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The role of exosomes in Pseudomonas Aeruginosa Corneal Infection

外泌体在铜绿假单胞菌角膜感染中的作用

基本信息

批准号：
10418656
负责人：
DANIELLE M. ROBERTSON
金额：
$ 40.5万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10418656
关键词：
Adrenal Cortex Hormones Anti-Bacterial Agents Anti-Inflammatory Agents Antibiotic Resistance Antimicrobial Effect Autologous Bioenergetics Biology Blindness Blood Body Fluids Cells Cellular biology Chemotaxis Communicable Diseases Contact Lenses Core Facility Cornea Corneal Diseases Country Coupled Data Disease Epithelial Cells Exhibits Eye Fluoroquinolones Genetic Transcription Goals Host Defense Host Defense Mechanism Human Human body Immune In Vitro Infection Infectious Agent Inflammation Inflammation Mediators Invaded Keratitis Laboratories Mass Spectrum Analysis Mediating Modeling Neutrophil Activation Ophthalmology Oryctolagus cuniculus Parotid Gland Pathologic Peptide Hydrolases Phagocytosis Pilot Projects Play Property Proteins Proteomics Pseudomonas Pseudomonas Infections Pseudomonas aeruginosa Pseudomonas aeruginosa infection Publishing Resolution Resources Role Saliva Salivary Salivary Glands Serum Small Interfering RNA Sterility System Testing Therapeutic Therapeutic Agents Therapeutic Uses Tissues Topical Antibiotic Trauma antimicrobial combat comparative efficacy corneal epithelial wound healing corneal epithelium design exosome extracellular vesicles immunoregulation in vivo in vivo Model inhibitor innovation intercellular communication microbial multidisciplinary neutrophil novel novel strategies novel therapeutic intervention novel therapeutics pathogen prevent response transcriptome sequencing translational applications uptake vesicular release

项目摘要

PROJECT SUMMARY Pseudomonas aeruginosa (PA) is the leading causative agent in microbial keratitis. During contact lens wear, host defense mechanisms are compromised. This allows PA to breach the tight corneal barrier and infect the otherwise healthy eye. Recently, exosomes have been implicated as major players in inflammation and infection. In addition, exosomes are becoming increasingly recognized as potential therapeutic agents. Our preliminary data shows that there is massive exosome release from corneal epithelial cells during infection by PA. These exosomes contain a unique mixture of proteases, transcriptional regulators and proteins involved in immune regulation. We further provide data that indicates that these exosomes both promote neutrophil activation and convey protection to corneal epithelial cells against further invasion. Moreover, we have found that exosomes isolated from autologous body fluids have antimicrobial and immunomodulatory properties. Based on our findings, we propose the primary hypothesis that exosomes released from PA-infected corneal epithelial cells promote PA clearance by innate immune cells and prime non-infected corneal epithelial cells to defend against PA infection. We further propose the secondary hypothesis that exosomes derived from exosome rich body fluids contain potent antimicrobial and anti-inflammatory mediators that can be harnessed to promote PA clearance and disease resolution in the cornea. We will test these hypotheses as follows: Aim 1. Establish how exosomes isolated from PA-infected corneal epithelial cells and human body fluids impact innate immune cells in vitro. Aim 2. Determine how exosomes isolated from PA-infected corneal epithelial cells and human body fluids impact the corneal epithelial response to PA in vitro. Aim 3. Determine whether exosomes isolated from autologous human body fluids exhibit protective antimicrobial and immunomodulatory properties in the rabbit contact lens model in vivo. To accomplish these studies, we have compiled a highly collaborative multidisciplinary team and have access to state of the art resources in the Department of Ophthalmology and UT Southwestern core facilities. These studies are significant and innovative because they are the first of their kind for PA infection in any tissue or cell system. The potential therapeutic use of exosomes from human body fluids represents a major paradigm shift for treating corneal infections and has broad therapeutic implications.

项目概要铜绿假单胞菌 (PA) 是微生物性角膜炎的主要病原体。佩戴隐形眼镜期间，宿主防御机制受到损害。这使得 PA 突破紧密的角膜屏障并感染否则眼睛健康。最近，外泌体被认为是炎症和炎症的主要参与者。感染。此外，外泌体越来越被认为是潜在的治疗剂。我们的初步数据表明，感染期间角膜上皮细胞释放大量外泌体由PA。这些外泌体含有独特的蛋白酶、转录调节因子和相关蛋白质的混合物在免疫调节方面。我们进一步提供的数据表明这些外泌体都促进中性粒细胞激活并保护角膜上皮细胞免受进一步侵袭。此外，我们还发现从自体体液中分离出的外泌体具有抗菌和免疫调节特性。根据我们的发现，我们提出主要假设：PA 感染的角膜释放外泌体上皮细胞通过先天免疫细胞促进 PA 清除，并促使未感染的角膜上皮细胞防御PA感染。我们进一步提出第二个假设，即外泌体来源于富含外泌体的体液含有可利用的有效抗菌和抗炎介质促进角膜 PA 清除和疾病解决。我们将按如下方式测试这些假设：目标 1. 确定如何从 PA 感染中分离外泌体角膜上皮细胞和人体体液在体外影响先天免疫细胞。目标 2. 确定从 PA 感染的角膜上皮细胞和人体液中分离出的外泌体如何影响体外角膜上皮对 PA 的反应。目标 3. 确定外泌体是否从自体人体液具有保护性抗菌和免疫调节特性兔体内隐形眼镜模型。为了完成这些研究，我们组建了一个高度协作的多学科团队，并拥有眼科和 UT 西南核心设施拥有最先进的资源。这些研究具有重要意义和创新性，因为它们是第一个针对 PA 感染的此类研究。组织或细胞系统。人体体液外泌体的潜在治疗用途代表了治疗角膜感染的重大范式转变，具有广泛的治疗意义。