What? Hypnozoites are dormant liver stage malaria parasites that can reactivate and cause repeated blood-stage infections without the bite of an infectious mosquito. We will, for the first time: - characterize the cellular environment contributing to dormancy at systems level (WP1) - explore the reactivation kinetic and tissue environment of hypnozoites within the natural host (WP2) - functionally characterize host & parasite factors governing dormancy or reactivation (WP3) Why? - Dormancy and reactivation of hypnozoites is an unresolved biological mystery since decades - Dormant parasites are a major obstacle to the curative treatment of malaria The challenge: Tracking the in vivo development and understanding the biology of these rare, quiescent parasites that normally reside inside the liver of the host The solution: A synergistic, multidisciplinary investigation, which is only possible if we combine the unique resources and complementary expertise of three leading laboratories in: - Radiopharmaceutical chemistry for the development of dedicated Positron Emission Tomography tracers for non-invasive investigation of the parasites in situ, as well as to capture infected tissue samples for systems level investigations - Systems biology for simultaneous multi-omics profiling of the parasite and the host cell at single-cell resolution and in the spatial context to be validated by parasitological assays - Parasitology for functional investigation through genetic engineering and manipulation of the parasites in vitro and validation within the natural host Anticipated project outcomes: - Detailed insights into the relapse characteristics of the parasite in vivo - Understanding how host and parasite factors collectively determine the fate of infection - Novel imaging, transfection and omics methods for malaria research and beyond - Opportunities for novel therapeutic strategies for awakening and killing these vicious pathogens
