Investigating hepatocyte signaling driven by host-pathogen interactions

Seattle Biomedical Research Institute, Seattle WA

Investigators

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Abstract

DESCRIPTION (provided by applicant): My career goal is to establish an independent research group, which simultaneously makes discoveries regarding the ways pathogens manipulate their host cells and contributes to the training and inspiring of the next generation of scientists. My background in cellular signaling, technology development, protein/protein interactions and parasitology has uniquely positioned me to apply a variety of powerful approaches to address important questions about pathogens and how they interact with their host cells. I have begun these efforts during my postdoctoral work in Stefan Kappe's group focusing on the malaria parasite and its hepatocyte host. I intend to expand these approaches moving forward to study the similarities and differences between divergent pathogens. Receipt of this K99/R00 award will greatly aid in accomplishing the vital tasks required to establish a productive and sustainable research group, and allow me to fully pursue my goal of leading a group focused on the fundamental biology of host-parasite interactions. Interaction networks of intracellular pathogens and their host cells are complex and predicted to be adaptive in promoting pathogen survival and life cycle progression. In this proposal, we utilize two related apicomplexan parasites: Plasmodium parasites whose co-evolution with the hepatocyte milieu has enabled their survival and Toxoplasma parasites whose persistence has occurred without requiring hepatocyte infection. We have recently demonstrated that liver stage malaria parasites subtly mold their host cells by lowering levels of the tumor suppressor p53, and that reversing this perturbation genetically or with small molecules dramatically reduces the ability of the parasite to develop within the liver. In this proposal, we aim to pursue three main objectives. First, we plan to further elucidate the mechanisms governing the malaria parasites dependence on low host p53 for intracellular survival, and investigate whether or not this perturbation is als required for robust Toxoplasma intracellular replication. We will then investigate which parasite molecules interact with p53 and whether or not this interaction is critical for Plasmodium liver stage development. Finally, we propose to expand upon our already intriguing molecular dataset for Plasmodium-infected hepatocytes by extensively interrogating signaling proteins in hepatocytes in response to both rodent and human Plasmodium parasites as well as Toxoplasma parasites using protein lysate microarrays, an approach that allows us to monitor hundreds of protein and post- translational modification levels using lysates derived from ~10,000 infected-cells. Taken together, the experiments proposed here will facilitate a deeper understanding of the environment in which intracellular parasites thrive and reveal interaction nodes that could be targeted by prophylactic drugs.