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病原体入侵的第一道防线之一。各种病原体编码结构（称为模式相关分子模式（PAMPs））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（PRRs））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反应的第一个事件。本研究的总体目的是深入了解泡沫病毒感染的先天感知机制和潜在的病原体逃避策略。fv是与其自然宿主共同进化的最古老的逆转录病毒之一，是非人灵长类动物、猫、牛和马的地方病。fv是基因治疗策略中有希望作为基因转移载体的候选者，其特点是它们在自然宿主和人畜共患疾病感染的人类中具有明显的致病性。关于控制FV在体内复制的免疫机制知之甚少，这可能是FV感染的良性性质的原因。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节的、有条件的复制，结合使用已建立的和具有良好特征的复制缺陷或复制能力的FV载体系统，我们想要检查病毒与两种相关免疫细胞类型的先天免疫系统的相互作用，即单核/巨噬细胞和浆细胞样树突状细胞（pDCs）。本研究以灵长类动物和猫科动物的FV为模型系统，阐明细胞系和单核/巨噬细胞和pDC来源的原代细胞中FV结构成分刺激或可以刺激的潜在先天感知通路的细节。此外，本文还将揭示fv先天感知的潜在规避策略。通过结合遗传学、生物化学、免疫学和成像技术，我们打算确定病毒结构、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中产生先天免疫反应所必需的条件。

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.