Role of Syndecan-1 in S. aureus Pneumonia

描述（由申请人提供）：本R21提案的中心目标是了解金黄色葡萄球菌如何破坏syndecan-1，一种主要的细胞表面硫酸肝素蛋白聚糖（HSPG），以促进其在肺部的发病机制。宿主-病原体相互作用在很大程度上决定了传染病的发病、进展和结果。许多细菌在体外与细胞表面HSPGs结合，这种活性被认为是体内初始附着于宿主细胞的关键。为了确定hspg -病原体在体内相互作用的生理意义，我们研究了syndecan-1在金黄色葡萄球菌肺炎小鼠模型中的作用。金黄色葡萄球菌肺炎是通气患者中常见的并发症，在年龄偏大且易患疾病的患者、接受免疫抑制治疗或患有疾病的患者以及囊性纤维化患者中也是一个严重的问题。初步研究表明，与野生型小鼠相比，syndecan-1缺失小鼠的肺部金黄色葡萄球菌毒力明显减弱。然而，出乎意料的是，金黄色葡萄球菌不与syndecan-1结合，金黄色葡萄球菌对肺上皮细胞的粘附不依赖于syndecan-1。这些数据表明，金黄色葡萄球菌利用syndecan-1作为其发病机制，但不是作为促进其最初附着于宿主细胞的细胞表面受体。相反，初步研究表明，分泌的可溶性syndecan-1以硫酸肝素依赖的方式促进金黄色葡萄球菌肺炎。基于这些数据，我们将在两个特定目的中探讨syndecan-1如何作为金黄色葡萄球菌肺炎的前致病因子发挥作用。在Aim 1中，我们将探讨syndecan-1外结构域通过抑制中性粒细胞介导的宿主防御机制和气道中可溶性防御因子的葡萄球菌活性来促进金黄色葡萄球菌肺炎的假设。在Aim 2中，我们将探讨一种假设，即诱导syndecan-1脱落是金黄色葡萄球菌肺炎发病机制中的一个关键毒力活性。通过这些研究，我们的目标是获得新的机制见解，这将有助于未来开发新的治疗方法来减轻，停止或逆转金黄色葡萄球菌肺炎的疾病进展-这是导致死亡率和发病率的重要原因。公共卫生相关性：金黄色葡萄球菌肺炎是美国和世界范围内死亡率和发病率的重要原因。这项拨款提案将探索金黄色葡萄球菌如何通过利用我们自己的一种叫做syndecan-1的分子促进其在肺部的生存并引起肺炎的潜在生物学机制。

DESCRIPTION (provided by applicant): The central goal of this R21 proposal is to understand how Staphylococcus aureus subverts syndecan-1, a major cell surface heparan sulfate proteoglycan (HSPG), to promote its pathogenesis in the lung. Host-pathogen interactions largely dictate the onset, progression, and outcome of infectious diseases. Many bacteria bind to cell surface HSPGs in vitro, and this activity is thought to be critical in the initial attachment to host cells in vivo. To determine the physiological significance of HSPG-pathogen interactions in vivo, we examined the role of syndecan-1 in a mouse model of S. aureus pneumonia. S. aureus pneumonia is a common complication among ventilated patients, and also a serious problem in patients at the extremes of ages with predisposing diseases, patients with immunosuppressive therapy or illness, and in individuals with cystic fibrosis. Preliminary studies showed that S. aureus virulence is significantly attenuated in the lungs of syndecan-1 null mice compared to those of wild type mice. However, unexpectedly, S. aureus did not bind to syndecan-1 and S. aureus adhesion to lung epithelial cells was not dependent on syndecan-1. These data suggested that S. aureus exploits syndecan-1 for its pathogenesis, but not as a cell surface receptor that facilitates its initial attachment to host cells. Instead, preliminary studies showed that a secreted soluble form of syndecan-1 promotes S. aureus pneumonia in a heparan sulfate-dependent manner. Based on these data, we will explore how syndecan-1 functions as a pro-pathogenic factor in S. aureus pneumonia in two specific aims. In Aim 1, we will explore the hypothesis that syndecan-1 ectodomain promotes S. aureus pneumonia by inhibiting neutrophil-mediated host defense mechanisms and the staphylocidal activity of soluble defense factors in the airway. In Aim 2, we will explore the hypothesis that the induction of syndecan-1 shedding is a critical virulence activity in the pathogenesis of S. aureus pneumonia. Through these studies, our goal is to gain new mechanistic insights that will facilitate future development of novel therapeutic approaches to attenuate, halt, or reverse disease progression in S. aureus pneumonia - a significant cause of mortality and morbidity. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus pneumonia is a significant cause of mortality and morbidity in the US and worldwide. This grant proposal will explore the underlying biological mechanisms of how Staphylococcus aureus promotes its survival in the lung and causes pneumonia by exploiting one of our own molecules called syndecan-1.