Kinetics and immunology of early Ebola virus infection (PREVIREMIX)

埃博拉病毒（EBOV）是最近在西非和中非流行的埃博拉病毒病（EVD）的病原体，并且在过去40年中在非洲引起严重出血热的暴发。人感染人畜共患病来源或暴露于其他受感染的人涉及直接接触受感染的体液和污染物，因此，需要皮肤和粘膜表面的初始病毒感染。一旦建立了初始感染，病毒需要传播到次级淋巴器官和血液，从而引起多器官疾病。在最近的西非疫情期间收集的大量数据表明，EVD的结果在很大程度上与病毒的系统性传播能力和在宿主体内维持高水平复制的能力相关。然而，EBOV从其入口进入血液的机制完全未知。该提案的目的是研究EBOV感染的动力学和从感染的初始部位到血液的传播。我们的模型系统将是分别保留野生型鼠和人造血、人细胞和组织的嵌合和人源化小鼠。我们将使用多参数和综合方法，包括Prime Flow RNA检测、多参数流式细胞术和质谱仪以及基因组学。主要目标将是识别早期病毒靶细胞，并确定迁移性树突状细胞对病毒传播和T细胞介导的免疫的作用。

Ebola virus (EBOV) is the etiological agent of the recent Ebola virus disease (EVD) epidemics in West and Central Africa and has caused outbreaks of severe hemorrhagic fever in Africa for the last 40 years. Human infection from either a zoonotic source of from exposure to other infected humans involves direct contact with infected body fluids and fomites, and therefore, requires initial virus infection of skin and mucosal surfaces. Once, initial infection is established, the virus needs to spread to secondary lymphoid organs and the blood, thereby causing a multiorganic disease. A wealth of data gathered during the recent West African outbreak, indicate that EVD outcome is correlated to a great extent with the ability of the virus to spread systemically and sustain high levels of replication within the host. However, the mechanisms by which EBOV travels from its portals of entry to the blood are entirely unknown. The goal of this proposal is to study the kinetics of EBOV infection and dissemination from the initial sites of infection to the blood. Our model systems will be chimeric and humanized mice retaining wild type murine and human hematopoiesis respectively, human cells and tissues. We will use a multiparametric and integrative approach including Prime Flow RNA assays, multiparamertric flow and mass cytometry and genomics. Major objectives will be to identify early virus target cells and to determine the role of migratory dendritic cells on virus dissemination and T-cell mediated immunity.