Integrative transcriptome and phenome analysis reveal unique regulatory cascades controlling the intraerythrocytic asexual and sexual development of human malaria parasites

Abstract

This doctoral study investigates three crucial aspects of malaria parasite development: 1) the atypical cell cycle that allows the rapid proliferation of asexual parasites; 2) the full molecular profile of gametocytogenesis enabling the cellular differentiation that allows the parasite to transmit; and 3) the metabolic differences between these proliferating and differentiating parasites . Here, we contributed a novel system by developing a cell cycle synchronization tool that reversibly blocks the development of asexual parasites at the G1/S transition. This system provided the opportunity to characterize cell cycle phases in the parasite and additionally evaluate molecular mechanisms associated with cell cycle arrest or re-initiation. These analyses indicate the close interaction between transcriptional regulation and signal transduction cascades in the progression through the parasite’s cell cycle and for the first time highlight aspects of controlled cell cycle regulation in Plasmodium. This study also contributes a detailed analysis of the parasite's sexual differentiation that revealed distinct developmental transitions within sexually differentiating parasites and propose possible epigenetic and transcriptional regulators of this process. Finally, a whole cell phenotype microarray system was evaluated for its ability to measure the metabolic processes that define asexual and sexual stage metabolism as a functional consequence of changed gene expression profiles during proliferation and differentiation.