Merozoite invasion of erythrocytes: Revealing functionalcharacteristics of the Plasmodium knowlesi Normocyte BindingProteins Pubblico
Semenya, Amma (2009)
Abstract
Abstract Merozoite invasion of erythrocytes: Revealing functional characteristics of the Plasmodium knowlesi Normocyte Binding Proteins By Amma Atei Semenya Malaria remains as one of the most problematic global infectious diseases; annually as many as 500 million people become clinically ill with malaria. For over thirty years a malaria vaccine has been promised, but to date, none has been implemented. My research has been focused on a family of proteins, the reticulocyte binding-like (RBL) protein superfamily that have been proposed as potential vaccine candidates. It is believed that RBL proteins function in the critical initial step of invasion when merozoites attach to the host cell via their apical end. The goal of my dissertation has been to characterize the functional properties of two RBL proteins that are expressed in the simian malaria species, Plasmodium knowlesi. The P. knowlesi Normocyte Binding Proteins, PkNBPXa and PkNBPXb, have been show to bind to rhesus macaque erythrocytes in in vitro erythrocyte binding assays. Additionally both proteins appear to be crucial for the propagation of blood-stage parasites, as genetic disruption of either pknbpx gene results in the inability to recover parasites. Importantly, an N-terminal domain of PkNBPXb has been identified that binds to erythrocytes, and specifically to a receptor cleaved by chymotrypsin. The binding of this domain (PkNBPXb-II) appears dependent on disulfide bond formation. PkNBPXb-II binds to erythrocytes from Old World monkeys and gibbons (i.e. Lesser Apes). Surprisingly, this domain was unable to bind to erythrocytes from New World monkeys and humans, which are known to be susceptible to P. knowlesi infection, indicating that an alternative binding domain or protein (i.e. PkNBPXa) mediates the attachment to erythrocytes. This dissertation confirms that RBL proteins function by binding to erythrocytes. Interestingly, this dissertation introduces data suggesting that PkNBPXa and PkNBPXb mediate independent binding functions. Additionally, a functional binding domain of PkNBPXb was identified and affords the opportunity to test this domain in pre-clinical vaccine studies.
Table of Contents
TABLE OF CONTENTS CHAPTER ONE: The malaria global health problem, simian malaria, vaccine candidates, and merozoite binding proteins
1 Malaria: Global Health Burden 2 Malaria Life Cycle 5 Clinical Symptoms of Malaria 7 Plasmodium knowlesi: Simian Malaria Parasite 8 Merozoite Structure 10 The Invasion Cascade 11 Plasmodium Merozoite Proteins: Vaccine Candidates 14 Reticulocyte Binding-Like (RBL) Protein Superfamily 21 Overview of P. knowlesi Normocyte Binding Protein Studies 24 References 25 CHAPTER TWO: The Reticulocyte Binding-Like proteins of P. knowlesi locate to the micronemes of merozoites and define two new members of this invasion ligand family 42 Abstract 43 Introduction 44 Materials and Methods 48 Results 56 Discussion 72 References 79
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