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THE ROLE OF DEFENSINS AND C-X-C CHEMOKINES IN MAMMALIAN INNATE IMMUNITY by Linda Marie Rehaume B.Sc., University of Victoria (with distinction), 2001 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate Studies (Microbiology & Immunology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) November 2010 © Linda Marie Rehaume, 2010 ABSTRACT In humans, defensins constitute the largest group of host defence peptides that are evolutionarily conserved components of innate immunity. Defensins share many structural and functional characteristics with C-X-C chemokines, including a C-X-C amino acid motif, net positive charge, disulphide bonding, three-dimensional shape and chemokine activity. Deficiencies in α-defensins and C-X-C chemokines have been correlated with susceptibility to infection and chronic inflammatory diseases. However the genetics and diversity of defensins and mechanisms underlying these disorders were not well understood. This thesis comprises three separate but overlapping approaches to address these issues. The genomic content of murine α-defensins within the reference C57BL/6J strain was characterized. Novel α-defensin (11) and defensin-related cryptdin (3) genes were found, as were gene duplications and differences in genomic content between strains of mice. A next-generation sequencing method was developed for the quantitative analysis of α-defensin and defensin- related cryptdin gene expression. The α-defensin DEFA1 induced interleukin (IL) 8 and IL10 release from human PBMCs. The mechanism(s) of action of defensins, which appears to involve induction of chemokines and anti-inflammatory cytokines, needs further elucidation in vivo. Consequently, novel murine models of inflammation and immunosuppression were developed. The IL8 and Il10 genes were separately cloned, behind an intestine-specific promoter, into eukaryotic expression vectors, which were used to transfect murine embryonic stem cells. Correct targeting was confirmed for both constructs and germline transmission achieved for the IL8 mice. Conditional homozygous mice were generated, which, upon breeding with Cre-expressing mice, will express IL8, a C-X-C chemokine, in an intestinal-specific manner. This will enable analyses of effects of chemokine overexpression on intestinal infection, and on peptide efficacy in the resolution of infection. In other studies to address innate immune mechanisms, the transcriptional profiles of patients susceptible to Salmonella and mycobacterial infections due to immunodeficiencies in IL12- and interferon-γ-mediated immunity were generated. These data indicated that the chemokines CXCL9 and CXCL10 might mediate immunity to Mycobacteria whereas additional defects in TLR4 responses appeared to underlie susceptibility to Salmonella. The data presented here strengthen our understanding of the murine defensin repertoire and provide tools that enable sophisticated systems level studies of in vivo function. ii PREFACE A version of Chapter 2 has been published in: Amid, C.*, Rehaume, L.M.*, Brown, K.L., Gilbert, J.G.R., Dougan G., Hancock, R.E.W. and Harrow J.L. 2009. Manual annotation and analysis of the defensin gene cluster in the C57BL/6J mouse reference genome. BMC Genomics 10:606. Authors retain copyright. * Equal contribution Manual annotation of the defensin gene cluster in the C57BL/6J mouse reference genome was performed by Clara Amid in the Human and Vertebrate Analysis and Annotation (HAVANA) group at the Wellcome Trust Sanger Institute (WTSI). Subsequent analyses and writing of the manuscript was shared by Linda Rehaume and Clara Amid with overall revisions being performed by our supervisors. The text has been significantly revised in this thesis. James Gilbert originally created Figure 2.1 that was further modified in collaboration with Clara Amid. Figures 2.10 and 2.11 were generated by Clara Amid. The defensin transcriptional and functional experiments were performed by Linda Rehaume, and have not been published. Ethical approval was obtained for the work in the thesis involving human material. The research in Chapter 2 is covered by The University of British Columbia Clinical Research Ethics Board Certificate H04-70232. The research in Chapter 4 is covered by The Royal Free Hampstead National Health Service Trust Research Ethics Committee Certificate 04/Q0501/119. Approval for the research carried out in Chapter 4 was also obtained from the Wellcome Trust Sanger Institute Human Material and Data Management Committee. Throughout the thesis, genes and proteins are referred to using approved nomenclature. This means that references to previous studies, where non-approved nomenclature was used, have been changed accordingly; although the non-approved nomenclature is also indicated in brackets for clarity. The distinction between human and mouse gene and protein symbols is made by capitalization. Human symbols contain all upper-case letters and mouse symbols begin with an upper-case letter followed by lower-case letters. iii TABLE OF CONTENTS ABSTRACT ................................................................................................................................................ ii PREFACE .................................................................................................................................................. iii TABLE OF CONTENTS...........................................................................................................................iv LIST OF TABLES.......................................................................................................................................v LIST OF FIGURES.................................................................................................................................. vii ABBREVIATIONS ....................................................................................................................................ix ACKNOWLEDGEMENTS..................................................................................................................... xii DEDICATION......................................................................................................................................... xiii 1 INTRODUCTION..................................................................................................................................1 1.1 MODULATORS OF THE IMMUNE SYSTEM .......................................................................................1 1.2 DEFENSINS .....................................................................................................................................2 1.3 PEPTIDE THERAPEUTICS IN MODELS OF INFLAMMATION..............................................................5 1.4 INTERLEUKIN 8 ..............................................................................................................................6 1.5 INTERLEUKIN 10 ............................................................................................................................9 1.6 CYTOKINES IN GASTROINTESTINAL DISEASE..............................................................................11 1.7 PROJECT GOALS AND HYPOTHESES.............................................................................................13 2 α-DEFENSIN GENE ANNOTATION, QUANTITATIVE TRANSCRIPT EXPRESSION AND FUNCTIONAL ACTIVITY ......................................................................................................15 2.1 INTRODUCTION ............................................................................................................................15 2.2 METHODS AND MATERIALS.........................................................................................................17 2.3 RESULTS.......................................................................................................................................30 2.4 DISCUSSION..................................................................................................................................69 3 TARGETED KNOCK-IN OF INTERLEUKIN 8 AND INTERLEUKIN 10 INTO MURINE EMBRYONIC STEM CELLS TO GENERATE MICE WITH CONDITIONAL INTESTINAL-SPECIFIC GENE EXPRESSION ..............................................76 3.1 INTRODUCTION ............................................................................................................................76 3.2 METHODS AND MATERIALS.........................................................................................................80 3.3 RESULTS.....................................................................................................................................102 3.4 DISCUSSION................................................................................................................................132 4 CHARACTERIZATION OF TRANSCRIPTIONAL PROFILES INVOLVED IN INTERLEUKIN 12- AND INTERFERON-γ-MEDIATED PRIMARY IMMUNODEFICIENCIES...............................................................................................................137 4.1 INTRODUCTION ..........................................................................................................................137 4.2 METHODS AND MATERIALS.......................................................................................................141 4.3 RESULTS.....................................................................................................................................146
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