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Microsoft Word Genetic and Immunological Dissection of Host Susceptibility to Cryptococcus neoformans Infection Mitra Shourian Department of Experimental Medicine McGill University Montreal, QC, Canada June 2017 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Doctor of Philosophy © Mitra Shourian, 2017 1 To my beloved parents, Parviz and Tahereh To Mojtaba, Shaghaiegh and Mahla I am blessed and grateful beyond words to have you in my life… 2 Acknowledgment First, I would like to thank my supervisor Dr. Salman Qureshi. Thank you for giving me the opportunity to do research in your lab. Thank you for your support, knowledge and scientific guidance over the past years. Thank you for the peaceful workplace, independence and trust you offered which allowed me to think, plan, study, fail and accomplish. I also highly appreciate your understanding and support while I was writing my thesis. Thank you to Isabelle Angers for scientific advice, assistance in performing experiments and lab management. A special thank you to Annie Beauchamp for breeding mice and helping me with long animal experiments. In addition, I would like to thank past lab members, Scott Carroll, Erin Lafferty and Adam Flaczyk for training me during my early years in the lab. I thank my supervisory committee members, Dr. Silvia Vidal, Dr. Danielle Malo, Dr. Maziar Divangahi and Dr. Jacques Lapointe, for taking the time to attend yearly committee meetings and their scientific suggestions. I also thank the RI-MUHC and the Division of Experimental Medicine for their financial support. Finally, I would like to thank all my friends and family members, who are essential parts of my happiness. I would like to express my gratitude and love to Damien, for invaluable support, love and encouragement especially while I was writing my thesis. A special thank you to Sedighe and Soroor my lovely friends for daily talks, support and friendship. 3 Table of Contents Acknowledgment .................................................................................................................................. 3 Abstract ................................................................................................................................................. 9 Résumé................................................................................................................................................ 10 Contribution of Authors and Statement of Originality ....................................................................... 13 Chapter 1. Introduction .................................................................................................................. 15 1.1. Cryptococcosis as a global health threat ..................................................................................... 16 1.1.1. Importance of invasive fungal diseases .................................................................................... 16 1.1.2. Epidemiology of Cryptococcus sp. ............................................................................................. 16 1.2. The pathogen Cryptococcus ......................................................................................................... 18 1.2.1. Taxonomy .................................................................................................................................. 18 1.2.2. Environmental niches and host ................................................................................................ 19 1.2.3. Life cycle .................................................................................................................................... 20 1.2.4. Virulence factors ....................................................................................................................... 22 1.3. Human Cryptococcosis ................................................................................................................. 24 1.3.1. Pulmonary infection .................................................................................................................. 24 1.3.2. Cryptococcal meningitis (CM) ................................................................................................... 24 1.3.3. Diagnosis and treatment ........................................................................................................... 25 1.4. Immune response to cryptococcal infection ............................................................................... 26 1.4.1. Innate immune response .......................................................................................................... 26 1.4.2. Adaptive immune response ...................................................................................................... 29 1.4.3. Immune Reconstitution Inflammatory Syndrome (IRIS) ........................................................... 30 1.5. Genetic Susceptibility to Cryptococcal Infection ......................................................................... 33 1.6. Mouse Models of Infection .......................................................................................................... 33 1.6.1. Forward genetic analysis ........................................................................................................... 34 Interval Specific Congenic Strains ....................................................................................................... 35 Forward genetic approaches to cryptococcal infection ...................................................................... 36 1.6.2. Reverse genetic analysis ........................................................................................................... 37 Reverse genetic approaches to cryptococcal infection ...................................................................... 37 1.7. Thesis rationale and specific aims ................................................................................................ 40 Figure 1.1. A: global burden of HIV-related cryptococcal meningitis. …………………………………………….18 Figure 1.2. Evolution of the C. neoformans species complex. ............................................................ 19 4 Figure 1.3. Model of C. neoformans life cycle. .................................................................................... 21 Figure 1.4. The immune response to C. neoformans. ......................................................................... 32 Table 1.1. C. neoformans Virulence Factors. ...................................................................................... 23 Table1.2. Reverse genetic studies in Cryptococcus infection using knockout mice. .......................... 38 Chapter 2. The Cnes2 locus on mouse chromosome 17 regulates host defense against cryptococcal infection through pleiotropic effects on host immunity ................................... 41 Preface to Chapter 2 ........................................................................................................................... 42 2.1. Abstract ....................................................................................................................................... 43 2.2. Introduction ................................................................................................................................. 44 2.3. Materials and Methods ............................................................................................................... 47 2.4. Results ......................................................................................................................................... 52 2.5. Discussion .................................................................................................................................... 58 Figures ................................................................................................................................................. 64 Figure 2.1: The Cnes2 chromosomal interval restricts C. neoformans pulmonary infection and dissemination to the brain and spleen. .............................................................................................. 64 Figure 2.2: B6.CBA-Cnes2 mice develop an altered pattern of pulmonary inflammation following C. neoformans infection. ..................................................................................................................... 65 Figure 2.3: Increased airway neutrophilia, decreased eosinophilia, and enhanced macrophage accumulation in C57BL/6.CBA-Cnes2 airways following C. neoformans infection ............................. 66 Figure 2.4: B6.CBA-Cnes2 lungs have a heightened inflammatory response to C. neoformans infection characterized by increased expression of Th1 cytokines and chemokines ......................... 67 Figure 2.5: B6.CBA-Cnes2 mice display greater accumulation of neutrophils, exudate macrophages, and CD11b+ dendritic cells in the lungs following C. neoformans infection. ...................................... 68 Figure 2.6: Pulmonary macrophages and dendritic cells of B6.CBA-Cnes2 mice develop a stronger classical activation phenotype in response to C. neoformans infection ............................................. 70 Figure 2.7: The lungs of B6.CBA-Cnes2 mice contain a greater number of T lymphocytes during the adaptive immune response against C. neoformans. ........................................................................... 71 Figure 2.8: Decreased Th2 type cytokine expression by CD4+ T cells from B6.CBA-Cnes2
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