The Role of Staphylococcus aureus SasD in Lung

金黄色葡萄球菌 SasD 在肺中的作用

基本信息

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
项目类别：
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

项目摘要

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.

概括尽管进行了强烈的研究重点，但金黄色葡萄球菌仍然是两个社区的重要原因获得的肺炎和病毒相关的超级感染。该领域最近确定了主机介导金黄色葡萄球菌诱导的机制驱动肺部感染和损伤。在先前的流感感染，我们的小组和许多其他人都将异常的免疫途径调节描述为S.的主要驱动力。金黄色的敏感性和发病机理。除了宿主介导的相互作用外，金黄色葡萄球菌还表达了一个数字在肺部感染中尚未完全表征的分泌和细胞壁毒力因子的。我们进行了金黄色葡萄球菌细胞壁的转座子突变筛，并在肺部感染和超级小鼠感染。该屏幕揭示了一种新颖的金黄色葡萄球菌毒力因子SASD，这是肺所需的炎症，伤害和死亡率。肺上皮细胞附着和炎症也需要SASD 巨噬细胞诱导细胞因子。在此应用中，我们假设金黄色葡萄球菌SASD是一种关键的毒力肺部感染的因子，肺部感染介导细菌粘附于肺基质，并与原发性肺吞噬细胞。我们将以两个独立但相关的目的检验这一假设。 1）调查 SASD在细菌粘附对肺上皮细胞和肺中体内生长中的作用，2）检查 SASD与金黄色葡萄球菌与肺吞噬细胞的相互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在单一和流感超级感染中的上下文作用。更远，我们将利用尖端工具来确定人和鼠标系统中的这些相互作用。生成的数据在这个项目中，将在潜在的治疗或疫苗靶标上关注金黄色葡萄球菌SASD 肺部感染。