Frendéus B, Wachtler C, Hedlund M, Fischer H, Samuelsson P, Svensson M, Svanborg C
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, Sölvegatan 23, S-223 62 Lund, Sweden.
Mol Microbiol. 2001 Apr;40(1):37-51. doi: 10.1046/j.1365-2958.2001.02361.x.
Fimbriae mediate bacterial attachment to host cells and provide a mechanism for tissue attack. They activate a host response by delivery of microbial products such as lipopolysaccharide (LPS) or through direct fimbriae-dependent signalling mechanisms. By coupling to glycosphingolipid (GSL) receptors, P fimbriae trigger cytokine responses in CD14 negative host cells. Here we show that P fimbriae utilize the Toll-like receptor 4 (TLR4)-dependent pathway to trigger mucosal inflammation. Escherichia coli strains expressing P fimbriae as their only virulence factor stimulated chemokine and neutrophil responses in the urinary tract of TLR4 proficient mice, but TLR4 defective mice failed to respond to infection. Mucosal cells were CD14 negative but expressed several TLR species including TLR4, and TLR4 protein was detected. Infection with P fimbriated bacteria stimulated an increase in TLR4 mRNA levels. The activation signal did not involve the LPS-CD14 pathway and was independent of lipid A myristoylation, as shown by mutational inactivation of the msbB gene. Co-staining experiments revealed that TLR4 and the GSL receptors for P fimbriae co-localized in the cell membrane. The results demonstrate that P fimbriae activate epithelial cells by means of a TLR4-dependent signalling pathway, and suggest that GSL receptors for P fimbriae can recruit TLR4 as co-receptors.
菌毛介导细菌与宿主细胞的附着，并提供一种组织攻击机制。它们通过传递微生物产物如脂多糖（LPS）或通过直接的菌毛依赖性信号传导机制激活宿主反应。通过与糖鞘脂（GSL）受体结合，P菌毛在CD14阴性宿主细胞中触发细胞因子反应。在此我们表明，P菌毛利用Toll样受体4（TLR4）依赖性途径触发黏膜炎症。表达P菌毛作为其唯一毒力因子的大肠杆菌菌株在TLR4功能正常的小鼠尿路中刺激趋化因子和中性粒细胞反应，但TLR4缺陷小鼠对感染无反应。黏膜细胞CD14阴性，但表达包括TLR4在内的几种TLR种类，并且检测到TLR4蛋白。感染P菌毛化细菌刺激TLR4 mRNA水平升高。如通过msbB基因突变失活所示，激活信号不涉及LPS - CD14途径且独立于脂质A肉豆蔻酰化。共染色实验表明，TLR4和P菌毛的GSL受体共定位于细胞膜。结果表明，P菌毛通过TLR4依赖性信号传导途径激活上皮细胞，并提示P菌毛的GSL受体可募集TLR4作为共受体。
