摘要

Toll样受体中的Toll /白细胞介素-1受体（TIR）结构域对于启动和增殖真核生物先天免疫信号级联反应是必不可少的。在这里，我们调查TirS，一种金黄色葡萄球菌TIR模拟物，它是新型细菌侵入机制的一部分。其在真核细胞中的异位表达抑制TLR信号，通过抑制TLR2，TLR4，TLR5和TLR9下调NF-kB途径。即使tirS突变株和野生型菌株在细菌负荷中没有差异，与野生型和恢复菌株相比，由金黄色葡萄球菌敲除tirS突变体诱导的皮肤损伤在小鼠模型中增加。 TirS也与较低的嗜中性粒细胞和巨噬细胞活性相关，证实了通过局部炎症反应减弱毒力的核心作用。 TirS总是定位于含有用于夫西地酸抗性的fusC基因但不总是携带mecA基因的葡萄球菌染色体盒（SCC）内。值得注意的是，夫西地酸的亚抑菌浓度增加了tirS的表达。流行病学研究发现这种效应和临床表现之间没有联系，但显示SCCmec元件与SCC fusC / tirS的选择性优势。因此，决定细菌感染成功和传播的两个关键特征是相关联的。

Toll/interleukin-1 receptor (TIR) domains in Toll-like receptors are essential for initiating and propagating the eukaryotic innate immune signaling cascade. Here, we investigate TirS, aStaphylococcus aureus TIR mimic that is part of a novel bacterial invasion mechanism. Its ectopic expression in eukaryotic cells inhibited TLR signaling, downregulating the NF-kB pathway through inhibition of TLR2, TLR4, TLR5, and TLR9. Skin lesions induced by the S.aureus knockout tirS mutant increased in a mouse model compared with wild-type and restored strains even though the tirS-mutant and wild-type strains did not differ in bacterial load. TirS also was associated with lower neutrophil and macrophage activity, confirming a central role in virulence attenuation through local inflammatory responses. TirS invariably localizes within the staphylococcal chromosomal cassettes (SCC) containing the fusC gene for fusidic acid resistance but not always carrying the mecA gene. Of note, sub-inhibitory concentration of fusidic acid increased tirS expression. Epidemiological studies identified no link between this effector and clinical presentation but showed a selective advantage with a SCCmec element with SCC fusC/tirS. Thus, two key traits determining the success and spread of bacterial infections are linked.

http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006092