The role of actin as a determinant of cell shape and virulence of the sexual blood stage of the malaria parasite, Plasmodium falciparum

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Plasmodium falciparum is an obligate intracellular parasite that cause severe malaria in sub-Saharan Africa. Parasite spreading relies on transmission of sexual blood stage gametocytes from humans to the mosquito host. P. falciparum gametocytes undergo remarkable morphological transformation into elongated cells that distort the host red blood cell and cytoadhere in the human vasculature. Our research aims to understand the molecular mechanisms that underlie the morphological transformation. We have evidence that the assembly and disassembly of a novel actin-based cytoskeleton is a key component of the parasite's shape-shifting abilities. We propose to characterize the actin cytoskeleton and delineate its "cross-talk" with the tubulin cytoskeleton. We suggest that these previously unrecognised cellular events represent a novel vulnerable target to prevent gametocyte transmission. To address these fundamental questions we propose the following research.1. Functional and biochemical characterization of the actin-based cytoskeleton in P. falciparum gametocytes.2. Identification and characterization of actin- and tubulin-binding proteins that regulate and facilitate cross-talk between cytoskeleton structures in gametocytes.3. Delineation of mechanisms leading to the falciform shape and its implication for parasite sequestration and transmission.We will utilize genetic engineering and biochemical inhibitors to reveal the function of cytoskeletal proteins. Super-resolution optical microscopy will be employed to probe the spatial-temporal organization of fluorescent-fusion proteins in parasitic-cytoskeletal networks. We will identify novel proteins using complementary proteomic approaches and comprehensively characterize their modulatory function within the gametocyte. To this end we will utilize ektocytometry and microphiltration to assess rheological parameters of gametocytes and mimic the splenic environment.A detailed understanding of the gametocyte cytoskeleton is required to delineate key mechanisms of gametocyte cell biology and to define promising intervention strategies.