The Apical Complex: a Targeted Investigation of the Molecular Functions of this Structure Essential to Apicomplexan Parasite Invasion and Replication.

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Apicomplexans are a large group of single-celled pathogens that cause significant disease in humans. The most notorious member of this group causes malaria, a devastating disease in many developing regions of the world and responsible for over 500 million cases, and 0.6 million deaths per year. Other apicomplexan species cause widespread human diseases: cryptosporidiosis, a leading cause of fatal infant diarrhoea; and toxoplasmosis, which infects approximately 30% of all humans. Further, several apicomplexans infected domesticated animals causing significant loss to human food production.All apicomplexans cause disease by growing and dividing within the cells of their human (or animal) hosts. They enter their host's cells by non-destructively forming a temporary pore in the host cell wall, through which they slide in and then reseal. By keeping the host cell alive it provides a constant source of food and nutrients to the parasite. Only once the parasites have divided to many times the original number do they burst open and kill the human cell, and then actively seek out and invade new host cells.The key structure used by the pathogen during invasion of the host's cells is a structure called the apical complex, and this is a shared feature of all apicomplexan pathogens. The apical complex can be observed using microscopes as an internally reinforced point at the tip of the cell that acts as a cellular nozzle or syringe. At its apex is a small opening, through which it first releases sticky molecules onto the pathogens surface that help it adhere to its host's cells. Subsequently, it uses this opening to inject invasion factors directly into its host that create the invasion pore through which it enters the host. Further pathogen molecules are then released from the apical complex that enable it to feed on its host. Thus, the apical complex is at the heart of these coordinated events of host cell invasion, and is therefore an essential structure for disease formation.Despite the importance of the apical complex, this structure remains poorly understood. Few of the molecular components are known, and this limits understanding of its architecture, assembled, and how it provides the general functions that it does. This study will use multiple approaches to identify and catalogue the molecular components of the apical complex. It will employ the apicomplexan Toxoplasma as the best developed experimental system for apicomplexans. A detailed model of the architecture of the apical complex will be generated, and using genetic tagging of individual structural components, their assembly and behaviour will be characterised in live cells, including during the invasion events. The function of the individual components, and of the apical complex as a whole, will then be dissected by selectively removing one component at a time at a genetic level. This will provide a mechanistic understanding of how the apical complex achieves the deadly tasks of host cell penetration and exploitation.An integrated understanding of the apical complex organisation and function will provide clearer insights into how apicomplexan organisms have achieved such success as pathogens. Moreover, understanding their mechanisms of pathogenesis provides the best opportunity for strategically designing disease treatment strategies.