Molecular requirements for morphogenesis in Plasmodium falciparum, the human malaria parasite

Abstract

Malaria, which is caused by Plasmodium parasites, remains a major cause of illness and death worldwide. P. falciparum, the parasite responsible for severe malaria, alters its shape dramatically during development to adapt to diverse environments across multiple hosts. However, the mechanisms behind these transformations are poorly understood. This thesis aims to uncover molecular drivers of major morphological changes in P. falciparum. The parasite’s unique cytoskeleton provides structural support during metamorphosis, but the proteins that enable assembly, expansion, and stability of the cytoskeleton are not well-characterized. In chapter 2 of this thesis, I describe our discovery of a novel protein, PfBLEB, that orchestrates cellular remodeling during development of the transmissible form of the parasite, known as gametocytogenesis. We find that PfBLEB defines polarity of P. falciparum gametocytes as they mature, drives expansion of the parasite cytoskeleton, and is required for gametocyte viability. P. falciparum, like other eukaryotes, uses intracellular signals including calcium to coordinate cellular responses. In fact, most morphological transformations within the P. falciparum life cycle rely on calcium, but mechanisms of calcium signaling in the parasite remain elusive. Additionally, the tools used to measure, monitor, and manipulate calcium levels in other organisms do not operate reliably in the parasite. To fully understand the role of calcium in parasite morphogenesis, we must first develop reliable tools. In chapter 3 of this thesis, I present my work on the development and optimization of tools to investigate calcium signaling in P. falciparum. Understanding molecular drivers of morphological changes in the parasite will uncover targets for antimalarial development, which, in light of increasing antimalarial resistance, is critical. In chapter 4, I describe a promising lead compound for development of new antimalarial combination therapy that retains activity against parasites that are resistant to current frontline treatments. With additional optimization and testing, a future derivative of this compound could be added to existing first-line therapies. Overall, our findings reveal parasite cell biology and further our understanding of the key molecular requirements for morphogenesis during the life cycle of P. falciparum – knowledge that is crucial for the development of novel antimalarials.