Clasen Sara J, Bell Michael E W, Borbón Andrea, Lee Du-Hwa, Henseler Zachariah M, de la Cuesta-Zuluaga Jacobo, Parys Katarzyna, Zou Jun, Wang Yanling, Altmannova Veronika, Youngblut Nicholas D, Weir John R, Gewirtz Andrew T, Belkhadir Youssef, Ley Ruth E
Department of Microbiome Science, Max Planck Institute for Biology, Tübingen 72076, Germany.
Gregor Mendel Institute (GMI), Austrian Academy of Sciences, Vienna BioCenter (VBC), Dr. Bohr-Gasse 3, Vienna, Austria.
Sci Immunol. 2023 Jan 6;8(79):eabq7001. doi: 10.1126/sciimmunol.abq7001.
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 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.
鞭毛蛋白是细菌鞭毛的蛋白质亚基，在模式识别后刺激天然免疫受体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共生菌鞭毛蛋白的弱激动作用，这就提出了TLR5反应是如何调节的问题。在这里，我们从人类肠道宏基因组中筛选了大量存在的鞭毛蛋白，以研究其对TLR5的识别和激活情况，并发现了一类称为沉默识别的鞭毛蛋白-TLR5相互作用。沉默鞭毛蛋白尽管能被模式识别，但却是弱TLR5激动剂。受体活性是由模式识别位点远端的TLR5-鞭毛蛋白相互作用调节的，这种相互作用存在于鞭毛蛋白中，而沉默鞭毛蛋白中不存在。这种相互作用使鞭毛蛋白能够结合预先形成的TLR5二聚体，并使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毛螺菌科产生，在非工业化人群中含量丰富。我们的研究结果为天然免疫系统耐受共生菌来源的鞭毛蛋白，同时对病原体产生的鞭毛蛋白保持警惕提供了一种机制。
