AbstractsBiology & Animal Science

Discriminating bacterial derived products by airway epithelial cells via p38 mitogen activated protein kinase

by Trevor Beaudoin




Institution: McGill University
Department: Department of Pharmacology & Therapeutics
Degree: PhD
Year: 2015
Keywords: Health Sciences - Pharmacology
Record ID: 2059706
Full text PDF: http://digitool.library.mcgill.ca/thesisfile130566.pdf


Abstract

The airway epithelium represents the first point of contact between inhaled pathogens and the host environment. Typically the host exhibits a number of innate immune defenses, including efficient mucociliary clearance of pathogens that act to keep the lungs a relatively sterile environment. When these defenses are compromised however, infections can occur in the lung and cause increased inflammatory responses. The airway epithelium itself can recognize pathogenic material to induce an inflammatory response. Patients that have Cystic Fibrosis (CF) show impaired mucociliary clearance and are more susceptible to respiratory infections. In fact, the majority of patients become chronically infected with Pseudomonas aeruginosa, a gram negative, opportunistic pathogen, by their teenage years. The presence of a chronic infection leads to increased inflammation in the lungs, increased morbidity and ultimately leading to respiratory failure, which is the leading cause mortality in these patients.The chronic infections observed in these CF patients exhibit a number of phenotypic changes that have not been extensively studied for their ability to initiate an immune response in the airway epithelium. Chronic infections are believed to be established by bacteria that form biofilms, which exhibit striking phenotypic differences to their planktonic, free swimming counterparts. The majority of existing studies looking at and identifying virulence determinants of P. aeruginosa on the airway epithelium have been done using purified ligands prevalent on planktonic bacteria. In this thesis I use a biofilm model to identify the differences in activation of airway epithelial cells to planktonic and biofilm derived materials. Additionally, the majority of P. aeruginosa strains isolated from chronically infected patients have adapted to exhibit a mucoid phenotype. The expression of a mucoid phenotype is protective in the CF environment, however various potential virulence determinants can also be differentially regulated. I will examine how this switch to a mucoid phenotype impacts activation of inflammatory mediators in airway epithelial cells.Taken together, the approaches I use in this thesis better identify the determinants that are important in regulating inflammatory mediator activation in airway epithelial. By understanding the key pathways involved in host defense, new methods in detecting key virulence determinants can be developed. L'épithélium des voies respiratoires représente le premier point de contact entre les agents pathogènes inhalés et l'environnement hôte. Typiquement l'hôte présente un certain nombre de défenses immunitaires innées, y compris la clairance mucociliaire efficace des agents pathogènes qui agissent pour maintenir les poumons d'un environnement relativement stérile. Lorsque ces moyens de défense sont compromises cependant, les infections peuvent se produire dans les poumons et provoquer une augmentation des réponses inflammatoires. L'épithélium des voies aériennes lui-même peut reconnaître matériau…