Research
Since its establishment, Loukeris laboratory is a member of the BioMalPar network of excellence. BioMalPar is a collaborative research Network of Excellence, funded by the European Commission under the sixth framework programme. BioMalPar conducts research on malaria parasites and their interactions with both, mammalian hosts and mosquito vectors It also aims to train talented young scientists from North and South in malaria research, with emphasis on interdisciplinary approaches. In addition, the lab is a member of COST857 Action (Cooperation On Science and Technology; Apicomplexan biology in post-genomic era), which allows interaction of the lab members with the broader apicomplexan community. Research Directions The main goal of our research is to unravel essential proteolytic mechanisms involved in invasion processes of apicomplexa parasites, and identify essential proteases as targets for transmission blocking interventions. Due to their complex life cycles apicomplexa parasites have developed sophisticated and highly organized surfaces, that apart of keeping them protected from the antagonistic environment of the host and the vector, play critical roles in motility, in their interactions with the target cells, in invasion, and in developmental transitions. Time dependent secretion, proteolysis and shedding of adhesins, provide layers of regulation and a high order of invasion control. There are several findings that indicate a critical involvement of proteases of parasite and/or host origin in the invasion, early development and survival of apicomplexa parasites. We consider proteases involved in host invasion good targets for drug design, since it is possible to interfere with protease function using naturally or synthetic inhibitory molecules, and/or engineered peptide-based inhibitors. Such inhibitors may be used as drugs to prevent and/or treat the disease. Alternatively, for proteases involved in the malaria life cycle inside the mosquito vector, inhibitors may be used to develop transmission-blocking strategies. Inexpensive chemical inhibitors may be for example used similarly to insecticides to lower transmission rates, while peptide-based inhibitors may be expressed in transgenic vectors. Our innovative approach is to generate parasites deficient for proteolysis by expressing ectopically natural or molecularly-engineered Macromolecular Protease Inhibitors (MPIs) and unravel the role of proteolysis and specific proteases in critical developmental transitions. Naturaly derived or molecularly modified MPIs in our lab are used in different ways: a) are expressed and purified from bacteria and subsequently used in in vitro invasion assays (Toxoplasma tachyzoite invasion, Plasmodium berghei membrane feeding to mosquitoes) b) are expressed in genetically modified parasites: using time-, stage- specific promoters and/or inducible expression systems MPIs are expressed in transgenic parasites with the aim to block vital proteolytic processes and generate attenuated parasites that may serve as genetically attenuated vaccine (GAV) candidates. c) are expressed in transgenic mosquitoe cell lines in order to define the best possible modifications in order to express them ultimately in transgenic mosquitoes with the aim to generate refractory mosquito strains |
