Hawn Thomas R, Verbon Annelies, Lettinga Kamilla D, Zhao Lue Ping, Li Shuying Sue, Laws Richard J, Skerrett Shawn J, Beutler Bruce, Schroeder Lea, Nachman Alex, Ozinsky Adrian, Smith Kelly D, Aderem Alan
Institute for Systems Biology, 1441 N. 34th St., Seattle, WA 98103, USA.
J Exp Med. 2003 Nov 17;198(10):1563-72. doi: 10.1084/jem.20031220.
Although Toll-like receptors (TLRs) are critical mediators of the immune response to pathogens, the influence of polymorphisms in this gene family on human susceptibility to infection is poorly understood. We demonstrated recently that TLR5 recognizes flagellin, a potent inflammatory stimulus present in the flagellar structure of many bacteria. Here, we show that a common stop codon polymorphism in the ligand-binding domain of TLR5 (TLR5392STOP) is unable to mediate flagellin signaling, acts in a dominant fashion, and is associated with susceptibility to pneumonia caused by Legionella pneumophila, a flagellated bacterium. We also show that flagellin is a principal stimulant of proinflammatory cytokine production in lung epithelial cells. Together, these observations suggest that TLR5392STOP increases human susceptibility to infection through an unusual dominant mechanism that compromises TLR5's essential role as a regulator of the lung epithelial innate immune response.
尽管Toll样受体（TLRs）是免疫应答病原体的关键介质，但该基因家族中的多态性对人类感染易感性的影响仍知之甚少。我们最近证明，TLR5识别鞭毛蛋白，这是一种存在于许多细菌鞭毛结构中的强效炎症刺激物。在这里，我们表明TLR5配体结合域中的一个常见终止密码子多态性（TLR5392STOP）无法介导鞭毛蛋白信号传导，以显性方式起作用，并且与由鞭毛菌嗜肺军团菌引起的肺炎易感性相关。我们还表明，鞭毛蛋白是肺上皮细胞中促炎细胞因子产生的主要刺激物。总之，这些观察结果表明，TLR5392STOP通过一种不寻常的显性机制增加了人类对感染的易感性，这种机制损害了TLR5作为肺上皮固有免疫反应调节剂的重要作用。
