Dynamics of the Plasmodium Actin Cytoskeleton during Host Cell Invasion

• Applicant: Dr. Herwig Schüler
• Subject Area: Cell Biology
• Term: from 2005 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5455416

Efficient and rapid host cell invasion is a prerequisite for an intracellular parasitic life style. Pathogens typically induce receptor-mediated endocytosis and hijack the force transducing system of a host cell to gain access to a replication-competent niche. In striking contrast apicomplexan parasites, such as the malarial parasite Plasmodium, employ their own actin/myosin motor machinery to propel themselves into prospective host cells. Understanding the regulation and dynamics of actin-based motility is therefore central to the pathogenesis of these parasites. During the funding periods we have succeeded to establish an in vitro assay system that enables us to characterize parasite actin kinetics, and used it to characterize several purified recombinant Plasmodium microfilament proteins. Moreover, the combination of biochemical characterization and reverse genetics employed by us has yielded important insights into parasite actin turnover. Together, our findings reveal that different motile stages of Plasmodium contain specific actin regulators that are essential for life cycle progression and display unique features not previously known from other orthologs of these proteins. For the next funding period we propose to concentrate our biochemical studies on the characteristics and regulation of some of the essential Plasmodium microfilament components that we have previously identified and characterized. These proteins include actin, two ADF/cofilin isoforms and their potential regulators, profilin, and capping protein. We know already, from reverse genetics in the rodent malaria model parasite, that some of these proteins constitute potential drug targets; however, we need to gain a deeper understanding of their dynamics, regulation, and structure to address the question how we could block their functioning with drugs.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1150: Signal Pathways to the Cytoskeleton and Bacterial Pathogenesis
• Participating Person: Professor Dr. Kai Matuschewski