Staphylococcus aureus Activation of TNF Signaling Pathways

描述（由申请人提供）：金黄色葡萄球菌是一种主要的人类病原体，经常导致正常婴儿和儿童、囊性纤维化患者的肺炎，尤其是重症监护室的医院感染。肺部葡萄球菌感染的特征是多形核白细胞反应。这些生物表达许多毒力因子，这些毒力因子直接与免疫系统的组分相互作用，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质A，一个主要的表面成分的S。金黄色葡萄球菌通过特异性结合TNFR1并激活气道上皮细胞中的TNF α信号级联而导致肺炎的发病。还引发抗炎反应，其包括TNF α转化酶的表达和TNFR1和IL-6受体的脱落。将通过检查与TNFR1的结合及其在激活促炎或抗炎信号传导中的相对效力来表征与临床爆发相关的SPA中蛋白A的结合和多态性的影响。spa-GFP融合将用于记录蛋白A表达何时在鼠肺中被激活。还将研究蛋白A是否通过TNF途径诱导上皮细胞凋亡。实验来定义蛋白A如何激活调节-抗炎级联反应，同时它刺激TNF信号被描述。与免疫细胞介导的信号传导相反，蛋白A激活上皮TNFR1的相对重要性将在仅在气道上皮中表达TNFR1的转基因小鼠中确定。由于炎症的控制在气道中特别重要，我们将确切地确定蛋白A和S。金黄色葡萄球菌通过激活TNF α转化酶诱导TNFR1和IL-6受体脱落。 这些研究将为葡萄球菌肺炎的发病机制提供新的见解，并提出新的治疗靶点。这些研究将提供关于葡萄球菌肺炎的发病机制的知识，葡萄球菌肺炎是婴儿、免疫功能低下宿主、囊性纤维化患者感染的主要原因，也是重症监护室发病的主要来源。

DESCRIPTION (provided by applicant): 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 immune system, 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 opposed to 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 Staphylococcal pneumonia 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.