Heterologous immunity and host susceptibility to emerging alphaviral infections

 描述(申请人提供)：节肢动物传播的病毒(虫媒病毒)在世界范围内对公共卫生和兽医具有重要意义，过去几十年来，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证明了这一点。城市化、移民和砍伐森林等驱动因素被认为是虫媒病毒病出现的根本原因。寄主易感性也被认为在决定一些虫媒病毒病的地理分布中起着关键作用，但这一重要因素对虫媒病毒病的贡献和机制尚未得到很好的研究。我们的目标是测量人类甲型病毒感染中可能影响宿主易感性的交叉反应程度，并阐明其背后的机制。在这个项目中要检验的中心假设是，异种免疫在甲型病毒感染中是保护性的，通过Fc受体介导的效应功能介导的非中和抗体。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，因此有可能迅速激活以防止疾病感染。我们建议通过检测血清抗体和记忆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，使用来自巴拿马达里安的银行标本。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(两者都属于甲型病毒属Togaviridae)。更多的甲型病毒，马雅罗病毒(MAYV)和现已大流行的基孔肯雅病毒(CHIKV)尚未在该区域出现，但即将出现，这增加了了解虫媒病毒疾病中异源免疫的必要性。这一假设将在两个特定的目标下进行检验：1.通过FCR介导的效应器功能和中和，确定VEEV暴露者与甲型病毒未感染者之间的异源免疫程度；2.通过检测纵向样本中的抗原特异性记忆B细胞(MBCs)和交叉反应的血清和MBC衍生抗体来评估体液免疫的持久性。该项目将在具有互补专业知识的世界级指导团队的指导下，提供病毒病原体-宿主免疫学方面的深入职业发展经验。多方面的培训计划包括严格的实验室部分，免疫学和传染病建模方面的国际知名课程，以及职业指导。如果成功，这项研究将为甲型病毒免疫反应提供新的见解，可用于疾病建模工作，以检查异种免疫对疾病出现的影响。这些见解还将直接应用于单抗治疗和疫苗开发。

 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.