Proteoglycans in Lung Innate Immunity and Host Defense

描述（由申请人提供）：本提案的中心目标是定义蛋白多糖如何调节肺炎球菌肺炎的肺部先天免疫反应。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每年在美国导致50万例肺炎和4万例死亡。Syndecan-1是上皮细胞的一种主要的细胞表面硫酸肝素蛋白聚糖，在细胞外环境中作为可溶性蛋白聚糖发挥作用，因为它的外结构域在炎症条件下由金属蛋白酶脱落。肺炎链球菌通过分泌因子激活宿主细胞，并通过金属蛋白酶毒力因子ZmpC直接切割syndecan-1胞外结构域，诱导syndecan-1脱落。初步数据表明，肺炎链球菌诱导的syndecan-1脱落是肺炎球菌肺炎发病的关键毒力机制。syndecan-1脱落促进肺炎球菌肺炎的潜在机制尚不清楚，但脱落增强了小鼠CXC趋化因子诱导的中性粒细胞浸润，并且脱落的外结构域以依赖硫酸肝素（HS）的方式抑制气道表面液体中表达的几种抗菌因子。此外，与野生型小鼠相比，syndecan-1缺失小鼠表现出较弱的肺炎球菌肺炎。基于这些数据，本研究将在3个特定目的中验证肺炎链球菌破坏syndecan-1脱落从而失调肺部先天免疫反应并促进其发病机制的假设。目的1将确定肺炎链球菌如何诱导syndecan-1脱落的分子和细胞细节。目的2将定义促进肺炎球菌肺炎的syndecan-1的结构特征，并确定HS是否是抗肺炎球菌肺炎治疗的治疗靶点。目的3将确定肺炎球菌肺炎中syndecan-1外结构域的生物学靶点。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提供基础，以对抗肺炎球菌性肺病。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，这种细菌是如何引起肺部疾病的还不完全清楚。本提案的目标是定义肺炎链球菌如何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。预期成功完成拟议的研究将确定潜在的机制，并找到更好地控制肺炎球菌肺部疾病的新方法。

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.