Medical Biology - Theses
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ItemCell-cell interactions during malaria parasite invasion of the human erythrocyte( 2015)Red blood cells are remarkably resilient, flexible and dynamic structures. These properties are required for their passage through small capillaries and are imparted by the cytoskeleton, a network of proteins that underlies and links to the cell membrane. To successfully invade the blood stage malaria parasite, called a merozoite, must induce rapid and drastic changes to the structure of the target erythrocyte, including the formation of a tight junction and a new cellular compartment, the parasitophorous vacuole. These key modifications involve the infolding of the red blood cell membrane, membrane fusion and fission events and the secretion of parasite proteins into the host. Although detailed cellular descriptions of merozoite invasion have been achieved over the past few decades, comparatively little is known about the molecular basis of how the host cell responds to parasite entry. In fact, in contrast to what is known about the invasion strategies of most other intracellular pathogens, the prevailing model of Apocomplexan invasion imagines a largely binary system within which an active parasite, driven by its acto-‐ myosin motor, invades a passive host cell. There is a growing body of evidence, however, that suggests that Apicomplexan host cells may not be as inactive as initially thought. Nonetheless, to date, there is no direct evidence for the notion that erythrocytes contribute actively to merozoite invasion. This PhD took at its starting point the hypothesise that to invade, merozoites interface with endogenous erythrocyte pathways that regulate membrane and cytoskeletal remodelling, and that the tight junction is a key structure that coordinates the this host-‐pathogen interaction during the brief moment of entry. To address this proposition, this PhD studied P. falciparum merozoite invasion using a combination of in silico bioinformatic screening, high-‐definition imaging, quantitative and high-‐throughput invasion inhibition assays and quantitative phospho-‐proteomics. Work presented in this thesis further elaborates the molecular architecture of the P. falciparum merozoite tight junction, outlines a model for the secretion of virulence factors by the parasite during entry, establishes that an active erythrocyte is a prerequisite for successful merozoite invasion and demonstrates, for the first time, that the red blood cell responds to early invasion events through the phosphorylation of components of its membrane and cytoskeleton. Taken together, these findings provide strong support for a shift in how we conceptualise invasion, from paradigm that focuses almost exclusively on the activity of the parasite towards one in which both the merozoite and the erythrocyte act cooperatively to achieve the requisite remodelling events that lead to successful intracellular infection. By further expounding the way in which the malaria merozoite orchestrates its interaction with its target red blood cell during invasion, and in particular shedding light on the potential host-‐cell contribution to this process, this work informs future endeavours aimed at the development of novel chemotherapeutic targets to stop invasion and hence prevent or treat malaria disease.