Polymicrobial Interactions in the Lung

肺部多种微生物的相互作用

• 批准号: 8538491
• 负责人: Jennifer Melinda Bomberger
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538491
• 关键词: Address; Air; Animal Model; Animals; Antigen Presentation; Bacterial Infections; Bacterial Proteins; Bacterial Toxins; Biochemical; Bronchiectasis; CD8B1 gene; Cell physiology; Cells; Cessation of life; Chloride Ion; Chlorides; Chronic; Clinical; Code; Communities; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytotoxic T-Lymphocytes; Data; Dimensions; Epithelial Cells; Genes; Goals; Haemophilus influenzae; Histocompatibility Antigens Class I; Human; Image; Immune; Immune response; Immunity; Immunologic Techniques; In Vitro; Infection; Influenza; Influenza A virus; Interferons; Laboratories; Liquid substance; Lung; Lung diseases; MHC Class I Genes; Mediating; Membrane; Microbe; Molecular; Morbidity - disease rate; Mucociliary Clearance; Mucous body substance; Names; Nosocomial Infections; Patients; Pneumonia; Proteins; Pseudomonas aeruginosa; Publishing; Research; Resolution; Respiratory Failure; Rhinovirus; Structure of parenchyma of lung; TAP1 gene; Testing; Toxin; Ventilator; Vesicle; Viral; Viral Antigens; Virulence Factors; Virus Diseases; Work; antigenic peptide transporter; cell injury; clinically relevant; cytokine; experience; in vivo; influenzavirus; insight; microbial; mortality; novel; novel therapeutic intervention; pathogen; research study; respiratory; respiratory infection virus; respiratory virus; response

Pseudomonas aeruginosa is an opportunistic pathogen and an important pathogen in patients with chronic obstructive pulmonary disorder (COPD), community acquired pneumonia (CAP), ventilator-associated pneumonia (VAP), non-CF bronchiectasis and cystic fibrosis (CF). Recent studies suggest that viral and P. aeruginosa infections of the lung are synergistic and dramatically contribute to the morbidity and mortality associated with COPD, CF, CAP, VAP, and non-CF bronchiectasis. The long-term goal of my research is to elucidate the cellular and molecular mechanisms whereby P. aeruginosa and respiratory viruses synergize to cause lung disease. My short-term research goal is to elucidate the mechanism whereby P. aeruginosa infection interferes with host clearance of respiratory virus. P. aeruginosa secretes a protein called Cif (CFTR Inhibitory Factor, originally named because of its ability to inhibit CFTR-mediated Cl secretion by airway cells), which is coded by the PA2934 (or cif) gene. Cif, which is secreted by laboratory and clinical isolates of P. aeruginosa, inhibits the host immune response by down-regulating CFTR Cl secretion and mucociliary clearance. In addition, Cif reduces the abundance of TAP1 (Transporter Associated with Antigen Processing), which my recent preliminary studies reveal, suppresses influenza A virus antigen presentation by class I MHC molecules and the ability of cytotoxic T lymphocytes (CTL) to clear viral infections. My preliminary data also demonstrate that cytokines, namely interferon-γ, released by the host in response to viral pathogens, increase the secretion of Cif from P. aeruginosa. Very little is known about how secreted bacterial proteins suppress the host immune response to viral pathogens, and there is minimal data elucidating how the host immune response alters the release of bacterial toxins from microbial pathogens. Accordingly, I will use in vitro biochemical, high resolution imaging, and in vivo immunological techniques to test the following four specific aims in this proposal: (1) Test the hypothesis that Cif reduces antigen presentation and CTL-mediated clearance; (2) Test the hypothesis that Cif reduces influenza virus antigen presentation and CTL-mediated clearance; (3) Test the hypothesis that P. aeruginosa and RSV co-infection benefits each pathogen by reducing viral antigen presentation and CTL-clearance of RSV and promoting P. aeruginosa colonization; and (4) Test the hypothesis that the host immune response increases virulence factor secretion by P. aeruginosa. I anticipate that these studies will elucidate how P. aeruginosa reduces the ability of the lung to clear viral infections and, ultimately, identify new therapeutic approaches to control combined P. aeruginosa and respiratory virus infections.

铜绿假单胞菌是一种条件致病菌，也是慢性病患者的重要致病菌。 阻塞性肺疾病 (COPD)、社区获得性肺炎 (CAP)、呼吸机相关性肺炎 肺炎 (VAP)、非 CF 支气管扩张和囊性纤维化 (CF)。最近的研究表明，病毒和 P. 肺部铜绿假单胞菌感染具有协同作用，极大地增加了发病率和死亡率 与 COPD、CF、CAP、VAP 和非 CF 支气管扩张相关。我研究的长期目标是 阐明铜绿假单胞菌和呼吸道病毒协同作用的细胞和分子机制 引起肺部疾病。我的短期研究目标是阐明铜绿假单胞菌的机制 感染会干扰宿主对呼吸道病毒的清除。铜绿假单胞菌分泌一种称为 Cif (CFTR 抑制因子，最初因其能够抑制气道细胞 CFTR 介导的 Cl 分泌而命名）， 由 PA2934（或 cif）基因编码。 Cif，由实验室和临床分离的 P. 铜绿假单胞菌，通过下调 CFTR Cl 分泌和粘液纤毛抑制宿主免疫反应 清除。此外，Cif 降低了 TAP1（与抗原加工相关的转运蛋白）的丰度， 我最近的初步研究表明，通过 I 类 MHC 抑制甲型流感病毒抗原呈递 分子和细胞毒性 T 淋巴细胞 (CTL) 清除病毒感染的能力。我的初步数据也 证明宿主响应病毒病原体释放的细胞因子，即干扰素-γ，会增加 铜绿假单胞菌分泌 Cif。关于分泌的细菌蛋白如何抑制 宿主对病毒病原体的免疫反应，并且很少有数据阐明宿主如何免疫 反应改变微生物病原体释放细菌毒素。因此，我将在体外使用 生化、高分辨率成像和体内免疫学技术来测试以下四种特定的 本提案的目的：(1) 检验 Cif 减少抗原呈递和 CTL 介导的假设 清除; (2)检验Cif减少流感病毒抗原呈递和CTL介导的假设 清除; (3) 检验铜绿假单胞菌和 RSV 共同感染对每种病原体有利的假设： 减少RSV的病毒抗原呈递和CTL清除并促进铜绿假单胞菌定植；和 (4) 检验宿主免疫反应增加铜绿假单胞菌毒力因子分泌的假设。我 预计这些研究将阐明铜绿假单胞菌如何降低肺部清除病毒的能力 感染，并最终确定新的治疗方法来控制铜绿假单胞菌和 呼吸道病毒感染。