲畜。所有这些疫苗减毒的基础是病毒毒力因子 NS 的删除/修饰。这些 Del NS 病毒在动物中产生保护性免疫反应，因为接种疫苗的动物可以免受野生型病毒的攻击。然而，直到最近，人们对于免疫反应的哪些特定成分对于这种保护很重要还知之甚少。我们报道说，CD4 T 细胞耗尽的小鼠在感染 Del NSs 病毒后患上了脑炎，这表明 CD4 T 细胞的某些功能对于提供针对这种病毒的保护很重要。在本提案中，我们将首先确定 CD4 耗竭小鼠中 Del NSs 脑炎的机制（病毒与免疫介导）。然后，由于至少有 5 种不同类型的 CD4 T 细胞具有不同的作用，我们将表征 Del NS 感染期间激活和发挥作用的 CD4 T 细胞亚群，并开始单独检查每个亚群，以确定它们如何有助于预防脑炎。最后将明确 B 细胞和抗体在预防脑炎方面的作用。这些实验将在小鼠模型中建立针对 RVFV 免疫的相关性。这些数据将用于设计未来的研究，旨在检查人类保护的免疫相关性。