Flagellin, the protein subunit of the bacterial flagellum, stimulates the innate immune receptor Toll-like receptor 5 (TLR5) after pattern recognition or evades TLR5 through lack of recognition. This binary response fails to explain the weak agonism of flagellins from commensal bacteria, raising the question of how TLR5 response is tuned. Here, we screened abundant flagellins present in metagenomes from human gut for both TLR5 recognition and activation and uncovered a class of flagellin-TLR5 interaction termed silent recognition. Silent flagellins were weak TLR5 agonists despite pattern recognition. Receptor activity was tuned by a TLR5-flagellin interaction distal to the site of pattern recognition that was present in Salmonella flagellin but absent in silent flagellins. This interaction enabled flagellin binding to preformed TLR5 dimers and increased TLR5 signaling by several orders of magnitude. Silent recognition by TLR5 occurred in human organoids and mice, and silent flagellin proteins were present in human stool. These flagellins were produced primarily by the abundant gut bacteria Lachnospiraceae and were enriched in nonindustrialized populations. Our findings provide a mechanism for the innate immune system to tolerate commensal-derived flagellins while remaining vigilant to the presence of flagellins produced by pathogens.

中文翻译：

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Toll 样受体 5 对人肠道共生菌鞭毛蛋白的沉默识别

鞭毛蛋白是细菌鞭毛的蛋白质亚基，在模式识别后刺激先天免疫受体 Toll 样受体 5 (TLR5) 或通过缺乏识别来逃避 TLR5。这种二元反应无法解释来自共生细菌的鞭毛蛋白的弱激动作用，提出了如何调整 TLR5 反应的问题。在这里，我们筛选了人类肠道宏基因组中存在的大量鞭毛蛋白，用于 TLR5 识别和激活，并发现了一类称为沉默识别的鞭毛蛋白-TLR5 相互作用。尽管有模式识别，但沉默的鞭毛蛋白是弱的 TLR5 激动剂。受体活性由位于模式识别位点远端的 TLR5-鞭毛蛋白相互作用调节，存在于沙门氏菌鞭毛蛋白，但在沉默的鞭毛蛋白中不存在。这种相互作用使鞭毛蛋白能够与预先形成的 TLR5 二聚体结合，并将 TLR5 信号增加几个数量级。TLR5 的沉默识别发生在人类类器官和小鼠中，沉默鞭毛蛋白存在于人类粪便中。这些鞭毛蛋白主要由丰富的肠道细菌 Lachnospiraceae 产生，并在非工业化种群中富集。我们的研究结果为先天免疫系统提供了一种机制来耐受共生衍生的鞭毛蛋白，同时对病原体产生的鞭毛蛋白的存在保持警惕。