Abstract
Cells use fatty acids (FAs) for membrane biosynthesis, energy storage, and the generation of signaling molecules. 3-hydroxyacyl-CoA dehydratase-DEH-is a key component of very long chain fatty acid synthesis. Here, we further characterized in-depth the location and function of DEH, applying in silico analysis, live cell imaging, reverse genetics, and ultrastructure analysis using the mouse malaria model Plasmodium berghei DEH is evolutionarily conserved across eukaryotes, with a single DEH in Plasmodium spp. and up to three orthologs in the other eukaryotes studied. DEH-GFP live-cell imaging showed strong GFP fluorescence throughout the life-cycle, with areas of localized expression in the cytoplasm and a circular ring pattern around the nucleus that colocalized with ER markers. Δdeh mutants showed a small but significant reduction in oocyst size compared with WT controls from day 10 postinfection onwards, and endomitotic cell division and sporogony were completely ablated, blocking parasite transmission from mosquito to vertebrate host. Ultrastructure analysis confirmed degeneration of Δdeh oocysts, and a complete lack of sporozoite budding. Overall, DEH is evolutionarily conserved, localizes to the ER, and plays a crucial role in sporogony.
Highlights
Malaria remains one of the world’s deadliest infectious diseases
P. berghei (PBANKA_1346500) and P. falciparum (Pf; PF3D7_1331600) DEH genes are annotated as PTPLA
Lipid metabolism is essential for cellular function, and includes critical pathways for fatty acids (FAs) synthesis and elongation
Summary
Malaria remains one of the world’s deadliest infectious diseases. Caused by apicomplexan parasites belonging to genus Plasmodium, malaria is responsible for great socioeconomic loss to affected countries. The disease is transmitted to vertebrate hosts by infected female Anopheles mosquitoes, which inject sporozoites into the dermis of the vertebrate host during a blood meal. The parasite enters the circulation, and once it invades liver cells, and subsequently erythrocytes, undergoes several rounds of atypical closed mitotic cell division through multiple rounds of DNA replication and asynchronous nuclear division (termed schizogony) to produce merozoites that invade erythrocytes. During this period of cyclic asexual proliferation in the blood stream, a subpopulation undergoes gametocytogenesis to develop into male and female gametocytes, which are transmitted to a mosquito during its blood meal. Thousands of sporozoites develop within each oocyst, and egress into the haemocoel to invade the salivary glands and begin a new life cycle
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