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Last Updated: 18/06/2024
Molecular processes essential for parasite sporogony
Objectives
- Study crystalloid loss in the oocyst. Plasmodium berghei lines expressing crystalloid proteins tagged with fluorescent protein as markers of the organelle will be examined by superresolution confocal microscopy to study the destination of the crystalloid and its protein cargo in live oocysts during sporogony;
- Refine the crystalloid protein interactome. Parasite lines expressing different crystalloid proteins fused to a Strep tag will be generated and used to harvest protein complexes from ookinetes by affinity purification, followed by mass spectrometry (MS)-based protein identification, to produce a high confidence crystalloid protein interaction network;
- Determine the crystalloid proteome. Parasite lines expressing Strep-tagged crystalloid membrane proteins will be used to purify intact organelles from mechanically lysed ookinetes by affinity purification, followed by MS-based protein identification, to determine the crystalloid proteome irrespective of protein interactions;
- Determine the crystalloid metabolome. Purified organelles from parasites expressing a Strep-tagged version of the NADPH-generating crystalloid enzyme NTH, and those expressing an enzymatically inactive NTH version, will be subject to MS-based global metabolite analysis to identify which NADPH-dependent biosynthetic processes are taking place in the organelle;
- Validate newly identified crystalloid proteins. Select proteins will be validated by GFP tagging and gene knockout studies in transgenic parasites to confirm their link with crystalloid function and sporogony.
London School of Hygiene and Tropical Medicine (LSHTM), United Kingdom
Apicomplexan parasites are widespread protozoan parasites of animals, which include major pathogens of humans, domestic animals and livestock. Many existing measures against these parasites remain insufficient for disease control, and new strategies for prophylaxis, treatment and control of transmission are urgently needed. Sporogony is defined as the production of sporozoites by repeated divisions of a zygote. It is an essential part of the life cycles of many apicomplexan parasites including Plasmodium, the causative agent of malaria, where sporogony takes place in the mosquito within extracellular encysted forms named oocysts. In Plasmodium, sporogony is critically dependent on a unique organelle named the crystalloid, which is exclusively found in the ookinete (a motile form of the zygote) and young oocyst stages. Many of the crystalloid proteins thus far identified in Plasmodium are conserved in and unique to the Apicomplexa, supporting the hypothesis that the molecular processes underlying sporogony are at least partly conserved across the phylum. This proposal will use an integrated cross-disciplinary approach to study the crystalloids of Plasmodium berghei aimed at increasing our fundamental knowledge of the essential cellular and molecular processes underlying sporogony. The collective results will provide new basic knowledge of the essential functions of the crystalloid in sporogony, and help to identify new molecules and molecular pathways for rational intervention strategies against development and transmission of malaria and related apicomplexan parasites. This proposal aims to increase the knowledge of the essential molecular processes that underlie sporogony in apicomplexan parasites by studying the crystalloid, a parasite organelle essential for sporogony in Plasmodium spp. This will help identify new molecules and molecular pathways for rational intervention of parasite development and transmission.
Sep 2021 — Sep 2024
$623,197
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