Staphylococcus aureus Activation of TNF Signaling Pathways

描述(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，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。这些生物表达许多毒力因子，这些因子直接与免疫系统的组件相互作用，包括免疫球蛋白、T和B细胞以及血小板。在这项建议中，我们将详细研究金黄色葡萄球菌的主要表面成分A蛋白是如何通过与TNFR1特异性结合并激活呼吸道上皮细胞中的TNFa信号级联而在肺炎发病机制中起作用的。还启动了一种抗炎反应，其中包括TNFa转换酶的表达以及TNFR1和IL-6受体的脱落。蛋白A的结合和SpA中与临床暴发相关的多态的影响将通过检测与TNFR1的结合以及它们在激活促炎或抗炎信号方面的相对效力来表征。SpA-GFP融合将被用来记录小鼠肺中蛋白A表达何时被激活。蛋白A是否通过肿瘤坏死因子途径诱导上皮细胞凋亡也将被研究。描述了定义蛋白A如何在刺激肿瘤坏死因子信号的同时激活调节-抗炎级联反应的实验。与免疫细胞介导的信号传递相反，由蛋白A激活上皮细胞TNFR1的相对重要性将在仅在呼吸道上皮中表达TNFR1的转基因小鼠中确定。由于炎症的控制在呼吸道中特别重要，我们将确切地确定蛋白A和金黄色葡萄球菌是如何通过激活TNFa转换酶来诱导TNFR1和IL-6受体脱落的。 这些研究应该为葡萄球菌肺炎的发病机制提供新的见解，并为治疗提供新的靶点。这些研究将提供有关葡萄球菌肺炎的发病机制的知识，葡萄球菌肺炎是婴儿感染的主要原因，免疫功能低下的宿主，囊性纤维化患者，以及重症监护病房的主要发病率来源。

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.