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

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。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不同类别的传感器(称为模式识别受体(PRRs))之间的相互作用，是通过复杂的信号级联网络触发潜在的先天免疫反应的第一个事件。这项建议的总体目标是深入了解泡沫病毒(FV)感染所涉及的先天感知机制和潜在的病原体逃避策略。FV是最古老的逆转录病毒之一，与它们的自然宿主共同进化，是非人类灵长类动物、猫、牛和马的地方病。FV在基因治疗策略中很有希望成为基因转移载体，其特点是在自然宿主和人畜共感染的人类中表现出明显的无致病性。目前对体内控制FV复制的免疫学机制知之甚少，这可能与FV感染的良性性质有关。通过开发一种新的FV载体系统，使病毒能够在组织中进行受调控的、有条件的复制，结合使用已建立的和特征良好的复制缺陷或复制能力FV载体系统，我们想要检查病毒与两种相关免疫细胞类型，即单核/巨噬细胞和浆细胞样树突状细胞(PDCs)中的天然免疫系统的相互作用。这项建议的重点是以灵长类和猫科动物FV为模型系统，阐明FV结构成分在单核/巨噬细胞和PDC来源的细胞系和原代细胞中刺激或能够刺激的潜在先天感知通路的细节。此外，还应发现FVS开发的先天感知的潜在规避策略。通过使用遗传、生化、免疫学和成像技术的组合，我们打算识别病毒结构、细胞传感器和必要的条件，这些是在病毒在这些免疫细胞中复制的进入和病毒形态形成步骤中启动先天免疫反应所必需的。

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.