Staphylococcus aureus Activation of TNF Signaling Pathways

金黄色葡萄球菌是一种主要的人类病原体，经常引起正常婴儿的肺炎 和儿童，囊性纤维化患者，特别是重症监护病房的医院感染。 肺部葡萄球菌感染的特征是多形核白细胞反应。的 生物体表达许多直接与免疫系统组分相互作用的毒力因子， 包括免疫球蛋白、T和B细胞以及血小板。在这个建议中，我们将详细研究 蛋白A是金黄色葡萄球菌的主要表面成分，如何通过以下方式促进肺炎的发病机制： 特异性结合TNFR 1并激活气道上皮细胞中的TNF α信号级联。一个反- 还引发炎症反应，其包括TNF α转化酶的表达， TNFR 1和IL-6受体的脱落。SPA中蛋白A的结合及多态性的影响 与临床爆发相关的肿瘤将通过检查与TNFR 1的结合及其在 激活促炎或抗炎信号传导。将使用spa-GFP融合物来记录蛋白A 表达在鼠肺中被激活。蛋白A是否通过TNF诱导上皮细胞凋亡 路也将进行研究。实验来确定蛋白A如何激活调节-抗炎 级联的同时，它刺激TNF信号被描述。上皮细胞的相对重要性- 与免疫细胞介导的信号传导相反，蛋白A对TNFR 1的激活将在 仅在气道上皮中表达TNFR 1的转基因小鼠。因为控制炎症是 在气道中尤其重要，我们将确切地确定蛋白A和金黄色葡萄球菌如何诱导TNFR 1， IL-6受体通过TNF α转化酶的活化而脱落。这些研究将提供 对葡萄球菌肺炎的发病机制有了新的认识，并提出了新的治疗靶点。 这些研究将提供关于葡萄球菌肺炎发病机制的知识， 婴儿、免疫功能低下的宿主、囊性纤维化患者的感染原因，以及 重症监护室的发病率。

Staphylococcus aureus is a major human pathogen that frequently causes pneumonia in normal infants and children, in patients with cystic fibrosis, and especially nosocomial infections in intensive care units. Staphylococcal infections in the lung are characterized by a polymorphonuclear leukocyte response. The organisms express many virulence factors that directly interact with components of the immunesystem, including immunoglobulin, T and B cells as well as platelets. In this proposal we will study in detail exactly how protein A, a major surface component of S.aureus, contributes to the pathogenesis of pneumonia by binding specifically to TNFR1 and activating TNFa signaling cascades in airway epithelial cells. An anti- inflammatory response is also initiated which includes the expression of the TNFa converting enzyme and the shedding of TNFR1 and IL-6 receptors. The binding of protein A and the effects of polymorphisms in spa linked to clinical outbreaks will be characterized by examining binding to TNFR1 and their relative potency in activating pro or anti-inflammatory signaling. A spa-GFP fusion will be used to document when protein A expression is activated in the murine lung. Whether protein A induces epithelial apoptosis via the TNF pathway will also be studied. Experiments to define how protein A activates a regulatory - anti-inflammatory cascade at the same time it stimulates TNF signaling are described. The relative importance of epithelial - TNFR1 activation by protein A, as opposedto signaling mediated by immune cells, will be defined in transgenic mice that express TNFR1 only in the airway epithelium. Since the control of inflammation is especially important in the airways, we will establish exactly how protein A and S.aureus induce TNFR1 and IL-6 receptor shedding through the activation of the TNFa converting enzyme. These studies should provide new insights into the pathogenesis of Staphylococcalpneumonia and suggest new targets for therapy. These studies will provide knowledge about the pathogenesis of Staphylococcal pneumonia, a major cause of infection in infants, immunocompromised hosts, patients with cystic fibrosis, and a major source of morbidity in intensive care units.