Extracellular vesicles released in response to Yersinia pestis

鼠疫耶尔森菌释放细胞外囊泡

• 批准号: 10439253
• 负责人: Matthew B Lawrenz
• 金额: $ 23.44万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439253
• 关键词: Anti-Inflammatory Agents; Antigen Presentation; Autoimmunity; Bacteria; Bacterial Infections; Bacterial Proteins; Biological; Biology; Carbohydrates; Cell Communication; Cells; Characteristics; 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; Malignant Neoplasms; Mediating; Membrane; Molecular; Nucleic Acids; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Phagocytosis Inhibition; Physiological; Plague; Play; 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; base; cytokine; exosome; extracellular vesicles; fungus; human disease; improved; intercellular communication; macrophage; 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.

概括 细胞外囊泡（EV）是膜结合的囊泡，由有效车辆的细胞释放 用于细胞间通信。 EV的信号传导能力是通过掺入不同的 生物分子（例如蛋白质，脂质，核酸和碳水化合物）。 中性粒细胞在识别多种刺激后产生电动汽车，但是电动汽车的生物学特性 根据遇到的刺激而改变。因此，根据刺激，中性粒细胞衍生的EV 已证明可以诱导受体细胞中的促和抗炎反应。中性粒细胞 还可以产生直接对细菌和真菌直接微生物骨化的电动汽车子集。但是， 嗜中性粒细胞的EV反应仅针对极少数细菌的特征，因此 我们对中性粒细胞衍生的电动汽车的全部潜力的理解有限 细菌感染。耶尔森氏菌是人类疾病的病因，称为瘟疫。 Y. Pestis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。具体而言，Y. Pestis使用三型分泌系统（T3SS） 将细菌蛋白（称为YOPS）直接分泌到宿主细胞中，这破坏了特定的宿主细胞信号传导 途径。 Yop易位到宿主中性粒细胞的结果包括：阻断吞噬作用， 抑制活性氧的产生，并降低了促炎的产生 中性粒细胞的细胞因子。最近，我们和其他人表明Y. Pestis能够阻止中性粒细胞 以T3SS依赖性方式进行颗粒胞吐作用。这些数据一起表明Y. Pestis有效 通过中性粒细胞改变内吞和胞吞活性。尽管它能够破坏内吞和 外囊肿途径，鼠疫耶和华的能力尚未 先前已调查。随着对电动汽车在炎症和细菌清除率中的欣赏， 我们缺乏对先天免疫细胞对Y. Pestis释放的电动汽车的正确理解 代表对Y. Pestis的免疫反应中的关键知识差距。基于先前出版的 研究和我们的初步数据，我们假设Y. Pestis会通过 先天免疫细胞，这种改变对电动汽车如何影响免疫有直接影响 对细菌的反应。为了检验这一假设，在目标1中，我们将定义 中性粒细胞响应Y. PESTIS感染以及是否T3SS，中性粒细胞包装成电动汽车的有效载荷 YOP效应子会改变电动汽车的产生。在AIM 2中，我们将确定电动汽车孤立的影响 来自感染Y. Pestis或Y. Pestis菌株的中性粒细胞，缺乏YOP效应子对免疫细胞的效应子 对Y. Pestis感染的反应。这些目标的完成将首次提供全面 人类嗜中性粒细胞对Y. PESTIS感染而产生的电动汽车的描述。