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Investigating the Impact of Polymicrobial Interactions on Mucorales Pathogenicity,” Submitted to the University of Birmingham in July 2019

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Investigating the Impact of Polymicrobial Interactions on Mucorales Pathogenicity,” Submitted to the University of Birmingham in July 2019 INVESTIGATING THE IMPACT OF POLYMICROBIAL INTERACTIONS ON MUCORALES PATHOGENICITY by Courtney Alice Kousser A thesis submitted to the University of Birmingham for the degree of DOCTOR OF PHILOSOPHY Institute of Microbiology and Infection School of Biosciences College of Life and Environmental Sciences University of Birmingham July 2019 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract Within the human body, microorganisms reside as part of a complex and varied ecosystem, where they rarely exist in isolation. Bacteria and fungi have co- evolved to develop elaborate and intricate relationships, utilising both physical and chemical communication mechanisms. Mucorales are filamentous fungi that are the causative agents of mucormycosis in immunocompromised individuals. Key to the pathogenesis is the ability to germinate and penetrate the surrounding tissues, leading to angioinvasion, vessel thrombosis, and tissue necrosis. It is currently unknown whether Mucorales participate in polymicrobial relationships, and if so, how this affects the pathogenesis. This project analyses the relationship between Mucorales and the microorganisms they may encounter. Here we show that Pseudomonas aeruginosa culture supernatants and live bacteria inhibit Rhizopus microsporus germination through the sequestration of iron. Therefore, treatment of P. aeruginosa in a patient could result in the release of this inhibition, leaving the patient more susceptible to an underlying fungal infection. However, P. aeruginosa responds to the presence of R. microsporus by enhancing siderophore production, which increases host mortality in a zebrafish co-infection model. This project highlights the complex competition between these organisms and the possible enhanced disease pathology when R. microsporus and P. aeruginosa meet in a host. Happiness does not come from doing easy work but from the afterglow of satisfaction that comes after the achievement of a difficult task that demanded our best. Theodore Isaac Rubin Acknowledgements I am a firm believer that it takes a village to make a PhD, and it feels almost impossible to thank everyone who has helped me along the way. This was the hardest and most rewarding experience of my life, and I couldn’t have done it without a strong support system. I truly believe I have emerged a stronger, more confident person, and I will always be grateful for this time in my life. Firstly, thank you to my supervisor, Rebecca Hall, who has provided immense support, both personally and professionally. Thank you for always being available for my endless questions, and for listening to me when I was panicking about research, careers, or life in general. Thank you to my PhD besties, Pau, Jes, Nick, Ria, Liam, and Emily. You will never know how grateful I am for your friendship and for always holding me up when I felt like crumbling. I am so lucky to have you guys, and I couldn’t have done this without you. Thank you to Callum Clark, who contributed to this body of work, taught me how to supervise a student, and became a wonderful support system and friend. A huge thank you to the entire HAPI lab, whose friendship and expertise made this experience so much easier. Thank you for welcoming me immediately, encouraging me to no end, and helping me become a confident scientist and communicator. Thank you especially to Sarah Sherrington for her contributions to this work. A special thank you to Robin May for being a wonderful mentor and providing advice and support when I needed it. Thank you to my husband, Anton, who went above and beyond to support me during the past four years. Thank you very much to my examiners for taking the time to read this tome. Last, but certainly not least, thank you to the Darwin Trust of Edinburgh for funding my PhD. Table of Contents List of Figures................................................................................................ viii List of Tables ................................................................................................... x List of Equations.............................................................................................. x List of Abbreviations ........................................................................................ xi Chapter 1 : GENERAL INTRODUCTION .......................................................... 1 1.1 Fungi. ........................................................................................................ 2 1.1.2 Fungi: friend or foe? ............................................................................ 2 1.1.3 Importance of studying pathogenic fungi. ........................................... 4 1.2 Mucorales.................................................................................................. 5 1.2.1 Mucoralean lifecycle. .......................................................................... 6 1.2.1.1 Asexual reproduction. ............................................................................. 6 1.2.1.2 Sexual reproduction. ............................................................................... 7 1.2.2 The cell wall. ....................................................................................... 8 1.2.3 Spore swelling and germination. ....................................................... 10 1.2.4 Mucormycosis. .................................................................................. 13 1.2.5 Pathogenesis and infection. .............................................................. 15 1.2.6 Iron dependency, uptake, and storage. ............................................. 17 1.2.7 Diagnosis. ......................................................................................... 20 1.2.8 Treatment. ........................................................................................ 21 1.2.8.1 Antifungals............................................................................................ 22 1.2.8.2 Alternative strategies. ........................................................................... 24 1.3 Polymicrobial interactions........................................................................ 25 1.3.1 Mechanisms of intra- and inter-species interactions. ........................ 27 1.3.2 Competitive vs. cooperative relationships. ........................................ 28 1.3.3 Mucorales and C. albicans. ............................................................... 29 1.3.4 Mucorales and bacteria. .................................................................... 30 1.4 Aim of this study. ..................................................................................... 33 Chapter 2 : MATERIALS AND METHODS ..................................................... 34 2.1 Strains and culture conditions. ................................................................ 35 2.1.2 Maintaining and sub-culturing Mucorales. ......................................... 38 2.1.3 Harvesting sporangiospores. ............................................................ 38 2.1.4 Creating frozen spore stocks. ........................................................... 38 2.2 Elucidating the effect of supernatants on Mucorales. .............................. 39 i 2.2.1 Exposing Mucorales to Candida albicans supernatant. .................... 39 2.2.2 Exposing Mucorales to bacterial supernatants.................................. 39 2.2.3 Testing the effect of pH change and nutrient starvation on germination. ............................................................................................... 40 2.2.4 Exposure of pre-germinated R. microsporus spores to P. aeruginosa supernatant. ............................................................................................... 40 2.2.5 Observing the effect of P. aeruginosa supernatant on R. microsporus antifungal susceptibility. ............................................................................. 41 2.3 Quantifying the effects of microbial secreted molecules on fungal germination. .................................................................................................. 41 2.3.1 Fungal quorum sensing molecules. .................................................. 42 2.3.2 Bacterial quorum sensing molecules. ............................................... 42 2.3.3 Bacterial toxins.................................................................................. 43 2.4 Characterising the inhibitory compound. ................................................. 43 2.4.1 Denaturation of proteins in P. aeruginosa supernatant. .................... 43 2.4.2 Organic extraction of P. aeruginosa supernatant. ............................. 44 2.5 Investigating the role of metal restriction on supernatant-dependent growth inhibition. ........................................................................................... 45 2.5.1 Addition of iron, zinc, copper, and manganese to R. microsporus spores following exposure to P. aeruginosa supernatant..........................
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