Impact of mucin fermenting microbes on the virulence of Pseudomonas aeruginosa in chronic rhinosinusitis

粘蛋白发酵微生物对慢性鼻窦炎铜绿假单胞菌毒力的影响

• 批准号: 10430744
• 负责人: Do-Yeon Cho
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-19 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430744
• 关键词: Adult; Affect; Airway Disease; American; Anaerobic Bacteria; Antibiotic Resistance; Antibiotics; Asthma; Bacterial Genes; Bacteroides fragilis; Benign; Brain Abscess; CT2584 HMS; Carbon; Cellulitis; Chronic Bronchitis; Chronic Disease; Chronic Obstructive Pulmonary Disease; Clinical; Congestive Heart Failure; Cystic Fibrosis; DNA Probes; Data; Digoxin; Disease; Environment; Enzymes; Epithelial; Epoxide hydrolase; Exhibits; Eye Infections; Fermentation; Gene Expression; Gene Proteins; Gram-Negative Bacteria; Growth; Health; Healthcare; Human; Impairment; In Situ Hybridization; In Vitro; Individual; Infection; Inflammation; Inflammatory; Invaded; Irrigation; Isocitrate Lyase; Label; Lead; Light; Liquid substance; Malignant - descriptor; Measurement; Methods; Microbe; Modeling; Mucins; Mucous Membrane; National Institute of Allergy and Infectious Disease; Nutrient; Operative Surgical Procedures; Oryctolagus cuniculus; Otitis Externa; Outcome; Pathogenicity; Patients; Peptic Ulcer; Phenotype; Population; Proliferating; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pyruvate synthase; Quality of life; Research; Research Personnel; Resolution; Ribosomal RNA; Role; Saline; Sinus; Source; Steroid therapy; Streptococcus; Submucosa; Symptoms; System; Techniques; Testing; Tissues; Translating; Virulence; Virulence Factors; bone erosion; chronic respiratory disease; chronic rhinosinusitis; design; effective therapy; experimental study; human tissue; in vivo; macrophage; microbial; microbial community; microbiota; mutant; novel; pathogen; protein biomarkers; protein expression; response; transcriptome sequencing; treatment strategy

Title: Impact of mucin fermenting microbes on the virulence of Pseudomonas aeruginosa in chronic rhinosinusitis Project Summary/Abstract Chronic rhinosinusitis (CRS) is a chronic airway disease defined as persistent inflammation and infection of the nasal and sinus mucosa. Microbes affect human health through interspecies interactions, with a broad spectrum of outcomes - some beneficial, others pathogenic. Disruption of the stable microbiota in the sinuses and pathogen overgrowth can lead to benign microbial communities becoming pro-inflammatory and invasive. Pseudomonas aeruginosa is an opportunistic, gram-negative bacterial species associated with severe, recalcitrant CRS; CRS patients with P. aeruginosa correlate with poor symptom resolution and worse clinical outcomes, leading to complications, such as orbital cellulitis and brain abscess, even in non- immunocompromised individuals. Thus, identifying the mechanisms underlying the virulence of P. aeruginosa in CRS progression is critical to developing new treatment strategies. Our aims are designed to test a hypothesis that mucin-fermenting microbes promote the microbial virulence of P. aeruginosa, leading to the progression of recalcitrant CRS. (1) To evaluate whether enhanced P. aeruginosa virulence and CRS progression in vivo rely on mucin fermentation by B. fragilis. We expect CRS rabbits inoculated with wild-type P. aeruginosa and wild-type B. fragilis to exhibit the most severe CRS phenotype with marked tissue invasion and virulence-associated gene/protein markers. (2) To determine how mucin-fermenting microbes modulate P. aeruginosa tissue invasion and antibiotic resistance in vitro. We expect to identify the critical actors in modulating antibiotic resistance and invasion in human tissue. We expect this proposal to answer fundamental questions regarding P. aeruginosa virulence in recalcitrant, destructive CRS, which, in turn, can lead to develop new, effective treatment strategies for a disease that exacts an enormous healthcare burden. The proposed experiments will also shed light on how interactions with mucin-fermenting microbes influence other airway diseases associated with P. aeruginosa, such as malignant otitis externa, cystic fibrosis, and chronic obstructive pulmonary disease.

标题：粘蛋白发酵微生物对慢性铜绿假单胞菌毒力的影响 鼻窦炎 项目概要/摘要 慢性鼻窦炎（CRS）是一种慢性气道疾病，定义为鼻窦持续炎症和感染。 鼻和鼻窦粘膜。微生物通过种间相互作用影响人类健康，影响范围广泛 结果的范围 - 有些是有益的，有些是致病的。破坏鼻窦内稳定的微生物群 病原体过度生长会导致良性微生物群落变得促炎和侵袭。 铜绿假单胞菌是一种机会性革兰氏阴性细菌，与严重、 顽固性CRS；患有铜绿假单胞菌的 CRS 患者与症状消退不良和临床症状较差相关 结果，导致并发症，例如眼眶蜂窝织炎和脑脓肿，即使在非 免疫功能低下的个体。因此，确定铜绿假单胞菌毒力的机制 CRS 进展对于制定新的治疗策略至关重要。我们的目标是测试 假设粘蛋白发酵微生物促进铜绿假单胞菌的微生​​物毒力，从而导致 顽固性 CRS 的进展。 (1) 评估体内铜绿假单胞菌毒力增强和CRS进展是否依赖于粘蛋白 由 B. fragilis 发酵。我们预计 CRS 兔子接种了野生型铜绿假单胞菌和野生型 B. fragilis 表现出最严重的 CRS 表型，具有明显的组织侵袭和毒力相关 基因/蛋白质标记。 (2) 确定粘蛋白发酵微生物如何调节铜绿假单胞菌组织侵袭和 体外抗生素耐药性。我们期望确定调节抗生素耐药性的关键因素 侵入人体组织。 我们期望该提案能够回答有关顽固性铜绿假单胞菌毒力的基本问题， 破坏性的 CRS，这反过来又可以导致针对以下疾病开发新的、有效的治疗策略： 造成巨大的医疗负担。拟议的实验还将揭示如何与 粘蛋白发酵微生物影响与铜绿假单胞菌相关的其他气道疾病，例如恶性 外耳炎、囊性纤维化和慢性阻塞性肺病。