Mechanisms of innate immune system sensing and evasion during foamy virus infections

泡沫病毒感染过程中先天免疫系统感知和逃避的机制

• 批准号: 318273940
• 负责人: Professor Dr. Dirk Lindemann
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie und Virolgie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/318273940?language=en
• 关键词: Mechanisms; innate; immune; system; sensing

The innate immune system of mammals is one of the first lines of defense against invading pathogens such a bacteria or viruses. The interaction between various pathogen encoded structures, referred to as pattern-associated molecular patterns (PAMPs), and different classes of sensors on the surface or within the host cells, called pattern recognition receptors (PRRs), are the first events that trigger a potential innate immune response, through a complex network of signal cascades. The overall aim of this proposal is to gain insight into the innate sensing mechanism and potential pathogen evasion strategies involved in infection by foamy viruses (FVs). FVs are one of the most ancient retroviruses having co-evolved with their natural hosts and are endemic to non-human primates, cats, cattle and horses. A hallmark of FVs, which are promising candidates as gene transfer vehicles in gene therapeutic strategies, is their apparent apathogenicity in natural hosts and also in zoonotically infected humans. Very little is known on the immunological mechanisms controlling FV replication in vivo, which might be responsible for the benign nature of FV infections. By developing a new FV vector system that enables a regulated, conditional virus replication in tissues, in combination with the use of established and well-characterized replication-deficient or replication competent FV vector systems, we want to examine interactions of the virus with the innate immune system in two relevant immune cell types, namely monocytes/macrophages and plasmacytoid dendritic cells (pDCs). The focus of this proposal is to elucidate the details of potential innate sensing pathways that are or can be stimulated by FV structural components in cell lines and primary cells of monocyte/macrophage and pDC origin, using primate and feline FVs as a model system. Furthermore, potential evasion strategies of innate sensing developed by FVs shall be uncovered. By using a combination of genetic, biochemical, immunologic and imaging techniques we intend to identify the viral structures, cellular sensors and required conditions that are necessary to mount an innate immune response during entry and virus morphogenesis steps of viral replication in these immune cells.

哺乳动物的先天免疫系统是抵御细菌或病毒等入侵病原体的第一道防线之一。各种病原体编码结构（称为模式相关分子模式（PAMP））与宿主细胞表面或内部的不同类型传感器（称为模式识别受体（PRR））之间的相互作用是通过复杂的信号级联网络触发潜在先天免疫应答的第一个事件。本提案的总体目标是深入了解泡沫病毒（FV）感染所涉及的先天传感机制和潜在的病原体逃避策略。FV是与其天然宿主共同进化的最古老的逆转录病毒之一，并且是非人灵长类动物、猫、牛和马特有的。FV是基因治疗策略中作为基因转移载体的有希望的候选物，其标志是其在天然宿主中以及在人畜共患感染的人类中的明显的无致病性。关于体内控制FV复制的免疫学机制知之甚少，这可能是导致FV感染的良性性质的原因。通过开发一种新的FV载体系统，该系统能够在组织中进行受调控的有条件的病毒复制，结合使用已建立的和充分表征的复制缺陷型或复制能力型FV载体系统，我们希望研究病毒与两种相关免疫细胞类型（即单核细胞/巨噬细胞和浆细胞样树突状细胞（pDC））中的先天免疫系统的相互作用。该提案的重点是阐明潜在的先天性传感途径的细节，这些途径是或可以被单核细胞/巨噬细胞和pDC来源的细胞系和原代细胞中的FV结构组分刺激，使用灵长类动物和猫FV作为模型系统。此外，潜在的逃避策略的先天感觉开发的FV将被发现。通过使用遗传学、生物化学、免疫学和成像技术的组合，我们打算鉴定病毒结构、细胞传感器和在这些免疫细胞中病毒复制的进入和病毒形态发生步骤期间安装先天免疫应答所必需的条件。