Activation of TAFI on the Surface of Streptococcus pyogenes Evokes Inflammatory Reactions by Modulating the Kallikrein/Kinin System
Activation of TAFI on the Surface of Streptococcus pyogenes Evokes Inflammatory Reactions by Modulating the Kallikrein/Kinin System
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DOI：
10.1159/000145543
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发表时间：
2009-01-01
影响因子：
5.3
通讯作者：
Herwald, Heiko
中科院分区：
文献类型：
--
作者：
Bengtson, Sara H.;Sanden, Caroline;Herwald, Heiko
细菌控制宿主对感染反应的调节是一种重要的毒力机制，已被证明有助于疾病进展。在这里，我们报道了人类病原体化脓链球菌利用原羧肽酶TAR（凝血酶活化纤维蛋白溶解抑制剂）来调节钾激肽/激肽系统。为此，细菌启动了从TAFI的招募和激活开始的一系列事件。随后在链球菌表面组装和诱导接触系统，最终触发缓激素（BK）的释放。BK随后被活化的TAFI截断羧基末端，TAFI将肽从激肽B-2受体配体转化为激肽B-1受体（B1R）激动剂。最后，我们发现链球菌上清液间接放大了B1R反应，因为它们作用于外周血单个核细胞，分泌炎症细胞因子，进而刺激人成纤维细胞B1R的上调。综上所述，我们的研究结果表明，与链球菌结合的TAR具有重要的新作用，因为它在细菌表面将BK加工成B1R激动剂，从而可能将炎症从短暂状态转移到慢性状态。版权所有2008 S. Karger AG，巴塞尔
Bacteria-controlled regulation of host responses to infection is an important virulence mechanism that has been demonstrated to contribute to disease progression. Here we report that the human pathogen Streptococcus pyogenes employs the procarboxypeptidase TAR (thrombin-activatablefibrinolysis inhibitor) to modulate the kallikrein/kinin system. To this end, bacteria initiate a chain of events starting with the recruitment and activation of TAFI. This is followed by the assembly and induction of the contact system at the streptococcal surface, eventually triggering the release of bradykinin (BK). BK is then carboxyterminally truncated by activated TAFI, which converts the peptide from a kinin B-2 receptor ligand to a kinin B-1 receptor (B1R) agonist. Finally, we show that streptococcal supernatants indirectly amplify the B1R response as they act on peripheral blood mononuclear cells to secrete inflammatory cytokines that in turn stimulate upregulation of the B1R on human fibroblasts. Taken together our findings implicate a critical and novel role for streptococci-bound TAR, as it processes BK to a B1R agonist at the bacterial surface and thereby may redirect inflammation from a transient to a chronic state. Copyright (C) 2008 S. Karger AG, Basel