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.

粘蛋白发酵菌对慢性肺炎铜绿假单胞菌毒力的影响 鼻-鼻窦炎 项目摘要/摘要 慢性鼻-鼻窦炎(CRS)是一种慢性呼吸道疾病，定义为持续性炎症和感染 鼻腔和鼻窦粘膜。微生物通过物种间的相互作用影响人类健康，具有广泛的 结果五花八门--有些有益，有些有害。破坏鼻窦内稳定的微生物区系 病原体的过度生长会导致良性微生物群落变得促炎和侵袭性。 铜绿假单胞菌是一种机会性的革兰氏阴性细菌，与严重的， 顽固性CRS；患有铜绿假单胞菌的CRS患者的症状缓解较差，临床较差 结果，导致并发症，如眼眶蜂窝组织炎和脑脓肿，即使在非 免疫功能受损的个体。因此，确定铜绿假单胞菌毒力的潜在机制 在CRS中，进展对于开发新的治疗策略至关重要。我们的目标是测试一个 假设粘蛋白发酵微生物促进了铜绿假单胞菌的微生物毒力，导致了 顽固性CRS的进展。 (1)评估体内铜绿假单胞菌毒力增强和CRS进展是否依赖粘蛋白 脆弱芽孢杆菌的发酵。预计CRS兔接种野生型铜绿假单胞菌和野生型B。 脆弱杆菌表现出最严重的CRS表型，具有显著的组织侵袭和毒力相关 基因/蛋白质标记。 (2)确定粘液发酵微生物如何调节铜绿假单胞菌的组织侵袭和 体外对抗生素的耐药性。我们希望确定在调节抗生素耐药性和 侵入人体组织。 我们希望这项建议能回答有关顽固性铜绿假单胞菌毒力的根本问题。 破坏性的CRS，这反过来可以导致为一种疾病开发新的、有效的治疗策略 带来了巨大的医疗负担。拟议中的实验还将阐明如何与 粘蛋白发酵微生物影响其他与铜绿假单胞菌相关的呼吸道疾病，如恶性 外耳炎、囊性纤维化和慢性阻塞性肺疾病。