Defining the impact of Extracellular Vesicles on inflammation during pneumonic plague

定义细胞外囊泡对肺鼠疫期间炎症的影响

• 批准号: 10750181
• 负责人: Katelyn Renee Sheneman
• 金额: $ 3.45万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750181
• 关键词: Antibacterial Response; Bacteria; Bacterial Infections; Binding; Biochemical; Cells; Communication; Data; Dependence; Development; Disease; Disease Progression; Endocytosis Inhibition; Environment; Etiology; Exocytosis; Generations; Goals; Hour; Human; Immune; Immune response; Immune system; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Intervention; Invaded; Knowledge; Lipids; Lung; Lung infections; Maintenance; Mediating; Mediator; Membrane; Neutrophil Infiltration; Nucleic Acids; Organism; Outcome; Pathogenesis; Pathway interactions; Phagocytes; Phagocytosis; Phase; Plague; Play; Pneumonic Plague; Population; Production; Productivity; Proliferating; Protein Secretion; Proteins; Pulmonary Inflammation; Role; Signal Pathway; Testing; Time; Tissues; Type III Secretion System Pathway; Vesicle; Virulence; Work; Yersinia pestis; acute infection; antimicrobial; cell type; cytokine; extracellular vesicles; human disease; immunoregulation; improved; in vivo; intercellular communication; mutant; neutrophil; new therapeutic target; pathogen; response; tool; trafficking

PROJECT SUMMARY/ABSTRACT During infection, immune cells rely on communication to productively target and eliminate invading pathogens. Extracellular vesicles (EVs) are one key mediator of intercellular communication between immune cells. These membrane-bound vesicles contain proteins, lipids, and nucleic acids that represent the inflammatory state of a given cell. Upon release, these EVs can fuse with other immune cells, establishing biochemical communication between cells and amplifying the inflammatory response to augment pathogen clearance. Yersinia pestis is the etiologic agent of the human disease known as plague. A hallmark of this disease is the sophisticated suppression of the host immune system in a biphasic manner. During acute infection, Y. pestis utilizes its type 3 secretion system (T3SS) to inject effector proteins into host cells which disrupt signaling pathways essential for bacterial clearance. Thus, acute infection is hallmarked by the maintenance of a non-inflammatory environment in which the bacteria can proliferate without host intervention. The second stage of infection, the pro- inflammatory phase, begins 36-48 hours post-infection, in which the host begins to successfully mount an immune response against the pathogen. However, the bacterial load ultimately overwhelms the host delayed responses, at which point the host may succumb to infection. Previous work has demonstrated that the generation of this non-inflammatory environment during acute infection is essential for Y. pestis virulence. While numerous studies have highlighted the importance of suppressing phagocytosis, exocytosis, and other antibacterial responses, there is a gap in knowledge of how Y. pestis manipulates the EV response and how this impacts intercellular communication. Preliminary studies suggest that Y. pestis can manipulate the proteins packaged into EVs by neutrophils in vitro. These data support the hypothesis that Y. pestis disrupts EVs production during infection to alter inflammation. The studies presented here will expand on our preliminary data by delineating the in vivo EV response during pneumonic plague (Aim 1) and defining the impact of EVs on immune modulation (Aim 2). These studies will be the first to investigate the role of EV-mediated intracellular communication during plague. Therefore, completion of these aims will significantly improve our understanding of how. Y. pestis exploits EV trafficking to manipulate the host immune response.

项目总结/摘要 在感染过程中，免疫细胞依赖于通信来有效地靶向和消除入侵的病原体。 细胞外囊泡（EV）是免疫细胞之间细胞间通讯的一种关键介质。这些 膜结合囊泡含有蛋白质、脂质和核酸，它们代表了炎症状态。 给定细胞。一旦释放，这些EV可以与其他免疫细胞融合，建立生化通讯 并放大炎症反应以增强病原体清除。鼠疫耶尔森菌是 鼠疫是人类疾病的病原体。这种疾病的一个特点是复杂的 以双相方式抑制宿主免疫系统。在急性感染期，Y.鼠疫利用其3型 分泌系统（T3 SS）将效应蛋白注入宿主细胞，从而破坏对细胞增殖至关重要的信号传导途径。 细菌清除。因此，急性感染的特点是维持非炎症环境 细菌可以在没有宿主干预的情况下增殖。感染的第二阶段，亲- 炎症阶段，开始于感染后36-48小时，在此期间宿主开始成功地安装一个 对病原体的免疫反应然而，细菌负荷最终使宿主延迟死亡， 反应，在这一点上，主机可能会屈服于感染。以前的工作表明， 在急性感染期间，这种非炎症环境的产生对于Y.鼠疫毒力而 许多研究已经强调了抑制吞噬作用、胞吐作用和其他细胞因子的重要性。 抗菌反应，在Y.鼠疫操纵EV反应， 影响细胞间的通讯初步研究表明Y.鼠疫菌可以操纵蛋白质 在体外被中性粒细胞包装成EV。这些数据支持Y.鼠疫破坏电动汽车 在感染期间产生以改变炎症。这里介绍的研究将扩展我们的初步数据 通过描述肺鼠疫期间EV的体内反应（目标1），并定义EV对 免疫调节（目标2）。这些研究将是第一个调查EV介导的细胞内的作用， 瘟疫期间的沟通因此，完成这些目标将大大提高我们的认识， 怎么做的Y.鼠疫利用EV贩运来操纵宿主免疫反应。