Stefan M. Kanzok
Bioinformatics Program Director, Associate Professor
Ph.D., 2001, University of Heidelberg, Germany
The Biology of the Malaria Parasite Plasmodium in its Anopheles Mosquito Vector
Plasmodium the causative agent of the infectious disease Malaria has a complex life cycle spanning two very different hosts: the human and the mosquito. This unicellular, protozoan parasite is the cause of 500 million infections and over 1 million deaths in the human population per year.
The interest of our lab centers on the developmental stages of Plasmodium within the Anopheles mosquito. For the parasite the mosquito serves two purposes: it provides a) the environment for the completion of sexual development and reproduction and b) transport to the next human host. Yet, the mosquito is not a mere inert flying syringe and represents a serious challenge for the parasite. The environment in the insect is dramatically different from the human blood. In addition to being part of a digesting blood meal the parasite also has to cope with the innate immune response of the mosquito and an expanding bacterial flora – at the same time. Plasmodium, therefore, has to reorganize its cell biology in order to survive, mate, develop, and move within the mosquito to ultimately facilitate transmission to the next human host. One major adaptive change is the switch from an intracellular lifestyle in the human blood to an extracellular lifestyle in the mosquito vector. This step has the consequence that Plasmodium is now directly exposed to its rather hostile environment which requires the parasite, in the form of an ookinete to actively move through and escape the blood meal. It then produces thousands of sporozoites which invade the salivary glands of the insect. From here they will be injected into the next human host.
Antioxidant defense systems of Plasmodium and their role in malaria transmission by Anopheles mosquitoes
How does the malaria parasite survive the hostile environment in the mosquito midgut? Like most aerobic organisms Plasmodium is exposed to cytotoxic reactive oxygen (ROS) and reactive nitrogen species (RNS). It therefore possesses, also like most aerobic organisms potent antioxidant defense mechanisms that guard it against the harmful impact of these compounds. How these mechanisms help to protect the parasite while in the mosquito vector is one of the prime objectives in our lab. Our data suggest that the parasite once taken up by the mosquito as part of a blood meal significantly increases the expression of numerous antioxidant genes with overlapping functions pointing to the importance of these mechanisms. We are investigating the regulation of known and putative antioxidant genes that may play key roles in the stress response and thus in the survival of the parasite in the mosquito. Understanding the molecular mechanisms that help the parasite survive may hold the key to the development of transmission-blocking strategies.
Mitochondrial energy metabolism in the mosquito stages of the malaria parasite
We also investigate the energy metabolism of the malaria parasite while in the mosquito. In particular, we are interested in the molecular pathways involved in oxidative phosphorylation: the Tricarboxylic acid (TCA-) cycle, the Electron Transport Chain (ETC), and the ATP synthase complex. All of these components are located in the mitochondrion. Interestingly, the literature indicates that the main role of the parasites’ mitochondrion in the human host is to provide pyrimidine precursor molecules for the production of the DNA nucleotides Thymine and Cytosine rather than for the production of ATP which for the most part is generated solely via glycolysis. Microscopic observations show that the mitochondrion significantly increases in size and complexity during parasite development in the mosquito suggesting an upregulation of mitochondrial genes indicating a more prominent role for this organelle in these stages.
Kanzok S. M. and Jacobs-Lorena, M. (2006) Entomopathogenic fungi as biological insecticides to control malaria. Trends Parasitol; 22(2):49-51.
Meister S., Kanzok S. M., Zheng X.-L., Luna C., Li T.-R., Hoa N. T, Clayton J. R., White K. P, Kafatos F. C., Christophides G. K and, Zheng L. (2005) Immune signaling pathways regulating bacterial and malaria parasite infection of the mosquito Anopheles gambiae. PNAS 102(32):11420-5.
Kanzok S. M., Hoa N. T., Bonizzoni M., Luna C., Huang Y., Malacrida A. R., Zheng L. (2004) Origin of Toll-like receptor-mediated innate immunity. Journal of Molecular Evolution 58(4):442-448.
Kanzok S. M. and Zheng L. (2003) The Mosquito Genome - A Turning Point? Trends in Parasitology 19(8):329-331. Review.
Becker K., Kanzok S. M., Iozef R., Fischer M., Schirmer R. H., Rahlfs S. (2003) Plasmoredoxin, a novel redox-active protein unique for malarial parasites. European Journal of Biochemistry 270(6):1057-1064.
Luna C., Hoa N. T., Zhang J., Kanzok S. M., Brown S. B., Imler J.-L., Knudson D. L. and Zheng L. (2002) Characterization of Three Toll-like Genes from Mosquito Aedes aegypty. Insect. Biochem. Mol. Biol. 12(1):67-74
Christophides G. K., Zdobnov E., Barillas-Mury C., Birney E., Blandin S., Blass C., Brey P. T., Collins F. H., Danielli A., Dimopoulos G., Hetru C., Hoa N. T., Hoffmann J. A., Kanzok S. M., Letunic I., Levashina E. A., Loukeris T. G., Lycett G., Meister S., Michel K., Moita L. F., M?H.-M., Osta M. A., Paskewitz S. M., Reichhart J. M., Rzhetsky A., Troxler L., Vernick K. D., Vlachou D., Volz J., von Mering C., Xu J., Zheng L., Bork P., Kafatos F. C. (2002) Immunity-related genes and gene families in Anopheles gambiae. Science 298(5591):159-165.
Kanzok, S. M., Rahlfs, S., Becker, K., and Schirmer, R. H. (2002) Thioredoxin, thioredoxin reductase, and thioredoxin peroxidase of malaria parasite Plasmodium falciparum. Methods in Enzymology. 347:370-381.
Kanzok, S. M., Fechner, A., Bauer, H., Ulschmid, J. K., Botella-Munoz, J., Schneuwly, S., M? H. M., Schirmer, R. H., and Becker, K. (2001) Substitution of the Thioredoxin System for Glutathione Reductase in Drosophila melanogaster. Science 291 (5504); 643-646
Kanzok, S. M., Schirmer, R. H., T?ova, I., Iozef, R., and Becker, K. (2000) The Thioredoxin System of the Malaria Parasite Plasmodium falciparum - Glutathione Reduction revisited. Journal of Biological Chemistry 275 (51); 40180-40186