Early airway innate immune responses to F. tularensis

对土拉弗朗西斯菌的早期气道先天免疫反应

• 批准号: 7920676
• 负责人: William M. Nauseef
• 金额: $ 33.77万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920676
• 关键词: Abbreviations; Acute; Aerosols; Alveolar; Alveolar Macrophages; Antigens; Apoptosis; Attenuated Vaccines; Breathing; Caspase-1; Cell Death; Cells; Cessation of life; Colony-forming units; Complement; Defect; Dendritic Cells; Depressed mood; Detergents; Development; Disease; Disease Outbreaks; Elements; Endothelial Cells; Epithelial; Epithelial Cells; Epithelium; Francisella tularensis; Gelatinase B; Gram-Negative Bacteria; Homeostasis; Host Defense; Human; Immune; Immune response; Immunologics; Infection; Inflammatory Response; Instruction; Intervention; Invaded; Lung; Lung diseases; Matrix Metalloproteinases; Mediating; Membrane; NADPH Oxidase; Organism; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Pneumonia; Property; Reactive Oxygen Species; Recruitment Activity; Resistance; Route; Skin; Sterility; Surface; Testing; Virulence; Virulent; aerosolized; antimicrobial; assault; base; capsule; caspase-3; chemokine; extracellular; human disease; innate immune function; insight; methionyl-leucyl-phenylalanine; microbial; neutrophil; novel; novel therapeutics; prevent; prophylactic; response; success; transmission process

PROJECT SUIVIMARY (See instructions): Francisella tularensis (Ft) is an intracellular Gram-negative bacterium that is highly pathogenic when aerosolized. We reason that the remarkable pathogenicity of aerosolized Ft reflects unique microbial features that render local innate host defenses in the lung quantitatively or qualitatively ineffective and hypothesize that specific surface features of Ft, including extracellular capsule-like material (CLM), subvert local pulmonary innate defenses, resulting in blunted host response in the lung and consequently the observed virulence of aerosolized Ft. As part of our comprehensive assessment of Ft-ain/vay innate host defense interaction and the contribution of CLM, Project 2 will examine alveolar epithelial cells (AEC), pulmonary microvascular endothelial cells (PMVEC) and neutrophils that traverse Ftstimulated AEC and PMVEC (rPMN) - three interconnected elements of early pulmonary innate host response. We will pursue the following two aims: Aim 1: To characterize the mechanisms and functional consequences of Ft resistance to endogenous pulmonary alveolar epithelial and endothelial cell defenses Do invading Ft or its CLM alter innate antimicrobial and proinflammatory responses of AEC and PMVEC? Do invading Ft alter PECAM-CD99 interactions involved in transmigration? Does Ft infection of AEC and PMVEC activate the inflammasome? Do interactions of AEC or PMVEC with Ft alter microbial phenotype and do such changes influence virulence? How do structural changes in CLM influence interactions between Ft and AEC or PMVEC and thereby alter PMN transmigration? How do ainway dendritic cells influence Ft invasion of AEC and AEC responses to invasion? Aim 2: To define the functional alterations In transmigrated PMN recruited by Ft that contribute to Ft virulence Does development of the rPMN phenotype require contact with Ft, shed bacterial components such as CLM, PMVEC-specific factor(s), or a combination of these elements? Does a similar phenotype develop in PMN that migrate across AEC? What is the functional phenotype of rPMN? What mechanism(s) underlie the depressed NADPH oxidase of rPMN? Do structural changes in Ft CLM alter interactions of Ft with PMVEC/AEC with subsequent effects on rPMN? Do rPMN that ingest Ft progress normally to undergo caspase-3-mediated apoptosis or are they redirected to a caspase-1-mediated proinflammatory cell death?

Suivimary项目（请参阅说明）： 弗朗西斯菌（Francisella toarlensis）（ft）是一种细胞内革兰氏阴性细菌，当时是高度致病性的 雾化。我们认为，雾化FT的显着致病性反映了独特的微生物 在定量或定性无效的肺中导致本地先天宿主防御的功能 假设FT的特定表面特征，包括细胞外胶囊样材料（CLM）， 颠覆局部肺先天防御，导致肺部的宿主反应钝化 因此，观察到的雾化ft的毒力。作为我们全面评估的一部分 ft-ain/vay先天主机防御互动和CLM的贡献，项目2将检查肺泡 上皮细胞（AEC），肺微血管内皮细胞（PMVEC）和中性粒细胞遍及FtStimentimentimentimentimentimentimentimentimentime ftStimentimeAC和PMVEC（rpmn） - 早期肺育宿主反应的三个相互连接的元素。我们将追求以下两个目标： 目标1：表征FT抵抗的机制和功能后果 内源性肺肺泡上皮和内皮细胞防御 入侵FT或其CLM会改变AEC和PMVEC的先天抗菌和促炎反应吗？入侵ft Alter Alter Pecam-CD99与移民有关的相互作用？ FT感染AEC和PMVEC会激活炎症体吗？ AEC或PMVEC与FT的相互作用是否改变了微生物表型并会影响毒力吗？ CLM的结构变化如何影响FT与AEC或PMVEC之间的相互作用，从而改变PMN转移？ Ainway树突状细胞如何影响AEC的FT侵袭和AEC对侵袭的反应？ 目的2：定义FT招募的转移PMN的功能改变，这有助于 FT毒力是否需要与FT，脱落细菌成分（例如CLM，PMVEC特异性因子）或这些元素组合的细菌成分接触？ PMN中类似的表型是否跨AEC迁移？ RPMN的功能表型是什么？ RPMN的抑郁NADPH氧化酶是什么机制？ FT CLM的结构变化是否改变了FT与PMVEC/AEC的相互作用，随后对RPMN产生影响？ RPMN是否会摄入FT通常会进展为caspase-3介导的细胞凋亡，还是将其重定向到caspase-1介导的促炎细胞死亡？