Prof. Sebastian Lourido

Professor Lourido's lab is interested in the molecular events that enable apicomplexan parasites to remain widespread and deadly infectious agents. These single-celled eukaryotes comprise a phylum of organisms that parasitize diverse animal hosts. Many important human pathogens belong to this group, including the causative agents of malaria (Plasmodium spp.), cryptosporidiosis (Cryptosporidium spp.), and toxoplasmosis (Toxoplasma gondii). We use T. gondii to model features conserved throughout the phylum, such as their reliance on calcium signaling to regulate motility. We combine several approaches that span phospho-proteomics, chemical-genetics, and genome editing to investigate the unique biology of these organisms. Our work seeks to expand our understanding of eukaryotic diversity and identify specific features that can be targeted to treat parasite infections.

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.

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.