Characterizing the Plasmodium falciparum Subpellicular Network

点击翻译按钮获取中文摘要

ABSTRACT The cytoskeleton of Plasmodium spp. is essential for replication, motility, and infectivity in both human and mosquito life stages. P. falciparum, the causative agent of the most severe form of human malaria, leverages a family of cytoskeletal proteins known as the alveolins to meet its diverse needs. These intermediate filament-like proteins are absent outside the Alveolate kingdom, making them attractive drug targets. The alveolins have stage-specific expression patterns and form an intricate lattice which envelops the parasite just below the pellicle, another hallmark of Alveolata consisting of the parasite plasma membrane and inner membrane complex. Remarkable progress has been achieved in characterizing the role of alveolins in P. berghei mosquito stages. However, the functional role of individual alveolins in Plasmodium asexual stages remains unexplored. We have recently demonstrated that the alveolin PfIMC1g is essential for P. falciparum asexual replication, but it remains unclear what function this protein serves within the larger context of the Plasmodium cytoskeleton. Using inducible knockdown (iKD) and knockout (iKO) systems in conjunction with super-resolution and platinum replica electron microscopy, I will characterize the role of alveolin PfIMC1g (PF3D7_0525800) in P. falciparum daughter cell segmentation and red blood cell invasion. This will elucidate its individual role in parasite cell shape and ability to endure mechanical stress. In addition, I will use expansion microscopy to map the other alveolins present in the asexual stages of the parasite, their interactions with each other, and test their essentiality for daughter cell formation through conventional KO and iKO approaches. This research will increase our understanding of the functional role that these building blocks of the P. falciparum SPN serve and determine how they come together to enable its formation, function, and remodeling during segmentation. Together, these insights into intermediate-filament-like cytoskeletal proteins and their organizing principles will bring us one step closer to targeting these proteins with new antimalarial drugs.