STAPHYLOCOCCUS AUREUS ACTIVATION OF TNF SIGNALING PATHWAYS

描述（由申请人提供）：S。金黄色葡萄球菌激活TNF信号通路项目概述金黄色葡萄球菌仍然是人类感染的主要原因，并且侵袭性葡萄球菌疾病的患病率在过去几年中有所增加。蛋白A或SpA是S.金黄色葡萄球菌，与免疫系统有多种相互作用。SpA的离散结构域激活TNF α信号传导、EGFR介导的应答和I型干扰素级联的激活。SpA IgG结合结构域激活TNFR 1，这是肺炎发病机制的核心相互作用。我们推测SpA-TNFRI相互作用在葡萄球菌通过激活RhoA GTP酶侵入粘膜屏障中是至关重要的，RhoA GTP酶扰乱肌动球蛋白动力学并破坏上皮紧密连接。SpA IgG结合结构域也是EGFR配体，刺激其磷酸化并激活ADAM 17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TLR 4/TRIF依赖的方式诱导上皮产生IFN-b和Jak-STAT磷酸化。葡萄球菌通过TLR 4级联激活I型干扰素被认为在肺炎和脓毒症的发病机制中起主要作用。由于Xr结构域是体内突变、复制和缺失的常见位点，我们将确定这些体内选择的突变是否是特异性地响应免疫压力而产生的，并确定Xr中的多态性如何有助于S的毒力。金黄色。 公共卫生相关性：S.金黄色葡萄球菌（Staphylococcus aureus）感染，特别是MRSA感染，是一个主要的公共卫生问题，导致先前健康的儿童和成人的发病率和死亡率增加。本申请集中于这些细菌的主要表面组分，蛋白A，其与宿主的免疫反应具有几种重要的相互作用。我们将确定蛋白A在葡萄球菌侵入粘膜屏障中的作用以及其激活肺中I型干扰素级联反应的能力。这些研究将证明蛋白A中的突变如何进化以增强生物体的毒力，并为治疗干预提供潜在的靶点。

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. PUBLIC HEALTH RELEVANCE: S. aureus activates TNF signaling pathways PROJECT NARRATIVE Staphylococcus aureus infection, especially MRSA infection, is a major public health problem causing increasing morbidity and mortality in previously healthy children and adults. This application focuses upon a major surface component of these bacteria, protein A, which has several important interactions with the immune responses of the host. We will establish the role of protein A in staphylococcal invasion across mucosal barriers as well as its ability to activate the type I interferon cascade in the lung. These studies will demonstrate how mutations in protein A have evolved to enhance the virulence of the organism and provide a potential target for therapeutic intervention.