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?

项目概要（见说明）：