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Acanthamoeba Mannose-Binding Protein: Structural and Functional Characterisation of a Therapeutic Target for Acanthamoeba Keratitis

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Acanthamoeba Mannose-Binding Protein: Structural and Functional Characterisation of a Therapeutic Target for Acanthamoeba Keratitis Acanthamoeba Mannose-Binding Protein: Structural and functional characterisation of a therapeutic target for Acanthamoeba keratitis A thesis submitted to the College of Medicine, Biological Sciences & Psychology, University of Leicester for the degree of Doctor of Philosophy Taiwo Abayomi Banjo Department of Infection, Immunity and Inflammation University of Leicester December 2017 i | P a g e STATEMENT OF ORIGINALITY I, Taiwo A. Banjo, confirm that the research work presented in this thesis for the degree of PhD entitled “Acanthamoeba mannose-binding protein: structural and functional characterisation of a therapeutic target for Acanthamoeba keratitis” was carried out by me in the Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom. I have referenced information from other sources appropriately. None of this work has been submitted for another degree in this or any other University. i | P a g e Acanthamoeba Mannose-Binding Protein: structural and functional characterisation of a therapeutic target for Acanthamoeba keratitis Taiwo A. Banjo Department of Infection, Immunity and Inflammation, University of Leicester submitted for the degree of Doctor of Philosophy 2017 ABSTRACT Acanthamoeba mannose-binding protein (AcMBP) is a virulence factor of the free-living amoeba, Acanthamoeba castellanii. It is crucial for the development of Acanthamoeba keratitis (AK), a corneal infection that often causes blindness. AK is associated with contact lens use and contaminated water sources. Therapeutic unresponsiveness is attributed to similarities in the biological processes that Acanthamoeba shares with humans and its ability to form drug-resistant cysts. I aimed to characterise AcMBP as a basis for developing future drugs against Acanthamoeba. To start with, I carried out morphological studies on the two well-known life stages of Acanthamoeba and characterised a third stage: the protocysts. Mature cysts and protocysts could not interconvert directly, but always excysted to trophozoites. This is important because Acanthamoeba can potentially be trapped as protocysts, which are likely to be more susceptible to drugs. I also studied Acanthamoeba adhesion towards various surfaces and cytopathic activities towards cells (including human corneal epithelial cells). Whilst AcMBP was important for adhesion, it is not the only receptor involved. To gain structure/function information, I expressed the extracellular portion of AcMBP and three truncated fragments. AcMBP is a Ca2+-dependent lectin (~100 kDa) that binds to mannose. Ca2+ is essential for lectin activity and stability. The extracellular fragment is monomeric, indicating that trimerisation, shown previously, depends on the membrane- spanning and/or intracellular regions. Bioinformatics revealed that lectin activity is almost certainly located in a DUF 4114 domain (~10 kDa, DUF: domain of unknown function). N-terminal fragments, including the DUF4114 domain did not bind to mannose-Sepharose, suggesting that part of the cysteine-rich domain is also important. AcMBP bound to a variety of mammalian glycans so may have more than one lectin activity. Although attempts to crystallise AcMBP were unsuccessful, future structural analysis will be useful for defining the domains and determining how it binds to mannose. Keywords: Acanthamoeba, extracellular, Mannose-binding, protein, monomer, Calcium, drug targets. Word count: 298 words. ii | P a g e DEDICATION Unto the Most High God, the Ancient of Days who sits enthroned between the cherubim and exalted over all the nations. ….. for He is HOLY! (Psalm 99:1) Great are God's riches, wisdom, and knowledge! (Romans 11:33) His merciful kindness is great toward us; and the truth of the Lord endureth forever. (Psalm 117:2) iii | P a g e ACKNOWLEDGEMENTS Unto the eternal, everlasting, immutable GOD be praise and Glory for his grace and loving-kindness to me. I am very delighted to have worked with Dr Simon Kilvington, and I gratefully appreciate the warm welcome and enabling working environment in his reference medical microbiology laboratory, Department of Infection, Immunity and Inflammation, University of Leicester. Professor Russell Wallis has been a thoughtful, insightful and outstanding supervisor. He is an erudite academia with passion for novel scientific discoveries. His unique problem- solving skills and unfailing enthusiasm is a tremendous talent to the ‘world of Science’! Russell is such a meticulous scientist who shares my dream and believes that...''every second counts'' and...''NEVER give-up'' no matter the challenges. I greatly appreciate his guidance and the meticulous training he provided. I am deeply appreciative of Dr Shaun Heaphy--my second supervisor for his unflinching support; Professor Peter Andrew for his consistent guide and critical analysis of my manuscripts; Professor Bibek Gooptu and Dr Kumar Rajakumar for their invaluable comments on my research work at different time-points in the course of my work. The insightful questioning, exciting discussions and creative thinking with Dr Uday Kishore and Dr Primrose Freestone have inspired new concepts in my learning experience. I owe the following individuals a great deal of gratitude: Dr Andrew Hudson, Department of Chemistry, University of Leicester, U.K., for providing the Dynamic Light scattering (DLS) spectroscopy facilities in his laboratory. Dr. Andrew Bottrill, Core Biotechnology Services, PNACL, University of Leicester, U.K., for providing the mass spectrometry facilities for the analyses of the AcL1 protein samples; and Mrs M. Jones for her helpful advice. Others include Professor Mahmood Yakubu, Professor Saburi Adesanya, Professor A.O.J Amoo, Professor A.A. Onilude, Professor A.O Ogundahunsi, Professor A.A. Ogun, Dr A. Osinupebi, Mrs O. Osunsanya and Mrs Olisa-Abass for their guidance, unflinching supports and inspirations. I love the enjoyable and rewarding experiences shared with my friends in Leicester-- David, Sadam, Hastyer, Luay, Nicholas, Odeh, Bayan, Agnes and others too numerous to iv | P a g e mention. They have always listened to me, providing me with unlimited encouragement and support at every turn. On a very personal note, I sincerely express my deepest gratitude to ‘my love’ --Monisola, and my children, Opemipo Oluwaromilola and Emmanuel for their unfailing sacrifices and perseverance especially during this journey. I am also grateful to Apostle Olanrewaju Aluko and Ibukun Aluko for their passionate and affectionate love to my family. The memories of my kind, affectionate and prayerful role-model late parents, Pa Abraham F. Banjo (whose demise during the course of this research was a big loss to me) and my mum, Mrs Abosede Banjo are still fresh in my mind. The time past cannot dull the effective inspirational words of wisdom, fatherly care and the sweet motherly affection you have both given me. Importantly, I am in complete gratitude and appreciation to the Federal Government of Nigeria for the grant in exploring this research. Finally, I hope that this research would not only succeed in conveying my concern for the contact lens-users infected with Acanthamoeba keratitis but the sense of relevance of this discovery would provide a step forward as AK therapeutics mainstay in the years to come towards improving the quality of your care and treatments. “Quality is never an accident; it is always the result of high intention, sincere effort, intelligent direction and skillful execution; it represents the wise choice of many alternatives.” William A. Foster. v | P a g e TABLE OF CONTENTS ABSTRACT ..................................................................................................................... ii DEDICATION ............................................................................................................... iii ACKNOWLEDGEMENTS .......................................................................................... iv TABLE OF CONTENTS .............................................................................................. vi LIST OF TABLES ........................................................................................................ xii LIST OF FIGURES ..................................................................................................... xiii LIST OF ABBREVIATIONS .................................................................................... xvii 1. General Introduction-Acanthamoeba in human infection and consequences .... 1 1.1 Background .................................................................................................... 1 1.2 Classification of Free-living Amoebae ........................................................... 1 1.3 Types of Acanthamoeba spp. ......................................................................... 4 1.4 Biology of Acanthamoeba spp. ...................................................................... 4 1.5 Life Cycle of Acanthamoeba spp. .................................................................. 6 1.5.1 Acanthamoeba trophozoites ............................................................................. 8 1.5.1.1 Acanthapodia/Pseudopodia of Acanthamoeba trophozoites ..................... 9 1.5.1.2 Cytoplasmic organelles of Acanthamoeba trophozoites ......................... 10 1.5.1.3 Differentiation of Acanthamoeba trophozoites ....................................... 10 1.5.2 Acanthamoeba mature cysts ..........................................................................
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