C.H.S.-Stiftung
zur Förderung biomedizinischer Forschung
Dr. Kai Matuschewski
C.H.S. Research Award 2006
since 2008 |
Professor at the MPI for Infection Biology, Berlin |
2001-2008 |
Junior Group Leader at Dept. of Parasitology, Heidelberg University School of Medicine. |
| 1998-2001 | Postdoctoral fellow at New York University School of Medicine. Supervisor: Victor Nussenzweig, MD, PhD. |
| 1994-1998 | PhD thesis at Center of Molecular Biology Heidelberg (ZMBH).Supervisor: Prof. Dr. Stefan Jentsch. |
Research
We are interested in the molecular mechanisms of host cell invasion and intracellular development of the malaria parasite. Based on our expertise in P. berghei transfection and phenotypical analysis of pre-erythrocytic stages we generated a collection of parasite lines that contain deletions of sporozoite-specific genes and display various defects, including developmental arrest and lack of sporozoite motility. Our group previously generated attenuated parasites that confer sterile stage-specific protection against natural malaria transmission. This model system is currently studied for the immune mechanisms that target the infected hepatocytes. We aim at translating the findings in the rodent malaria model system to the human parasite. Importantly, we wish to greatly expand our collection of liver-stage arrested parasites by deletion of additional genes and stage-specific expression of engineered inhibitors. Our long-term goal is to generate tailor-made mutants and tools to block the Plasmodium life-cycle at will.
More recently we aimed at understanding the vital role of two vital membrane proteins, which reside in the parasitophorous vacuole in liver stage development. We could identify two hepatocyte-specific proteins that are recruited to the parasite in infected host cells. Notably, the corresponding mouse loss-of-function mutants are resistant to natural malaria transmission. These recent findings suggest that the essential function of the parasite proteins is the interaction with host cell factors. We plan to take these studies further and employ a medium-throughput approach to identify host cell factors that interact with parasite surface ligands. Their corresponding cellular function will then be tested by RNAi and, if promising, in mouse knock-out model systems.
We believe that these approaches will enhance our understanding of Plasmodium cell biology and contribute to the rational design of novel intervention strategies. Initially, we have focussed our work on pre-erythrocytic stages of the P. berghei model system. Currently we expand our analysis to blood and early mosquito stages and transfer the corresponding assays to our lab. Similarly, we established the P. falciparum gametocyte culture system and membrane feeding resulting in continuous production of infectious sporozoites. In the future, we wish to take advantage of both systems, not least to expedite transfer from the rodent model system to the human parasite. With the Chica and Heinz Schaller award we wish to strengthen our biochemical expertise. We will study central aspects of Plasmodium microfilament dynamics and the cellular function of vital parasite membrane proteins through biochemical approaches.
Selected publications:
Original papers
Schüler, H., Mueller, A.K., and Matuschewski, K. (2005). A Plasmodium actin depolymerizing factor that binds exclusively to actin monomers. Mol. Biol. Cell 16, 4013-4023.
Aly, A.S.I., and Matuschewski, K. (2005). A malarial cysteine protease is necessary for Plasmodium sporozoite egress from oocysts. J. Exp. Med. 202, 225-230.
Frevert, U., Engelmann, S., Zougbédé, S., Stange, J., Ng, B., Matuschewski, K., Liebes, L., and Yee, H. (2005). Intravital observation of Plasmodium berghei sporozoite infection of the liver. PLoS Biol. 3, e192.
Mueller, A.K., Camargo, N., Kaiser, K., Andorfer, C., Frevert, U., Matuschewski, K., and Kappe, S.H.I. (2005). Plasmodium liver stage developmental arrest by depletion of a protein at the parasite-host interface. Proc. Natl. Acad. Sci. USA 102, 3022-3027.
Schüler, H., Mueller, A.K., and Matuschewski, K. (2005). Unusual properties of Plasmodium falciparum actin: new insights into microfilament dynamics of apicomplexan parasites. FEBS Lett. 579, 655-660.
Mueller, A.K., Labaied, M., Kappe, S.H.I., and Matuschewski, K. (2005). Genetically modified Plasmodium parasites as a protective experimental malaria vaccine. Nature 433, 164-167.
Reviews and bookchapters
Matuschewski, K., and Schüler, H. Actin/myosin-based motility in apicomplexan parasites. In: Molecular mechanisms of parasite invasion, eds. Burleigh, B. and Soldati, D. (Landes Biosciences, Austin, TX), in press.
Schüler, H. and Matuschewski, K. (2006). Regulation of apicomplexan microfilament dynamics by a minimal set of actin-binding proteins. Traffic 7, 1433-1439.
Matuschewski, K. (2006). Getting infectious: formation and maturation of Plasmodium sporozoites in the Anopheles vector. Cell Microbiol. 8, 1547-1556.
Matuschewski, K. (2006). Vaccine development against malaria. Curr. Opin. Immunol. 18, 449-457.
Schüler, H. and Matuschewski, K. (2006). Plasmodium motility: actin not actin’ like actin. Trends Parasitol. 22, 146-147.
Sinden, R.E., and Matuschewski, K. (2005) The sporozoite. In: Molecular Approaches to Malaria, ed. Sherman I.W. (Am. Soc. Microbiol., Washington, DC), pp. 169-190.
Contact
Prof. Dr. Kai Matuschewski
Max Planck Insititute for Infection Biology
Parasitology Unit
Charitéplatz 1
Campus Charité Mitte
D-10117 Berlin
phone: #49 30 28 460 535
fax: : #49 30 28 460 225
e-mail: matuschewski@mpiib-berlin.mpg.de
web: http://www.mpiib-berlin.mpg.de/research/parasitology.htm