Detection of intestinal pathogens through host surveillance of bacterial toxins

项目摘要/摘要 虽然共生菌和病原菌可以被宿主模式识别受体识别， 肠上皮细胞通过以下途径靶向对病原体的保护性炎症反应 不完全了解的机制。必须存在病原体感知的其他机制 允许肠道细胞在感染期间针对真正的病原体进行炎症防御，而不是 无害的共生细菌。病原菌可以表达毒力决定因素。奋乃静毒素是 氧化还原活性毒力决定因素家族，由多种人类病原体产生，包括P. 铜绿假单胞菌。铜绿假单胞菌可定植于免疫功能低下患者的肠道并引起暴发性 败血症和随后的死亡。肠道上皮细胞检测铜绿假单胞菌的机制，以及 这是否涉及吩嗪毒素的监测，目前尚不清楚。核激素受体(NHR)是 转录因子，在识别特定的外源基因或基因后对适应性宿主反应进行编程 内源性配体。特别是，HNF4NHR是一种在肠道中表达的⍺。在模式生物C. 线虫，hNF4⍺同源基因nhr-86是天然免疫效应转录激活所必需的 保护铜绿假单胞菌免受感染的基因。这一提议的中心假设是肠道 上皮细胞通过NHR-86监测病原体衍生的吩嗪毒素来检测感染 HNF4⍺，它直接激活肠道上皮细胞的保护性抗病原体防御。以下是 关键的初步发现支持这一中心假设：i)不能产生吩嗪的铜绿假单胞菌突变株 毒素不会激活线虫的天然免疫防御；ii)合成的吩嗪毒素可以激活免疫 基因；iii)吩嗪毒素对免疫基因的诱导依赖于NHR-86/ HNF4⍺。在这项提案中，目标1将描述线虫对细菌吩嗪的免疫反应。 Aim 2将确定肠道NHR-86/HNF4⍺在检测铜绿假单胞菌感染中的作用。 优雅女装。本文提出的研究将定义肠道上皮细胞免疫激活的新概念 并将为NHR在肠道病原体感知方面发挥新的作用。从这些方面获得的见解 研究结果可能确定开发抗炎和抗感染药物的未探索方法 治疗。

PROJECT SUMMARY/ABSTRACT Although commensal and pathogenic bacteria can be recognized by host pattern recognition receptors, intestinal epithelial cells target protective inflammatory responses towards pathogenic organisms through mechanisms that are incompletely understood. Additional mechanisms of pathogen sensing must exist that allow intestinal cells to target inflammatory defenses towards bona fide pathogens during an infection, and not harmless commensal bacteria. Pathogenic bacteria can express virulence determinants. Phenazine toxins are a family of redox active virulence determinants that are produced by a variety of human pathogens, including P. aeruginosa. P. aeruginosa can colonize the intestines of immunocompromised patients and cause fulminant septicemia and subsequent death. The mechanism by which intestinal epithelial cells detect P. aeruginosa, and whether this involves the surveillance of phenazine toxins, is not known. Nuclear hormone receptors (NHR) are transcription factors that program adaptive host responses following recognition of specific exogenous or endogenous ligands. In particular, HNF4⍺ is an NHR expressed in the intestine. In the model organism C. elegans, the HNF4⍺ homolog NHR-86 is required for the transcriptional activation of innate immune effector genes that protect against P. aeruginosa infection. The central hypothesis of this proposal is that intestinal epithelial cells detect infection through the surveillance of pathogen-derived phenazine toxins by NHR-86/ HNF4⍺, which directly activates protective anti-pathogen defenses in the intestinal epithelium. The following key preliminary findings support this central hypothesis: i) P. aeruginosa mutants that cannot make phenazine toxins do not activate C. elegans innate immune defenses; ii) synthetic phenazine toxins can activate immune genes; and iii) induction of immune genes by phenazine toxins is dependent on the expression of NHR-86/ HNF4⍺. In this proposal, Aim 1 will characterize the C. elegans immune response towards bacterial phenazine toxins, and Aim 2 will define the role of intestinal NHR-86/HNF4⍺ in detecting P. aeruginosa infection in C. elegans. The research proposed here will define a new concept of immune activation in intestinal epithelial cells and will also attribute a novel role for NHRs in pathogen sensing in the intestine. Insights from these findings may identify unexplored approaches for the development of anti-inflammatory and anti-infective therapies.