Fibrinogen depletion attenuates Staphyloccocus aureus infection by preventing density-dependent virulence gene UP-regulation
Fibrinogen depletion attenuates Staphyloccocus aureus infection by preventing density-dependent virulence gene UP-regulation
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DOI：
10.4049/jimmunol.171.10.5389
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发表时间：
2003-11-15
影响因子：
4.4
通讯作者：
Gresham, HD
中科院分区：
文献类型：
--
作者：
Rothfork, JM;Dessus-Babus, S;Gresham, HD
金黄色葡萄球菌经历了密度依赖性的表型从组织粘附到组织损伤和吞噬细胞逃避的转化，其部分由群体感应操纵子agr及其效应子RNAIII介导。尚未研究宿主因素对这种调节毒力机制的贡献。我们假设，纤维蛋白原，作为炎症反应的一个组成部分，可以创建空间受限的细菌周围的微环境，增加密度独立的细菌数量，从而增强群体感应依赖的毒力基因的表达。在这里，我们表明，短暂的纤维蛋白原消耗显着减少细菌负荷和相应的发病率和死亡率在实验感染野生型S。金黄色葡萄球菌，但不与缺乏群体感应操纵子，agr的表达的细菌。此外，它抑制agr效应子、RNAIII和RNAIII下游靶点的启动子的体内激活，包括溶血素和荚膜产生。此外，在体外和体内，促进这种毒力表型转换的机制涉及细菌的聚集，表明S。金黄色葡萄球菌通过增强密度依赖性毒力基因表达来响应纤维蛋白原介导的细菌凝集。这些数据表明，下调增强细菌群体感应的宿主特定炎症组分可以是增强宿主对感染防御的策略。
Staphylococcus aureus undergoes a density-dependent conversion in phenotype from tissue-adhering to tissue-damaging and phagocyte-evading that is mediated in part by the quorum-sensing operon, agr, and its effector, RNAIII. Contributions of host factors to this mechanism for regulating virulence have not been studied. We hypothesized that fibrinogen, as a component of the inflammatory response, could create spatially constrained microenvironments around bacteria that increase density independently of bacterial numbers and thus potentiate quorum-sensing-dependent virulence gene expression. Here we show that transient fibrinogen depletion significantly reduces the bacterial burden and the consequential morbidity and mortality during experimental infection with wild-type S. aureus, but not with bacteria that lack expression of the quorum-sensing operon, agr. In addition, it inhibits in vivo activation of the promoter for the agr effector, RNAIII, and downstream targets of RNAIII, including a hemolysin and capsule production. Moreover, both in vitro and in vivo, the mechanism for promoting this phenotypic switch in virulence involves clumping of the bacteria, demonstrating that S. aureus responds to fibrinogen-mediated bacterial clumping by enhancing density-dependent virulence gene expression. These data demonstrate that down-modulation of specific inflammatory components of the host that augment bacterial quorum sensing can be a strategy for enhancing host defense against infection.