Single-celled apicomplexan parasites are among the most common and deadly microbial pathogens of humans. Toxoplasma gondii, for example, infects an estimated 25% of the world’s population, while malaria-causing Plasmodium parasites contribute to more than a million deaths each year. Across their lifecycles, apicomplexans undergo numerous transitions: between replication within host cells and migration, and between different developmental stages. These transitions must be coordinated with environmental cues, requiring rapid responses from the parasite cell. Our aim is to understand the molecular basis of these transitions by studying the protein kinases that regulate them.
Our work focuses on a family of enzymes called calcium-dependent protein kinases (CDPKs), which respond to calcium changes within the parasite. Interest in these kinases stems from their potential as therapeutic targets, as well as their demonstrated importance in many of the essential transitions apicomplexans must undergo during their lifecycles. Our own work in T. gondii has characterized the important roles of two CDPKs in the initiation of parasite motility, which contributes to the parasite’s exit from the intracellular site of replication and invasion of new host cells.
To further understand the role of CDPKs in parasite biology, we are currently using chemical-genetic approaches to generate T. gondii strains in which we can specifically inhibit individual kinases and monitor their effects on parasite biology. In complementary experiments, we are using quantitative phosphoproteomics to identify the targets of these kinases and to understand the mechanism for their regulation of cellular processes. Taken together, these approaches will help define the specific roles of individual kinases and hopefully identify new components of the cellular pathways they regulate. More broadly, by providing the basis for comparing CDPK functions across different organisms, these studies aim at understanding how this family of kinases has been adapted to regulate the behavior of different apicomplexans.
- DBBS Scholars Award, Washington University, Saint Louis, MO (2006)
- Molecular Cellular and Immunoparasitology Scientific Award (2008)
- Molecular Cellular and Immunoparasitology Scientific Award (2011)
- Spencer T. and Ann W. Olin Fellowship, Washington University, Saint Louis, MO (2012)