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Title: Anopheles/Plasmodium interactions at the ookinete-to-oocyst developmental transition
Author: Akinosoglou, Karolina-Anthoula
ISNI:       0000 0004 2707 275X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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The ookinete to oocyst developmental transition of the Plasmodium parasite represents amajor population bottleneck in the malaria life cycle. This suggests that it could be a target forintervention strategies, such as transmission blocking vaccines, provided essential parasite targetmolecules can be identified. A recent microarray analysis has identified a large number of transcriptsdifferentially expressed during the parasite?s developmental transitions. Genes differentiallyregulated during the ookinete-to-oocyst transition may determine the development of the parasitewithin the mosquito host, as well as, participating directly in parasite/mosquito interactions. Yet, thefunction of the majority of such molecules is largely unknown.This PhD thesis aims to identify and functionally characterise genes putatively involved inookinete development and/or the interactions between the parasite and the mosquito host in the modelsystem Plasmodium berghei. Thirty three proteins likely to be implicated in the parasite?s interactionwith the mosquito immune system and local epithelial response were identified based on theirexpression pattern and predicted structural features. Generation of knock-out mutants throughtargeted gene disruption by homologous recombination was the first step towards functionalcharacterization of these candidates. Successful mutants were assessed for their ability to completetheir sexual sporogonic development, as well as, their impact on mosquito immunity followinginfection of Anopheline mosquitoes of various immune backgrounds. Interestingly, two of thesuccessful mutants were hampered in their ability to undergo normal differentiation during ookinetedevelopment while the third one?s ability to invade the mosquito midgut epithelium was impaired.The inability to invade implies a potential interaction of this gene product with mosquito midgutligands. Eventually malaria transmission through Anopheline mosquitoes was affected in all threemutants. Moreover, challenging of a mosquito protein LRIM1, a major parasite antagonist, alsorevealed potential involvement of the three mutants in mosquito/parasite immune response pathways.Genetic crosses with parasite lines deficient in the production of either male or female fertile gametesdemonstrated in the case of two mutants that, this defect in ookinete development is sex dependent,thus underlining the critical importance of maternal and/or paternal control during the first few hoursof parasite development in the mosquito.
Supervisor: Vlachou, Dina ; Kafatos, Fotis ; Christophides, George Sponsor: A.G. Leventis Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral