Anopheles/Plasmodium interactions at the ookinete-to-oocyst developmental transition
Author(s)
Akinosoglou, Karolina-Anthoula
Type
Thesis
Abstract
The ookinete to oocyst developmental transition of the Plasmodium parasite represents a
major population bottleneck in the malaria life cycle. This suggests that it could be a target for
intervention strategies, such as transmission blocking vaccines, provided essential parasite target
molecules can be identified. A recent microarray analysis has identified a large number of transcripts
differentially expressed during the parasite’s developmental transitions. Genes differentially
regulated during the ookinete-to-oocyst transition may determine the development of the parasite
within the mosquito host, as well as, participating directly in parasite/mosquito interactions. Yet, the
function of the majority of such molecules is largely unknown.
This PhD thesis aims to identify and functionally characterise genes putatively involved in
ookinete development and/or the interactions between the parasite and the mosquito host in the model
system Plasmodium berghei. Thirty three proteins likely to be implicated in the parasite’s interaction
with the mosquito immune system and local epithelial response were identified based on their
expression pattern and predicted structural features. Generation of knock-out mutants through
targeted gene disruption by homologous recombination was the first step towards functional
characterization of these candidates.Successful mutants were assessed for their ability to complete
their sexual sporogonic development, as well as, their impact on mosquito immunity following
infection of Anopheline mosquitoes of various immune backgrounds. Interestingly, two of the
successful mutants were hampered in their ability to undergo normal differentiation during ookinete
development 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 midgut
ligands. Eventually malaria transmission through Anopheline mosquitoes was affected in all three
mutants. Moreover, challenging of a mosquito protein LRIM1, a major parasite antagonist, also
revealed 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 gametes
demonstrated 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 hours
of parasite development in the mosquito.
major population bottleneck in the malaria life cycle. This suggests that it could be a target for
intervention strategies, such as transmission blocking vaccines, provided essential parasite target
molecules can be identified. A recent microarray analysis has identified a large number of transcripts
differentially expressed during the parasite’s developmental transitions. Genes differentially
regulated during the ookinete-to-oocyst transition may determine the development of the parasite
within the mosquito host, as well as, participating directly in parasite/mosquito interactions. Yet, the
function of the majority of such molecules is largely unknown.
This PhD thesis aims to identify and functionally characterise genes putatively involved in
ookinete development and/or the interactions between the parasite and the mosquito host in the model
system Plasmodium berghei. Thirty three proteins likely to be implicated in the parasite’s interaction
with the mosquito immune system and local epithelial response were identified based on their
expression pattern and predicted structural features. Generation of knock-out mutants through
targeted gene disruption by homologous recombination was the first step towards functional
characterization of these candidates.Successful mutants were assessed for their ability to complete
their sexual sporogonic development, as well as, their impact on mosquito immunity following
infection of Anopheline mosquitoes of various immune backgrounds. Interestingly, two of the
successful mutants were hampered in their ability to undergo normal differentiation during ookinete
development 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 midgut
ligands. Eventually malaria transmission through Anopheline mosquitoes was affected in all three
mutants. Moreover, challenging of a mosquito protein LRIM1, a major parasite antagonist, also
revealed 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 gametes
demonstrated 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 hours
of parasite development in the mosquito.
Date Issued
2011-05
Date Awarded
2011-08
Advisor
Christophides, George
Vlachou, Dina
Kafatos, Fotis
Sponsor
A.G. Leventis Foundation
Publisher Department
Cell and Molecular Biology
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)