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Title: Plasmodium falciparum rhoptry proteins play diverse roles in the asexual erythrocytic life cycle, including in erythrocyte invasion, protein export and nutrient import
Author: Sherling, Emma
ISNI:       0000 0004 7658 3089
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Plasmodium falciparum invades, replicates within and egresses from red blood cells. This asexual red blood cell stage is crucial for the propagation of the parasite and also accounts for all clinical manifestations of the disease. There is currently no effective vaccine available, and drug resistance is increasingly being seen across all classes of antimalarials. As a member of the Apicomplexa phylum, Plasmodium parasites contain a characteristic apical complex of organelles that includes the micronemes, rhoptries and dense granules. Proteins are resident within each of these organelles but there is only limited information about their roles within the parasite. Very few of the tens of proteins thought to localise to the paired and club-shaped rhoptries have been functionally categorised. Conventional gene disruption attempts indicated two rhoptry-resident proteins, RhopH3 and RAMA, to be essential, but their precise function remains undescribed. A third rhoptry protein, RON3, was annotated based on weak orthology to proteins of other apicomplexan parasites. The essentiality and the function of RON3 within P. falciparum remains to be determined. In this thesis, conditional disruption of the P. falciparum RhopH3, RAMA and RON3 genes confirms all three are essential for the blood stage cycle. Distinct, but universally lethal, phenotypic consequences result. Parasites expressing an internally truncated RhopH3 protein show two distinct phenotypes: a significant reduction in invasion and, for those parasites still able to invade, a complete block in nutrient uptake across the red blood cell membrane. Contrastingly, RAMA-null parasites show a complete block in invasion, which in turn is thought to be reflective of aberrant rhoptry morphology. Finally, RON3-null parasites are capable of invading but incapable of exporting parasite-derived proteins into the host red blood cell. These studies conclude that RhopH3, RAMA and RON3 play essential, yet distinct, roles across multiple stages of the asexual blood stage cycle.
Supervisor: Blackman, Michael ; Baum, Jake ; Holder, Tony Sponsor: Wellcome Trust ; National Institutes of Health (U.S.)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral