An Immune Surveillance Network in C. elegans

项目摘要 激活先天免疫防御的一种进化上古老的策略涉及监测免疫系统的变化。 细胞生理学，而不是病原体本身的存在。对这些机制的重要见解 来自于对线虫C.以细菌为食的秀丽线虫， “监测免疫”，以区分潜在的食物来源的病原体。虽然几个优雅的 已经描述了监视免疫的例子，感知细胞内病原体的宿主蛋白， 激活保护性宿主应答的相关配体是未知的。作为解决这个问题的关键的第一步 问题，我们已经确定了一个细胞监视网络，协调免疫效应诱导C。 优雅这些数据提供了一个新的范例，免疫途径是如何在肠上皮细胞激活， 后生动物宿主的细胞。这项建议的核心假设是，一个由以下人员组成的监视网络 核激素受体（NHRs）起着小分子毒素（或其 影响），并参与保护性免疫反应。为了支持这一假设，我们提出了几个关键问题。 观察提供了拟议工作的基本原理：（i）一种免疫刺激性小分子，称为 R24通过与已知的先天免疫效应不同的机制引起免疫效应子的强烈诱导。 免疫途径，但依赖于保守的转录调节因子MDT-15/MED 15。(ii)单个 NHR是细胞网络中的中央调节器，该细胞网络调查肠上皮细胞的外源性毒素。 我们已经证明，这种NHR通过物理相互作用驱动保护性防御反应的诱导， MDT-15 (iii)一种特定的脂肪酸，其合成受MDT-15的调节，是诱导所必需的。 免疫防御系统。在这项提案中，我们将描述一个监控网络，激活免疫 毒素暴露后的防御（目标1）。我们将定义脂肪酸信号在控制 免疫激活（目标2）。我们将确定免疫监视网络是否在局部范围内起作用， 肠上皮细胞或全身介导病原体防御（目的3）。监督调节机制 免疫是后生动物中病原体检测的最原始形式之一， 人类因此，我们期望这些研究的启示，在C。秀丽线虫将揭示进化 哺乳动物免疫激活、毒素识别和细胞内稳态的保守策略 免疫力

PROJECT SUMMARY An evolutionarily ancient strategy to activate innate immune defenses involves monitoring for changes in cellular physiology, rather than the presence of pathogens themselves. Key insights into these mechanisms have come from studies in the nematode C. elegans, which consume bacteria for food, and rely on “surveillance immunity” to discriminate pathogens from potential food sources. Although several elegant examples of surveillance immunity have been described, the host proteins that sense intracellular pathogen- associated ligands to activate protective host responses are not known. As a critical first step to solving this problem, we have identified a cellular surveillance network that coordinates immune effector induction in C. elegans. These data offer a new paradigm of how immune pathways are activated in the intestinal epithelial cells of a metazoan host. The central hypothesis of this proposal is that a surveillance network composed of nuclear hormone receptors (NHRs) functions an intracellular monitor for small molecule toxins (or their effects) and engages protective immune responses. In support of this hypothesis, we have made several key observations that provide the rationale for the proposed work: (i) An immunostimulatory small molecule called R24 causes the robust induction of immune effectors via a mechanism that is distinct from known innate immune pathways, but is dependent on the conserved transcriptional regulator MDT-15/MED15. (ii) A single NHR is the central regulator in a cellular network that surveys intestinal epithelial cells for xenobiotic toxins. We have shown that this NHR drives the induction of protective defense responses by physically interacting with MDT-15. (iii) A specific fatty acid, whose synthesis is regulated by MDT-15, is required for the induction of immune defenses. In this proposal, we will characterize a surveillance network that activates immune defenses following toxin exposure (Aim 1). We will define the role of the fatty acid signal in controlling immune activation (Aim 2). We will determine whether the immune surveillance network acts locally within intestinal epithelial cells or systemically in mediating pathogen defense (Aim 3). Mechanisms of surveillance immunity are among the most primitive forms of pathogen detection in metazoans, and are conserved in humans. Thus, it is our expectation that insights from these studies in C. elegans will reveal evolutionary conserved strategies of immune activation, toxin recognition and cellular homeostasis in mammalian immunity.