Heterologous immunity and host susceptibility to emerging alphaviral infections

 描述（由申请方提供）：节肢动物传播的病毒（虫媒病毒）在全球范围内的公共卫生和兽医学方面的重要性日益增加，如过去几十年中西尼罗河、裂谷、登革热、基孔肯雅热、委内瑞拉马脑炎和日本脑炎等病毒的地理范围扩大和发病率上升所证明的。城市化、移民和森林砍伐等驱动因素被认为是虫媒病毒疾病出现的根本原因。宿主易感性也被推测在确定一些虫媒病毒疾病的地理分布中起关键作用，但是对于虫媒病毒疾病，这个重要因素的贡献和机制还没有得到很好的研究。我们的目标是测量人类甲病毒感染中可能影响宿主易感性的交叉反应性程度，并阐明其潜在机制。本项目中待检验的中心假设是，异源免疫在甲病毒感染中具有保护性，由通过Fc受体介导的效应子功能发挥作用的非中和抗体介导。这些机制作为适应性体液反应和先天免疫反应之间的桥梁，因此，有可能被迅速激活，以防止疾病的获得。我们建议通过检查血清抗体和记忆B细胞对异源病毒的交叉反应来研究这些机制。我们有一个独特的机会来研究这些机制使用库标本从达连，巴拿马。2010年，东部马脑炎病毒（EEEV）在该地区新出现，已知是委内瑞拉马脑炎病毒（VEEV）的地方病（两者都是披膜病毒科甲病毒属的成员）。其他甲病毒，马亚罗（MAYV）和现在流行的基孔肯雅病毒（CHIKV），尚未出现在该地区，但准备这样做，增加了迫切需要了解虫媒病毒疾病的异源免疫。该假设将在两个具体目标中进行检验：1.通过FcR介导的效应子功能和中和作用，确定VEEV暴露受试者与甲病毒初治受试者的异源免疫程度; 2.通过检测纵向样本中抗原特异性记忆B细胞（MBC）和交叉反应性血清和MBC衍生抗体，评估体液免疫的持久性。该项目将提供病毒病原体宿主免疫学方面的密集职业发展经验，并由具有互补专业知识的世界级指导团队提供指导。多方面的培训计划包括严格的实验室组成部分，免疫学和传染病建模的国际知名课程，以及职业指导。如果成功，这项研究将为甲病毒免疫反应提供新的见解，这些免疫反应可以用于疾病建模工作，以研究异源免疫对疾病发生的影响。这些见解也将直接应用于单克隆抗体治疗和疫苗开发。

 DESCRIPTION (provided by applicant): Arthropod-borne viruses (arboviruses) have gained in public health and veterinary importance worldwide, as demonstrated by the expansion of geographic range and rising incidence of viruses such as West Nile, Rift Valley, dengue, Chikungunya, Venezuelan equine encephalitis and Japanese encephalitis during the past decades. Drivers such as urbanization, migration, and deforestation have been implicated as underlying causes for arboviral disease emergence. Host susceptibility has also been speculated to play a key role in determining the geographic distribution of some arboviral diseases, but the contribution and mechanism of this important factor has not been well studied for arboviral diseases. It is our objective to measure the degree of cross-reactivity in human alphaviral infections which may impact host susceptibility and to elucidate the mechanisms underlying this. The central hypothesis to be tested in this project is that heterologous immunity is protective in alphaviral infection, mediated by non-neutralizing antibodies acting via Fc receptor-mediated effector functions. These mechanisms act as a bridge between the adaptive humoral response and the innate immune response, and as such, have the potential to become activated quickly to prevent disease acquisition. We propose studying these mechanisms by examining serum antibody and memory B-cell cross-reactivity to heterologous virus. We have a unique opportunity to study these mechanisms using banked specimen from Darien, Panama. In 2010, eastern equine encephalitis virus (EEEV) newly emerged in this region known to be endemic for Venezuelan equine encephalitis virus (VEEV) (both are members of the Alphavirus genus, family Togaviridae). Additional alphaviruses, Mayaro (MAYV) and the now-pandemic Chikungunya (CHIKV), have not yet emerged in this region, but are poised to do so, adding urgency to the need to understand heterologous immunity in arboviral disease. The hypothesis will be tested in two Specific Aims: 1. Determine the extent of heterologous immunity in VEEV-exposed versus alphavirus-naïve subjects via FcR-mediated effector functions and neutralization; 2. Assess durability of humoral immunity by detection of antigen-specific memory B-cells (MBCs) and cross-reactive serum- and MBC-derived antibodies in longitudinal samples. This project will provide intensive career development experience in viral pathogen-host immunology with guidance from a world-class mentoring team with complementary expertise. The multi-faceted training plan includes a rigorous laboratory component, courses of international repute in immunology and infectious disease modeling, and career guidance. If successful, this study will provide novel insights into alphaviral immune responses that can be harnessed in disease modeling efforts to examine implications of heterologous immunity for disease emergence. These insights will also have direct application for monoclonal antibody therapeutics and vaccine development.