Hydra as an Antiviral Innate Immunity Model System

描述(由申请人提供)：在机体、细胞和分子水平上了解宿主-病毒相互作用对于减轻病毒发病至关重要。该项目的目标是在模式生物Hydra中发现病毒微生物组和特定的抗病毒免疫基因。通过这样做，我们将确定九头蛇是否含有类似人类病毒的病毒，并能够测试九头蛇对病毒存在做出反应的特定免疫基因。九头蛇提供了一个理想的模型来测试这些宿主与病毒的相互作用，因为它们的组成简单，易于实验操作，而且它们的上皮细胞暴露在没有保护屏障的环境中。此外，九头蛇缺乏获得性免疫功能，不包含任何可移动的吞噬细胞，只利用粘液作为保护其上皮的手段。因此，Hydra特别适合于研究宿主病毒在粘膜上皮细胞的天然免疫。为此，该项目由两个具体目标组成：1.利用病毒元基因组学确定九头蛇病毒成分。2.)阐明在胞浆核酸存在的情况下九头蛇抗病毒的先天免疫反应。通过实现这两个目标，我们将识别导致九头蛇致病的病毒，以及识别类似导致人类致病的病毒。然后，这些病毒可以在这个先天免疫模型系统中进行测试。此外，通过识别对病毒感染有反应的九头蛇抗病毒基因，我们将通过基因敲除来操纵九头蛇，以确定哪些基因在限制病毒致病方面至关重要。 公共卫生相关性：将Hydra建立为一种抗病毒的粘膜天然免疫模式生物对人类健康非常重要，这一点从系统发育的遗传变异中得到了证明。古老的天然免疫基因参与了上皮性屏障慢性炎症性疾病的病因学，如克罗恩病、特应性皮炎和哮喘。这些多基因疾病的特点是黏膜的慢性复发性炎症。这种疾病状态和对它们的反应可以在九头蛇模型系统中研究。

DESCRIPTION (provided by applicant): Understanding host-viral interactions at the organismal, cellular, and molecular levels are vital in mitigating viral pathogenesis. The goals of this project are to discover the viral microbiome and specific antiviral immunity genes in the model organism Hydra. By doing so, we will determine whether Hydra contains viruses similar to human viruses as well as being able to test Hydra specific immunity genes responsive to viral presence. Hydra provides an ideal model to test these host-viral interactions because of their simplistic composition, their ease of experimental manipulation, and their epithelial exposure to the environment without a protective barrier. Further, Hydra lack adaptive immunity features, do not contain any motile phagocytic cells, and only utilize mucous as a means to preserve its epithelium. Therefore, Hydra is uniquely suited for the study of host-viral innate immunity at the mucosal epithelium. To establish this, the project consists of two specific aims: 1.) Determine the Hydra viral composition utilizing viral metagenomics. 2.) Elucidate the Hydra antiviral innate immune response in the presence of cytosolic nucleic acids. By accomplishing these two aims we will identify viruses that cause pathogenic conditions in Hydra as well as discern viruses that similarly cause human pathogenesis. These viruses can then be tested in this innate immunity model system. Further, by identifying the Hydra antiviral genes responsive to viral infection, we will manipulate the Hydra through gene knockdown, to determine which genes are vital in limiting viral pathogenesis. PUBLIC HEALTH RELEVANCE: Establishing Hydra as an antiviral mucosal innate immunity model organism is important for human health as demonstrated by genetic variants in phylogenetically ancient innate immune genes are involved in the etiology of chronic inflammatory diseases of the epithelial barrier, such as Crohn's disease, atopic dermatitis, and asthma. These polygenic diseases are characterized by chronic relapsing inflammation of the mucosa. Such disease states and the response to them can be studied in the Hydra model system.