Immune Correlates of Protection form Rift Valley Fever Virus

 求职者：我拥有医学博士学位，是一名儿科传染病内科医生和基础科学家。我职业生涯中的每一步都集中在成为一名内科科学家的目标上。我正处于我的第一次教职任命的开始，并发现这一次是我有机会扩大我在免疫学领域的技能的唯一一次机会。在K08获奖期间，我的主要目标是发展最先进的实验免疫学专业知识。我将在几位病毒学家和免疫学家的指导下，在拟议的研究项目的背景下，通过教学指导实现这一点，该研究项目旨在研究CD4T细胞在预防裂谷热病毒脑炎中的作用。我的主要导师，医学博士保罗·斯皮尔曼是一名病毒免疫学家，也是一名内科科学家和我的部门主任。作为一名职业和科学导师，他将指导我在获奖期间的研究进展，促进咨询委员会会议，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年里，我计划利用这些新获得的技能来确立自己的专家地位。 在研究宿主免疫反应和新出现的病毒之间的相互作用。环境：我的任命是在埃默里大学医学院儿科儿科传染病科。在2014年美国国立卫生研究院儿科资助排名中，埃默里大学儿科排名第九。该部门在支持初级内科科学家方面有既定的记录。我在埃默里有很多资源可以用来进行研究和职业发展。这些实验将在美国疾病控制和预防中心的BSL-3E空间进行，我在那里担任病毒特殊病原体分部的客座研究员，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，可在非洲和中东的人和动物中引起疾病。在过去的几年里，已经有几种新的减毒活疫苗可用于家畜。所有这些疫苗的减毒基础是病毒毒力因子NSS的删除/修改。这些Del NSS病毒在动物中产生保护性免疫反应，因为接种疫苗的动物受到保护，免受野生型病毒的攻击。然而，直到最近，关于免疫反应的哪些特定成分对这种保护是重要的，人们知之甚少。我们报道，在感染Del NSS病毒后，耗尽其CD4T细胞的小鼠出现脑炎，这表明CD4T细胞的某些功能对于提供对该病毒的保护很重要。在这项建议中，我们将首先确定(病毒和免疫介导的)Del NSS脑炎在CD4耗尽小鼠中的机制。然后，由于至少有5种不同类型的CD4T细胞具有不同的作用，我们将描述在Del NSS感染期间激活和功能正常的CD4T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，我们将明确B细胞和抗体在预防脑炎中的作用。这些实验将在小鼠模型中建立对抗RVFV的免疫关联。这些数据将被用来设计未来的研究，目标是检查人类免疫保护的相关性。

 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.