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Centrosome and basal body function in human parasites

Centrosomes are the main microtubule organizing center of eukaryotic cells with critical roles in cell division, polarity, signaling and structure. In most cells, one or both centrioles act as basal body (BB), nucleating microtubules to form cilia or flagella, sensory and motile organelles of vital importance for a wide range of biological functions. Notorious deadly diseases such as cancer, microcephaly and ciliopathies correlate with dysregulation in the number and/or structure of the centrosome/BB. Defects in centriolar proteins also impact cell division and flagellar function of parasitic protists. Notably, T. gondii can assemble flagella during its sexual cycle within the cat’s enteroepithelial tissue, a largely unattainable life stage in vitro. The state of the art of the field points at the centrosome and basal body of apicomplexan and trypanosomatid parasites as potentially rich sources of novel therapeutic targets to fight parasitic diseases. However, their molecular composition and the regulation of their biogenesis remain ill-described. Albeit a number of structural components appear to be conserved between parasitic protozoa and their vertebrate hosts, the absence of conserved homologs of regulatory components, suggests that their biogenesis is likely controlled by divergent triggers of unknown targets. Within the framework of a funded ACIP grant (076-2017), this team pursued the characterization of the centrosome composition in T. gondii, and explored the localization of newly identified principles in T. brucei. This proposal focuses on deciphering the role of the newly identified proteins in the biology of the centrosome in Toxoplasma gondii, as a model for the phylum apicomplexa, and to analyze the role of these conserved proteins in basal body biogenesis and function in Trypanosoma brucei. Based on our preliminary identification of novel centrosomal/basal body components and the powerful tools available in our model organisms, we now propose: 1. To analyze the phylogenetic distribution and functional domains of 20 novel proteins of T. gondii through bioinformatic approaches. 2. To assess the localization of these 20 proteins, and the function and cell cycle dynamics of those localized to the centrosome, in T. gondii. 3. To characterize the function of a protein complex linking the centrosome to nascent daughter cells in T. gondii. 4. To characterize the role of 3 novel T. brucei proteins homologs in basal body biology.