Investigations upon the virus-host interaction of the bluetongue disease

相同致病性病毒的感染可导致不同宿主的不同临床结果，从亚临床感染到致死性疾病，直到现在还缺乏对这种显著差异的潜在机制的理解。蓝舌病是由蓝舌病病毒（BTV）引起的反刍动物的主要疾病之一。感染宿主蓝舌病的临床结果在反刍动物之间差异很大。BTV感染的绵羊（"易感"宿主）可表现出严重的、有时致命的疾病过程，而奶牛（"适应性"宿主）尽管表现出高水平的病毒血症，但仅表现出轻微的症状。这项提议旨在解决一个根本问题：致病病毒如何使一些受感染的宿主生病，而另一些宿主只显示轻微或没有疾病（尽管病毒在两个宿主中都有大量复制）？BTV感染的临床结局将在病毒复制、先天免疫系统和适应性免疫应答（牛）和易感物种（羊）之间复杂相互作用的背景下进行评价。为了达到这一目标，计划在实验BTV感染的牛和羊中研究干扰素系统，以表征物种差异以及潜在的分子决定因素。应用RNA和蛋白质水平分析不同细胞类型的干扰素产生。将通过感染动物内皮细胞的RNA测序评价基因表达的比较分析。将比较确定感染牛和羊的不同器官的形态变化以及病毒复制、病毒血症、抗体产生和特异性。在蓝舌病期间局部淋巴结的滤泡树突状细胞的感染和细胞功能的丧失代表了研究的中心目标。获得的结果总是与两个物种的临床数据相关。本研究的第一个和第二个模块是比较研究感染的早期阶段，重点是BTV感染的细胞类型，病毒复制和干扰素的产生。在第二个模块中，也解决了BTV感染的早期阶段的结束，病毒诱导的内皮细胞损伤的机制进行了分析。在研究的第三个模块中，体液免疫应答以及疾病恢复阶段的形态和分子变化是研究的中心。这种方法将使我们能够以前所未有的规模解剖自然发生的虫媒病毒感染，通过系统地关联两个不同物种的病毒复制，适应性和获得性免疫反应，病理学和临床症状。此外，本研究还将提供有关感染早期宿主干扰素系统影响虫媒病毒感染临床进程的程度的信息。

Infections by the same pathogenic virus can result in variable clinical outcomes in different hosts, from subclinical infections to fatal disease, until now there is a lack of understanding the underlying mechanisms of such remarkable differences. Bluetongue is one of the major diseases of ruminants caused by Bluetongue virus (BTV), an arbovirus transmitted by biting midges. The clinical outcome of bluetongue in the infected host varies considerably between ruminants. BTV infected sheep ("susceptible" hosts) can show a severe, at times lethal, course of the disease while cows (“resilient” hosts), show only mild symptoms despite displaying high levels of viremia. This proposal aims to address a fundamental issue: how can a pathogenic virus make some infected hosts ill, while others display only mild or no disease (despite abundant virus replication in both hosts)? The clinical outcome of BTV infection will be evaluated in the context of the complex interplay between viral replication, the innate immune system, and the adaptive immune response of resilient (cows) and susceptible species (sheep). To reach this aim, it is planned to investigate the interferon system in experimentally BTV-infected cattle and sheep in order to characterize species differences as well as underlying molecular determinants. The interferon production of different cell types will be analysed on RNA and protein-level applying. The comparative analysis of gene expression will be evaluated by using RNA sequencing of endothelial cells in infected animals. Morphological changes in different organs of infected cows and sheep will be comparatively determined as well as viral replication, viremia, antibody-production and -specificity. Infection of the follicular dendritic cells of the regional lymph nodes during bluetongue disease and the loss of function of the cells represents a central goal of the study. Obtained results are always correlated with clinical data of both species. The first and second module of this study is comparatively examining the early phase of the infection focusing on BTV-infected cell types, viral replication and interferon production. In the second module, which also addresses the end of the early phase of BTV-infection, the mechanisms of virus-induced endothelial cell damage are analyzed. In the third module of the investigation the humoral immune response as well as morphologcial and molecular changes during the recovery phase of the disease are at the center of the investigation. This approach will allow us to dissect a naturally occurring arbovirus infection at an unprecedented scale by systematically correlating viral replication, adaptive and acquired immune response, pathology and clinical symptoms in two different species. In addition, this study will provide information on the extent to which the host interferon system during the early stages of infection influences the clinical course of arboviral infection.