Extracellular vesicles released in response to Yersinia pestis

鼠疫耶尔森菌释放细胞外囊泡

• 批准号: 10552010
• 负责人: Matthew B Lawrenz
• 金额: $ 19.56万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-18 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10552010
• 关键词: Anti-Inflammatory Agents; Antigen Presentation; Autoimmunity; Bacteria; Bacterial Infections; Bacterial Proteins; Binding; Biological; Biology; Carbohydrates; Cell Communication; Cells; Characteristics; Classification; Cytoplasmic Granules; Data; Exocytosis; Future; Generations; Goals; Grant; Growth; Human; Immune; Immune Evasion; Immune response; Immune signaling; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Knowledge; Lipids; Macrophage; Malignant Neoplasms; Mediating; Membrane; Molecular; Nucleic Acids; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Phagocytosis; Physiological; Plague; Population; Production; Property; Proteins; Publishing; Reactive Oxygen Species; Reporting; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Stimulus; System; Testing; Therapeutic; Therapeutic Intervention; Time; Vesicle; Yersinia pestis; cytokine; exosome; extracellular vesicles; fungus; human disease; improved; intercellular communication; monocyte; mutant; neutrophil; novel; novel strategies; recruit; response; tool; vesicular release

SUMMARY Extracellular vesicles (EVs) are membrane-bound vesicles released by cells that are potent vehicles for intercellular communication. The signaling capacity of EVs is mediated by incorporation of different biomolecules (e.g. proteins, lipids, nucleic acids, and carbohydrates) within individual vesicles. Neutrophils produce EVs upon recognition of a variety of stimuli, but the biological properties of EVs change depending on the stimuli encountered. Thus, depending on stimulation, neutrophil-derived EVs have been shown to induce both pro- and anti-inflammatory responses in recipient cells. Neutrophils can also produce a subset of EVs that are directly microbiostatic to bacteria and fungi. However, the EV response by neutrophils has only been characterized for very few bacterial species, and therefore, we have a limited understanding of the full potential of neutrophil-derived EVs in response to different bacterial infections. Yersinia pestis is the causative agent of the human disease known as plague. Y. pestis evades immune cell recognition via direct interactions with innate immune cells that disrupt the normal responses by these cells. Specifically, Y. pestis uses a type three secretion system (T3SS) to directly secrete bacterial proteins (called Yops) into host cells, which disrupt specific host cell signaling pathways. The outcomes of Yop translocation into host neutrophils include: blocking phagocytosis, inhibition of the generation of reactive oxygen species, and decreased production of pro-inflammatory cytokines by neutrophils. Recently, we and others have shown that Y. pestis is able to block neutrophil granule exocytosis in a T3SS-dependent manner. Together, these data show that Y. pestis efficiently alters endocytic and exocytic activities by neutrophils. Despite its ability to disrupt endocytic and exocytic pathways, the ability of Y. pestis to alter the production of EVs by host cells has not been previously investigated. With a growing appreciation for EVs in inflammation and bacterial clearance, our lack of a proper understanding of the EVs released by innate immune cells in response to Y. pestis represents a critical knowledge gap in the immune response to Y. pestis. Based on previously published studies and our preliminary data, we hypothesize that Y. pestis actively alters the production of EVs by innate immune cells, and that this alteration has a direct impact on how EVs can influence the immune response to the bacterium. To test this hypothesis, in Aim 1 we will define the composition of the payloads packaged into EVs by neutrophils in response to Y. pestis infection and whether the T3SS and Yop effectors alter the production of EVs. In Aim 2, we will determine the impact of EVs isolated from neutrophils infected with Y. pestis or a Y. pestis strain lacking the Yop effectors on immune cell response to Y. pestis infection. Completion of these Aims will provide for the first time a comprehensive description of the EVs produced by human neutrophils in response to infection with Y. pestis.

总结 细胞外囊泡是由细胞释放的膜结合囊泡，是有效的载体 进行细胞间通讯EV的信号传导能力是通过掺入不同的 在单个囊泡内的生物分子（例如蛋白质、脂质、核酸和碳水化合物）。 中性粒细胞在识别各种刺激后产生EV，但EV的生物学特性 变化取决于所遇到的刺激。因此，根据刺激，嗜中性粒细胞衍生的EV 已经显示在受体细胞中诱导促炎和抗炎反应。中性粒 还可以产生对细菌和真菌直接具有微生物抑制作用的EV子集。但 嗜中性粒细胞的EV应答仅在极少数细菌物种中得到表征，因此， 我们对嗜水气单胞菌衍生的电动汽车在应对不同的气候变化方面的全部潜力的了解有限。 细菌感染鼠疫耶尔森氏菌是人类疾病鼠疫的病原体。Y. 鼠疫通过与先天免疫细胞的直接相互作用来逃避免疫细胞的识别， 这些细胞的正常反应。具体来说，Y。鼠疫菌使用三型分泌系统（T3SS）， 直接分泌细菌蛋白（称为Yops）进入宿主细胞，破坏特定的宿主细胞信号传导 途径。Yop易位进入宿主嗜中性粒细胞的结果包括：阻断吞噬作用， 抑制活性氧的产生，并减少促炎性物质的产生， 中性粒细胞的细胞因子。最近，我们和其他人已经表明，Y。鼠疫杆菌能够阻断中性粒细胞 以T3SS依赖性方式的颗粒胞吐。这些数据表明，Y。鼠疫有效 改变中性粒细胞的内吞和外吞活性。尽管它有能力破坏内吞和 胞吐途径、Y.鼠疫杆菌改变宿主细胞产生EV的能力还没有被证实。 以前调查过。随着人们对电动汽车在炎症和细菌清除方面的日益重视， 我们缺乏对先天免疫细胞响应Y.鼠疫 代表了对Y的免疫反应的关键知识缺口。鼠疫根据此前发布的 研究和我们的初步数据，我们假设Y。鼠疫通过以下方式积极改变EV的生产： 先天免疫细胞，这种改变对EV如何影响免疫细胞有直接影响。 对细菌的反应。为了验证这一假设，在目标1中，我们将定义 中性粒细胞响应Y.以及T3SS是否 和Yop效应子改变EV的产生。在目标2中，我们将确定隔离电动汽车的影响 来自感染Y.鼠疫或Y.免疫细胞上缺乏Yop效应子的鼠疫菌株 回答Y。鼠疫感染这些目标的完成将首次提供一个全面的 描述了人类嗜中性粒细胞对感染Y.鼠疫