The Role of Staphylococcus aureus SasD in Lung

金黄色葡萄球菌 SasD 在肺中的作用

• 批准号: 10748089
• 负责人: John F Alcorn
• 金额: $ 57.16万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-23 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748089
• 关键词: Address; Adherence; Adhesions; Alveolar Macrophages; Animal Model; Antibiotic Therapy; Antibiotics; Antigen Presentation; Attenuated; Bacteria; Bacterial Adhesion; Bacterial Attachment Site; Binding; COVID-19 pandemic; Cell Culture Techniques; Cell Death; Cell Wall; Cell-Matrix Junction; Cells; Clinical; Data; Enzymes; Epithelial Attachment; Epithelial Cells; Epithelium; Extracellular Matrix Proteins; Future; Genome; Growth; Human; Imaging Techniques; Immune; Immune system; Immunity; In Vitro; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Influenza; Injury; Interleukin-1 beta; Laboratories; Lung; Lung infections; Macrophage; Mediating; Membrane Proteins; Monoclonal Antibodies; Mus; Mutation; Organoids; Pathogenesis; Pathway interactions; Phagocytes; Phagolysosome; Pneumonia; Predisposition; Prevention; Production; Protein Family; Proteins; Publishing; Pulmonary Inflammation; Regulation; Research; Role; Signal Transduction; Stains; Staphylococcus aureus; Staphylococcus aureus infection; System; T-Lymphocyte; Testing; Therapeutic; Vaccine Design; Vaccines; Viral; Virulence; Virulence Factors; Virus Diseases; Work; attenuation; bacterial resistance; community acquired pneumonia; cytokine; experimental study; human model; humanized mouse; immunoregulation; in vitro Assay; in vivo; influenza infection; influenzavirus; lung injury; member; methicillin resistant Staphylococcus aureus; mortality; mutant; new therapeutic target; novel; pre-clinical; protein expression; recruit; sortase; superinfection; therapeutic evaluation; therapeutic target; therapy design; tool; uptake

SUMMARY Despite intense research focus, Staphylococcus aureus has remained an important cause of both community acquired pneumonia and viral-related super-infections. The field has recently determined host mediated mechanisms induced by S. aureus that drive lung infection and injury. In the context of preceding influenza infection, our group and many others have delineated aberrant immune pathway regulation as key drivers of S. aureus susceptibility and pathogenesis. In addition to host mediated interactions, S. aureus expresses a number of secreted and cell wall virulence factors that have not been fully characterized in pulmonary infection. We performed a transposon mutant screen of S. aureus cell wall anchored proteins in pulmonary infection and super- infection in mice. This screen revealed a novel S. aureus virulence factor, SasD, which is required for lung inflammation, injury, and mortality. SasD was also required for lung epithelial cell attachment and inflammatory cytokine induction by macrophages. In this application, we hypothesize that S. aureus SasD is a critical virulence factor in pulmonary infection, which mediates bacterial adherence to the lung stroma and interactions with primary lung phagocytes. We will test this hypothesis with two independent, but related Aims; 1) investigate the role of SasD in bacterial adhesion to lung epithelial cells and in vivo growth in the lung, 2) examine the role of SasD in mediating S. aureus interaction with pulmonary phagocytes and the impact on lung inflammation. We will determine the context dependent roles of S. aureus SasD in single and influenza super-infection. Further, we will utilize cutting edge tools to determine these interactions in human and mouse systems. Data generated in this project will inform upon focusing on S. aureus SasD at a potential therapeutic or vaccine target in pulmonary infections.

摘要 尽管高度重视研究，但金黄色葡萄球菌仍然是这两个社区的重要原因 获得性肺炎和病毒相关的超级感染。该领域最近确定了宿主中介 金黄色葡萄球菌引起肺部感染和损伤的机制。在前一次流感的背景下 感染，我们的团队和其他许多人已经将异常的免疫途径调节描述为S。 金黄色葡萄球菌的敏感性和发病机制。除了宿主介导的相互作用外，金黄色葡萄球菌还表达了许多 分泌性和细胞壁的毒力因子，在肺部感染中尚未得到充分的表征。我们 进行了金黄色葡萄球菌细胞壁锚定蛋白的转座子突变筛选 小鼠的感染。这个屏幕显示了一种新的金黄色葡萄球菌毒力因子SasD，它是肺部所必需的 炎症、损伤和死亡。SasD也是肺上皮细胞附着和炎症所必需的 巨噬细胞诱导的细胞因子。在这个应用中，我们假设金黄色葡萄球菌SasD是一种临界毒力 肺部感染中的因子，介导细菌与肺间质的黏附和相互作用 原代肺吞噬细胞。我们将用两个独立但相关的目标来检验这一假设：1)调查 SasD在细菌与肺上皮细胞黏附和体内生长中的作用，2)检测SasD的作用 SasD在介导金黄色葡萄球菌与肺吞噬细胞相互作用中的作用及其对肺部炎症的影响。我们 将确定金黄色葡萄球菌SasD在单一感染和流感双重感染中的上下文相关作用。此外， 我们将利用尖端工具来确定人类和老鼠系统中的这些相互作用。生成的数据 在这个项目中，将重点关注金黄色葡萄球菌SasD在潜在的治疗或疫苗目标 肺部感染。