STAPHYLOCOCCUS AUREUS ACTIVATION OF TNF SIGNALING PATHWAYS

描述(申请人提供)：金黄色葡萄球菌激活肿瘤坏死因子信号通路项目摘要金黄色葡萄球菌仍然是人类感染的主要原因，侵袭性葡萄球菌疾病的流行在过去几年中有所增加。蛋白A或SpA是金黄色葡萄球菌高度保守的表面成分，与免疫系统有多种相互作用。SpA的离散结构域激活TNFa信号、EGFR介导的反应和I型干扰素级联反应。SpA的Ig G结合域激活TNFR1，这种相互作用是肺炎发病机制的核心。我们推测，SpA-TNFRI的相互作用通过激活RhoA GTP酶，扰乱肌球蛋白的动力学，破坏上皮的紧密连接，在葡萄球菌跨越粘膜屏障的侵袭中起关键作用。SpA的Ig G结合域也是一种EGFR配体，刺激其磷酸化并激活ADAM17金属蛋白酶。我们预测，EGFR还介导SpA的内化，SPA通过其XR结构域激活I型干扰素级联，以TLR4/TRIF依赖的方式诱导上皮细胞产生干扰素-b和Jak-STAT磷酸化。葡萄球菌通过TLR4级联激活I型干扰素，被认为在肺炎和败血症的发病机制中起着重要作用。由于XR结构域是体内突变、复制和缺失的常见部位，我们将确定这些体内选择的突变是否是针对免疫压力而产生的，并确定XR基因的多态是如何影响金黄色葡萄球菌的毒力的。

DESCRIPTION (provided by applicant): S. aureus activates TNF signaling pathways PROJECT SUMMARY Staphylococcus aureus remains a major cause of human infection and the prevalence of invasive staphylococcal disease has increased in the past few years. Protein A or SpA is a highly conserved surface component of S. aureus that has multiple interactions with the immune system. Discrete domains of SpA activate TNFa signaling, EGFR-mediating responses and the activation of the type I interferon cascade. The SpA IgG binding domain activates TNFR1, an interaction that is central to the pathogenesis of pneumonia. We postulate that the SpA-TNFRI interaction is critical in staphylococcal invasion across mucosal barriers through its activation of RhoA GTPases that perturb actomyosin dynamics and disrupt epithelial tight junctions. The SpA IgG binding domain also is an EGFR ligand, stimulating its phosphorylation and activating the ADAM17 metallo-protease. We predict that EGFR also mediates the internalization of SpA, which, through its Xr domain, activates the type I interferon cascade, inducing epithelial production of IFN-b and Jak-STAT phosphorylation in a TLR4/TRIF-dependent fashion. Staphylococcal activation of type I interferons via the TLR4 cascade is postulated to have a major role in the pathogenesis of pneumonia and sepsis. As the Xr domain is a common site of in vivo mutation, duplication and deletion, we will determine if these mutations selected in vivo are generated specifically in response to immune pressure and establish how polymorphisms in Xr contribute to the virulence of S. aureus.