Non-canonical pattern recognition of a pathogen-derived metabolite by a nuclear hormone receptor identifies virulent bacteria in C. elegans
Non-canonical pattern recognition of a pathogen-derived metabolite by a nuclear hormone receptor identifies virulent bacteria in C. elegans
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DOI：
10.1016/j.immuni.2023.01.027
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发表时间：
2023-04-11
期刊：
影响因子：
32.4
通讯作者：
Pukkila-Worley，Read
中科院分区：
文献类型：
--
作者：
Peterson，Nicholas D.;Tse，Samantha Y.;Pukkila-Worley，Read
区分感染性病原体和无害微生物对动物健康至关重要。用于识别感染性微生物的机制还不完全清楚，特别是在以细菌为食物来源的后生动物宿主中。在这里，我们描述了一个非规范的模式识别系统在秀丽隐杆线虫中，它评估了毒力铜绿假单胞菌激活天然免疫的相对威胁。我们发现先天免疫反应是由致病菌株OFP产生的有毒代谢物吩嗪-1-甲酰胺(PCN)触发的。我们将核激素受体NHR-86/HNF4鉴定为PCN传感器Inc.，并验证了PCN与NHR-86/HNF4的配体结合域结合。PCN激活NHR-86/HNF4直接参与肠上皮细胞的转录程序，该程序可保护肠道上皮细胞免受铜绿假单胞菌的感染。因此，细菌代谢物是一种由线虫监测的致病模式，以识别其细菌饮食中的病原体。
Distinguishing infectious pathogens from harmless microorganisms is essential for animal health. The mechanisms used to identify infectious microbes are not fully understood, particularly in metazoan hosts that eat bacteria as their food source. Here, we characterized a non-canonical pattern-recognition system inCaenorhabditis elegans(C. elegans) that assesses the relative threat of virulentPseudomonas aeruginosa(P. aeruginosa) to activate innate immunity. We discovered that the innate immune response inC. eleganswas triggered by phenazine-1-carboxamide (PCN), a toxic metabolite produced by pathogenic strains ofP. aeruginosa. We identified the nuclear hormone receptor NHR-86/HNF4 as the PCN sensor inC. elegansand validated that PCN bound to the ligand-binding domain of NHR-86/HNF4. Activation of NHR-86/HNF4 by PCN directly engaged a transcriptional program in intestinal epithelial cells that protected againstP. aeruginosa. Thus, a bacterial metabolite is a pattern of pathogenesis surveilled by nematodes to identify a pathogen in its bacterial diet.