Tuesday, May 14, 2024
5/14/2024
PROJECT SUMMARY Malaria is an important global cause of morbidity and mortality. Most of this disease burden falls on children and pregnant women and is caused by infection with Plasmodium falciparum. The signs and symptoms of human malaria result from the exponential expansion of parasite biomass that occurs during asexual replication of parasites in human red blood cells. During this clinically important blood stage, P. falciparum parasites divide by schizogony – a process wherein components for several daughter cells are produced within a common cytoplasm prior to a complex and synchronized cytokinesis known as segmentation. Cytokinesis via segmentation is highly divergent from the process of cell division in human cells. The generation of the invasive daughter parasites, known as merozoites, occurs with high fidelity, ensuring that each daughter has a single nucleus and the required organelles. The fundamental molecular mechanisms that facilitate segmentation are incompletely understand, and this is a significant knowledge gap. Successful segmentation requires two parasite-specific structures, the inner membrane complex (IMC) and the basal complex. The IMC is a double lipid bilayer with associated proteins that, together with an underlying cytoskeletal network, dictates parasite shape and rigidity. The basal complex is a group of proteins at the posterior (i.e., basal) end of the IMC. This multi-protein molecular machine is essential for parasite cell division and is hypothesized to facilitate proper biogenesis of the IMC, likely to contribute to cell shape, and to mediate the final abscission step of cytokinesis. In the current proposal, we will move stepwise towards a molecular understanding of basal complex function. We have a high-confidence list of basal complex components, and our preliminary data demonstrate that individual proteins define subcompartments within the complex and dynamically join and depart the complex. In the first aim, we will utilize high-resolution live-cell time lapse microscopy to determine the precise order of assembly and disassembly of the basal complex. In the second aim, we will utilize super-resolution ultrastructure expansion microscopy to localize individual proteins into subcompartments of the basal complex and proximity labeling to identify novel components within these compartments. In the third aim, we evaluate the requirement for the remaining basal complex components for segmentation and determine the minimal core of proteins that are essential for basal complex function. In summary, the basal complex is essential for asexual replication of P. falciparum, is insufficiently understood, and is not targeted by any current therapeutics. The studies in this proposal will narrow the significant knowledge gap around the molecular mechanisms of basal complex function and may identify important targets for future antimalarials.
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