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，与许多类型的感染有关，包括严重肺炎。金黄色葡萄球菌在肺部激活多个通常是多余的促炎信号级联反应，涉及呼吸道上皮细胞、中性粒细胞、肺泡巨噬细胞、树突状细胞和募集的T细胞。虽然中性粒细胞在根除金黄色葡萄球菌中起关键作用，但过度的促炎信号也会导致肺损伤。我们正在进行的研究表明，金黄色葡萄球菌通过表达多种超抗原直接激活NA�ve CD4+T细胞，导致炎症反应。驻留的肺泡巨噬细胞通过表达IL-27等细胞因子和PD-L1等共抑制信号，正常发挥调节T细胞激活的功能。在提出的实验中，我们将确定金黄色葡萄球菌引起的坏死性下垂如何限制巨噬细胞免疫调节分子在T细胞调节中的作用，以及巨噬细胞与T细胞的相互作用是否可以成为改善耐甲氧西林金黄色葡萄球菌肺炎(MRSA)预后的治疗靶点。这将使用急性肺炎的野生型和基因敲除小鼠模型、人外周血单核细胞、肺泡巨噬细胞和细胞系来完成。通过增加巨噬细胞数量、阻断共刺激蛋白或传递外源性共抑制分子来防止T细胞激活的策略将被评估其在急性MRSA肺炎中的有效性。考虑到目前可用的抗生素在设置MRSA感染方面的有限疗效，我们假设加强正常的免疫清除机制可以极大地改善结果。

DESCRIPTION (provided by applicant): Staphylococcus aureus is a major human pathogen, associated with many types of infection including severe pneumonia. S. aureus activate multiple, often redundant proinflammatory signaling cascades in the lungs involving the airway epithelium as well as neutrophils, alveolar macrophages, dendritic cells and recruited T cells. While neutrophils are critical in the eradication of S. aureus, excessive proinflammatory signaling contributes to pulmonary damage. Our ongoing studies suggest that S. aureus directly activate na�ve CD4+ T cells through expression of multiple superantigens resulting in a hyperinflammatory response. Resident alveolar macrophages, through expression of cytokines such as IL-27 and co-inhibitory signals such as PD-L1, normally function to regulate T cell activation. In the experiments proposed we will establish how S. aureus induced necroptosis may limit the contribution of macrophage immunoregulatory molecules in T cell regulation and whether the macrophage-T cell interaction could be therapeutic target to improve the outcome of methicillin-resistant S. aureus (MRSA) pneumonia. This will be accomplished using wild type and knockout murine models of acute pneumonia, human PBMCs, alveolar macrophages and cell lines. Strategies to prevent T cell activation, by increasing macrophage numbers, blocking co-stimulatory proteins, or delivering exogenous co-inhibitory molecules will be evaluated for their efficacy in the setting of acute MRSA pneumonia. Given the limited efficacy of currently available antibiotics in the setting of MRSA infection, we postulate that enhancing normal immune clearance mechanisms could greatly benefit outcome.