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Download The PROBING THE INTERACTION OF ASPERGILLUS FUMIGATUS CONIDIA AND HUMAN AIRWAY EPITHELIAL CELLS BY TRANSCRIPTIONAL PROFILING IN BOTH SPECIES by POL GOMEZ B.Sc., The University of British Columbia, 2002 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2010 © Pol Gomez, 2010 ABSTRACT The cells of the airway epithelium play critical roles in host defense to inhaled irritants, and in asthma pathogenesis. These cells are constantly exposed to environmental factors, including the conidia of the ubiquitous mould Aspergillus fumigatus, which are small enough to reach the alveoli. A. fumigatus is associated with a spectrum of diseases ranging from asthma and allergic bronchopulmonary aspergillosis to aspergilloma and invasive aspergillosis. Airway epithelial cells have been shown to internalize A. fumigatus conidia in vitro, but the implications of this process for pathogenesis remain unclear. We have developed a cell culture model for this interaction using the human bronchial epithelium cell line 16HBE and a transgenic A. fumigatus strain expressing green fluorescent protein (GFP). Immunofluorescent staining and nystatin protection assays indicated that cells internalized upwards of 50% of bound conidia. Using fluorescence-activated cell sorting (FACS), cells directly interacting with conidia and cells not associated with any conidia were sorted into separate samples, with an overall accuracy of 75%. Genome-wide transcriptional profiling using microarrays revealed significant responses of 16HBE cells and conidia to each other. Significant changes in gene expression were identified between cells and conidia incubated alone versus together, as well as between GFP positive and negative sorted cells. The identification of biologically relevant responses in both species validates this methodology, and motivates further work to characterize the interactions ii between A. fumigatus conidia and primary airway epithelial cells obtained from normal and asthmatic patients. iii TABLE OF CONTENTS ABSTRACT .............................................................................................................................ii TABLE OF CONTENTS........................................................................................................... iv LIST OF TABLES ................................................................................................................... vii LIST OF FIGURES ................................................................................................................ viii LIST OF ABBREVIATIONS ..................................................................................................... ix ACKNOWLEDGEMENTS ..................................................................................................... xiii DEDICATION ...................................................................................................................... xiv CHAPTER 1: INTRODUCTION ............................................................................................... 1 1.1 HOST-PATHOGEN INTERACTIONS IN MICROBIAL PATHOGENESIS ............................ 1 1.1.1 The damage-response framework of microbial pathogenesis .......................... 2 1.1.2 Transcriptional profiling of host-pathogen interactions ................................... 5 1.2 THE AIRWAY EPITHELIUM ......................................................................................... 7 1.2.1 Immune function of the airway epithelium ....................................................... 8 1.2.2 Roles of the airway epithelium in asthma pathogenesis ................................. 10 1.3 ASPERGILLUS FUMIGATUS ...................................................................................... 11 1.3.1 Virulence factors of Aspergillus fumigatus ...................................................... 12 1.3.2 Host defenses against Aspergillus fumigatus .................................................. 13 1.3.3 Diseases caused by Aspergillus fumigatus ....................................................... 14 1.4 OVERVIEW OF EXPERIMENTAL GOALS AND APPROACHES OF THE PRESENT RESEARCH ..................................................................................................................... 17 CHAPTER 2: CO-INCUBATION AND INTERNALIZATION OF ASPERGILLUS FUMIGATUS CONIDIA BY HUMAN BRONCHIAL EPITHELIAL CELLS ........................................................ 18 2.1 INTRODUCTION ....................................................................................................... 18 2.2 METHODS ................................................................................................................ 20 2.2.1 Aspergillus fumigatus strain and growth conditions ....................................... 20 2.2.2 Culture of human bronchial epithelial cells ..................................................... 21 2.2.3 Visualization of conidia uptake by 16HBE and NHBE cells by three dimensional rendering of the cell monolayer ............................................................................... 23 2.2.4 Quantification of conidia uptake by 16HBE cells by immunofluorescent staining ...................................................................................................................... 25 2.2.5 Quantification of conidia uptake by 16HBE cells by nystatin protection assay ................................................................................................................................... 26 iv 2.3 RESULTS ................................................................................................................... 28 2.3.1 Localization of Aspergillus fumigatus conidia within 16HBE and NHBE cell monolayers ............................................................................................................... 28 2.3.2 Quantification of internalization of Aspergillus fumigatus conidia by 16HBE cells by immunofluorescent staining ........................................................................ 28 2.3.3 Confirmation and determination of time course of internalization by nystatin protection assay ........................................................................................................ 31 2.4 DISCUSSION ............................................................................................................. 33 2.5 SUMMARY ............................................................................................................... 36 CHAPTER 3: FLOW CYTOMETRIC ANALYSIS AND SORTING OF HUMAN BRONCHIAL EPITHELIAL CELLS INTERACTING WITH ASPERGILLUS FUMIGATUS CONIDIA ................... 38 3.1 INTRODUCTION ....................................................................................................... 38 3.2 METHODS ................................................................................................................ 41 3.2.1 Preparation of cell culture samples for flow cytometric analysis ................... 41 3.2.2 Flow cytometric analysis of 16HBE cells and Aspergillus fumigatus conidia .. 41 3.2.3 Sorting of 16HBE cells co-incubated with conidia into negative and positive cell samples ............................................................................................................... 42 3.3 RESULTS ................................................................................................................... 44 3.3.1 Flow cytometric analysis of samples of Aspergillus fumigatus conidia, 16HBE cells, and cells and conidia co-incubated together .................................................. 44 3.3.2 Sorting and re-analysis of 16HBE cells co-incubated with Aspergillus fumigatus conidia ....................................................................................................................... 44 3.3.3 Microscopic visualization of negative and positive sorted samples of 16HBE cells ........................................................................................................................... 47 3.4 DISCUSSION ............................................................................................................. 50 3.5 SUMMARY ............................................................................................................... 52 CHAPTER 4: TRANSCRIPTIONAL ANALYSIS OF HUMAN BRONCHIAL EPITHELIAL CELLS INTERACTING WITH ASPERGILLUS FUMIGATUS CONIDIA ................................................ 53 4.1 INTRODUCTION ....................................................................................................... 53 4.2 METHODS ................................................................................................................ 55 4.2.1 Overview of experimental design for dual-species transcriptional analysis ... 55 4.2.2 Extraction of RNA from samples of 16HBE cells and Aspergillus fumigatus conidia ....................................................................................................................... 56 4.2.3 Quantitative real-time PCR analysis of human and fungal mRNA signals from co-incubated samples ............................................................................................... 60 4.2.4 Microarray analysis of human and fungal transcriptomes .............................. 61 4.2.5 Statistical analysis of 16HBE cell transcriptional responses to Aspergillus fumigatus conidia
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