Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins
Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins
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DOI：
10.1038/nm1734
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发表时间：
2008-04-01
期刊：
影响因子：
82.9
通讯作者：
Miethke, Thomas
中科院分区：
文献类型：
--
作者：
Cirl, Christine;Wieser, Andreas;Miethke, Thomas
病原微生物已经进化出复杂的分子策略来破坏宿主的防御。本研究表明，毒力细菌通过分泌Toll/白细胞介素- 1受体（TIR）结构域的抑制同源物，直接干扰Toll样受体（TLR）的功能。在大肠杆菌CFT073 （TcpC）和布鲁氏菌melitensis （TcpB）中分别鉴定出编码TIR结构域-蛋白（tps）的基因。我们发现TcpC在最毒的尿路致病性大肠杆菌菌株中很常见，并促进细菌的存活和体内肾脏病理。硅分析预测了与人类TLR1的TIR结构域具有显著的三级结构同源性，并且我们发现由于Tcps与MyD88直接结合，Tcps通过髓样分化因子88 （MyD88）接头蛋白阻碍TLR信号传导。Tcps是一类新的毒力因子，它通过抑制TLR-和MyD88-特异性信号传导起作用，从而抑制先天免疫并增加毒力。
Pathogenic microbes have evolved sophisticated molecular strategies to subvert host defenses. Here we show that virulent bacteria interfere directly with Toll- like receptor ( TLR) function by secreting inhibitory homologs of the Toll/ interleukin- 1 receptor ( TIR) domain. Genes encoding TIR domain containing - proteins ( Tcps) were identified in Escherichia coli CFT073 ( TcpC) and Brucella melitensis ( TcpB). We found that TcpC is common in the most virulent uropathogenic E. coli strains and promotes bacterial survival and kidney pathology in vivo. In silico analysis predicted significant tertiary structure homology to the TIR domain of human TLR1, and we show that the Tcps impede TLR signaling through the myeloid differentiation factor 88 ( MyD88) adaptor protein, owing to direct binding of Tcps to MyD88. Tcps represent a new class of virulence factors that act by inhibiting TLR- and MyD88- specific signaling, thus suppressing innate immunity and increasing virulence.