An Immune Surveillance Network in C. elegans

项目总结 肠道上皮细胞保护宿主免受病原体侵袭，防止过度的炎症反应 会造成连带伤害。定义调节肠道炎症的细胞机制是一种 关键的第一步是发现可以操纵这些生理过程的治疗靶点 东道主的优势。核激素受体是配体激活的转录因子，调节 新陈代谢和细胞生理学的许多其他方面。然而，人们对核能是如何形成的知之甚少 激素受体影响肠道炎症或对细菌病原体的先天识别。在C。 与其他后生动物相比，精美动物的核激素受体家族已经大幅扩大， 尤其是那些与人类肠道核激素受体肝细胞核同源的基因 因子4(HNF4)。因此，这些蛋白质可能在线虫生理学中起着关键作用。在这场竞争中 更新应用，我们的目标是确定核激素受体如何调节免疫激活和 病原菌抗性。我们将测试概念上的创新假设，核激素受体 作为病原体传感器，直接激活肠道上皮细胞的天然免疫防御。C。 线虫似乎不依赖典型的模式识别受体(例如，Toll样受体)来感知 病原体感染和激活肠道上皮细胞的免疫防御。因此，我们的关键含义是 研究结果是线虫的核激素受体家族扩大了，至少部分是因为它们的 在病原体检测和免疫调节中的作用。 在第一个资助期，我们确定了一种哺乳动物HNF4的同源物，它研究了化学环境 并激活抗病原体免疫防御系统。在这项竞争性续订申请中，我们将测试 概念上的创新假设是通过这个核来感知病原体衍生的细菌代谢物 激素受体是线虫用来检测其体内产毒病原体的一种古老机制。 已经发展到危险水平并可能导致疾病的环境(目标1)。在目标2中，我们将 确定病原体衍生的代谢物是否是NHR-86的天然配体，直接与NHR-86结合并激活 这种核激素受体，这一努力将成为第一个真正的天然免疫模式的特征 线虫识别受体及其天然配体和去孤儿核激素受体。最后，在 目的3，我们将表征另一个HNF4同源物在先天性免疫中的作用，这将为我们提供重要的 支持这种蛋白质家族成员作为病原体感受器在 缺乏典型的模式识别机制的有机体。 这项拟议的研究将揭示对以前未被认识的、进化的古代 免疫激活和调节策略对天然免疫的研究具有广泛的意义 在所有后生动物中。

PROJECT SUMMARY Intestinal epithelial cells protect the host from pathogens and prevent exaggerated inflammatory responses that cause collateral injury. Defining the cellular mechanisms that regulate intestinal inflammation is an essential first step to uncover therapeutic targets that can manipulate these physiological processes to the host's advantage. Nuclear hormone receptors are ligand-activated transcription factors that regulate metabolism and many other aspects of cellular physiology. However, little is known about how nuclear hormone receptors influence intestinal inflammation or the innate recognition of bacterial pathogens. In C. elegans, the family of nuclear hormone receptors has dramatically expanded compared to other metazoans, particularly those that are homologous to the human intestinal nuclear hormone receptor hepatocyte nuclear factor 4 (HNF4). These proteins may, therefore, have critical roles in nematode physiology. In this competitive renewal application, we aim to determine how nuclear hormone receptors regulate immune activation and pathogen resistance. We will test the conceptually innovative hypothesis that nuclear hormone receptors function as pathogen sensors that directly activate innate immune defenses in intestinal epithelial cells. C. elegans does not seem to rely on canonical pattern recognition receptors (e.g., Toll-like receptors) to sense pathogen infection and activate immune defense in intestinal epithelial cells. Thus, the key implication of our findings is that the nuclear hormone receptor family in C. elegans expanded, at least in part, because of their function in pathogen detection and immune regulation. In the first funding period, we identified a homolog of mammalian HNF4 that surveys the chemical environment and activates anti-pathogen immune defenses. In this competitive renewal application, we will test the conceptually innovative hypothesis that sensing of a pathogen-derived bacterial metabolite by this nuclear hormone receptor is an ancient mechanism utilized by C. elegans to detect toxigenic pathogens in its environment that have grown to dangerous levels and are poised to cause disease (Aim 1). In Aim 2, we will determine if this pathogen-derived metabolite is a natural ligand for NHR-86 that directly binds to and activates this nuclear hormone receptor, an effort that will characterize the first bona fide innate immune pattern recognition receptor and its natural ligand in C. elegans and de-orphan a nuclear hormone receptor. Finally, in Aim 3, we will characterize the role of another HNF4 homolog in innate immunity, which will provide important support for the innovative idea that members of this protein family function as pathogen sensors in an organism that lacks canonical mechanisms of pattern recognition. The proposed study will reveal fundamental insights into previously unrecognized, evolutionary ancient strategies of immune activation and regulation that will have broad implications for the study of innate immunity in all metazoans.