Proteoglycans in Lung Innate Immunity and Host Defense

描述（由申请方提供）：本提案的中心目标是确定蛋白聚糖如何调节肺炎球菌肺炎中的肺部先天免疫应答。肺炎链球菌，即肺炎球菌，是社区获得性细菌性肺炎最常见的病原体。据估计，这种革兰氏阳性细菌在美国每年导致50万例肺炎和4万例死亡。多配体蛋白聚糖-1是上皮细胞的主要细胞表面硫酸乙酰肝素蛋白聚糖，其可以在细胞外环境中作为可溶性蛋白聚糖起作用，因为其胞外域在炎症条件下被金属蛋白酶脱落。S.肺炎克雷伯氏菌通过分泌因子激活宿主细胞并通过ZmpC（其肺部感染的金属蛋白酶毒力因子）直接切割多配体蛋白聚糖-1胞外域来诱导多配体蛋白聚糖-1脱落。初步数据表明，S。肺炎球菌诱导的多配体蛋白聚糖-1脱落是肺炎球菌肺炎发病机制中的关键毒力机制。syndecan-1脱落如何促进肺炎球菌肺炎的潜在机制尚不清楚，但脱落可增强小鼠中CXC趋化因子诱导的中性粒细胞浸润，脱落的胞外域以硫酸乙酰肝素（HS）依赖性方式抑制气道表面液体中表达的几种抗菌因子。此外，syndecan-1缺失小鼠相对于野生型小鼠显示减弱的肺炎球菌肺炎。基于这些数据，本建议将测试的假设，S。在3个特定目的中，肺炎链球菌破坏syndecan-1脱落以失调肺先天免疫应答并促进其发病机制。目的1将确定S.肺炎链球菌诱导多配体蛋白聚糖-1脱落。目的2将确定syndecan-1的结构特征，促进肺炎球菌性肺炎，并确定HS是否是抗肺炎球菌性肺炎治疗的治疗靶点。目的3：确定syndecan-1胞外结构域在肺炎球菌肺炎中的生物学作用靶点。预计这些研究将确定syndecan-1在肺炎球菌性肺炎中的关键机制，并为设计和开发新的治疗方法以对抗肺炎球菌性肺病提供基础。公共卫生相关性：肺炎链球菌是一种主要的人类病原体，是细菌性肺炎的主要原因。然而，这种细菌如何导致肺部疾病还不完全清楚。这个建议的目的是定义S。肺炎利用我们自己的分子来促进其感染，使用最先进的分子、生物化学、细胞生物学和基因靶向方法。成功完成拟议的研究，预计将确定潜在的机制，并确定新的方法，使肺炎球菌肺部疾病得到更好的控制。

DESCRIPTION (provided by applicant): The central goal of this proposal is to define how proteoglycans modulate the lung innate immune response in pneumococcal pneumonia. Streptococcus pneumoniae, the pneumococcus, is the most common causative agent of community-acquired bacterial pneumonia. It is estimated that this Gram-positive bacterium causes 500,000 cases of pneumonia and 40,000 deaths annually in the US. Syndecan-1 is a major cell surface heparan sulfate proteoglycan of epithelial cells that can function as a soluble proteoglycan in the extracellular environment because its ectodomain is shed by metalloproteinases under inflammatory conditions. S. pneumoniae induces syndecan-1 shedding by activating host cells through a secreted factor and directly cleaving syndecan-1 ectodomains through ZmpC, a metalloproteinase virulence factor for its lung infection. Preliminary data suggest that S. pneumoniae-induced syndecan-1 shedding is a key virulence mechanism in the pathogenesis of pneumococcal pneumonia. The underlying mechanisms of how syndecan-1 shedding promotes pneumococcal pneumonia are not known, but shedding enhances CXC chemokine-induced neutrophil infiltration in mice, and shed ectodomains inhibit several antibacterial factors expressed in airway surface fluids in a heparan sulfate (HS)-dependent manner. Further, syndecan-1 null mice show attenuated pneumococcal pneumonia relative to wild type mice. Based on these data, this proposal will test the hypothesis that S. pneumoniae subverts syndecan-1 shedding to dysregulate the lung innate immune response and promote its pathogenesis in 3 Specific Aims. Aim 1 will determine the molecular and cellular details of how S. pneumoniae induces syndecan-1 shedding. Aim 2 will define the structural features of syndecan-1 that promote pneumococcal pneumonia and determine if HS is a therapeutic target for anti-pneumococcal pneumonia therapy. Aim 3 will identify the biological targets of syndecan-1 ectodomains in pneumococcal pneumonia. It is anticipated that these studies will define the key mechanisms of syndecan-1 in pneumococcal pneumonia, and provide a foundation for the design and development of novel therapeutic approaches to combat pneumococcal lung diseases. PUBLIC HEALTH RELEVANCE: Streptococcus pneumoniae is a major human pathogen that is the primary cause of bacterial pneumonia. However, how this bacterium causes lung disease is incompletely understood. The goal of this proposal is to define how S. pneumoniae takes advantage of our own molecules to promote its infection, using state-of-the- art molecular, biochemical, cell biological, and gene targeting approaches. Successful completion of the proposed studies is anticipated to define the underlying mechanisms and identify new means of brining pneumococcal lung diseases under better control.