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.

项目摘要/摘要 在感染期间，免疫细胞依靠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信的一个关键介体。这些 膜结合的囊泡含有代表A的炎性态的蛋白质，脂质和核酸 给定单元。释放后，这些电动汽车可以与其他免疫细胞融合，建立生化通信 在细胞之间并扩大对增强病原体清除率的炎症反应。耶尔西尼亚柴油是 人类疾病的病因学因素被称为瘟疫。这种疾病的标志是先进的 以双相的方式抑制宿主免疫系统。在急性感染期间，Y. Pestis使用其3型 分泌系统（T3SS）将效应蛋白注入宿主细胞中，这破坏了信号通路必不可少的信号通路 细菌清除率。因此，维持非炎症环境使急性感染是标志性的 其中细菌可以在不宿主干预的情况下增殖。感染的第二阶段，亲 炎症阶段，感染后36-48小时开始，宿主开始成功安装 对病原体的免疫反应。但是，细菌载荷最终使宿主延迟了 反应，届时宿主可能会屈服于感染。以前的工作证明了 急性感染期间这种非炎症环境的产生对于病虫毒力至关重要。尽管 许多研究强调了抑制吞噬作用，胞吞作用和其他的重要性 抗菌反应，关于Y. pestis如何操纵EV响应以及如何这种情况的知识存在差距 影响细胞间沟通。初步研究表明Y. Pestis可以操纵蛋白质 由中性粒细胞在体外包装成电动汽车。这些数据支持Y. Pestis破坏电动汽车的假设 感染期间的生产以改变炎症。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的体内EV反应（AIM 1）并定义电动汽车对 免疫调节（AIM 2）。这些研究将是第一个研究EV介导的细胞内作用的研究 瘟疫期间的交流。因此，这些目标的完成将大大改善我们的理解 如何。 Y. Pestis利用EV贩运来操纵宿主免疫反应。