Malaria parasites multiply asexually in the human bloodstream, thereby causing chronic infection and all the complications associated with this devastating disease. During each round of multiplication, a small proportion of parasites develop into non-dividing gametocytes instead. Gametocytes are infectious to mosquitoes and are therefore the catalyst for transmitting malaria to other humans. Understanding how malaria parasites control the switch to gametocyte production is central to support the development of therapeutic interventions that could block malaria transmission.
Whether a parasite continues to multiply or develops into a gametocyte is controlled by a molecular switch. The commitment is triggered by activation of AP2-G, the master transcriptional regulator of gametocytogenesis. Heterochromatin protein 1 (HP1)–dependent silencing of ap2-g prevents sexual conversion in proliferating parasites. A recent publication in Cell demonstrated that this switch responds to a lipid molecule present in human blood: lysophosphatidylcholine (LPC). Under high LPC concentrations, parasites multiply, consuming LPC to build new membranes. When LPC concentrations drop, as they do during acute infections, parasites convert into gametocytes to secure their transmission to the next human host.
The study in Science further shows that GDV1 is only produced in parasites destined to develop into gametocytes. Researchers have now identified a parasite protein (GDV1) that plays a crucial role in activating the gametocyte conversion switch. "GDV1 basically ignites a process that reprograms gene expression in the parasite such that gametocyte development occurs", said corresponding author of the study.
Authors found that GDV1 targeted heterochromatin and triggered HP1 eviction, thus derepressing ap2-g. Expression of GDV1 was responsive to environmental triggers of sexual conversion and controlled via a gdv1 antisense RNA. In multiplying parasites, an inhibitory molecule prevents expression of GDV1. "We were amazed to observe that after targeted disruption of this inhibitory molecule using CRISPR-Cas9 technology, all parasites expressed the GDV1 protein", said first author of the study. Another important finding of this study is that GDV1 production is likewise inhibited by LPC.
Drugs and vaccines that target gametocytes are urgently needed to reach the declared aim of eliminating and eradicating malaria. "Although our study does not offer immediate solutions for novel therapies, it sheds new light on the mechanisms responsible for the production of gametocytes," said the author. "If we can block this mechanism or eliminate gametocytes altogether, we might get an important step closer to interrupting malaria transmission."
The new knowledge also allows to produce high quantities of gametocytes in the laboratory. "Research on gametocytes is hampered by the fact that they usually only arise in very small numbers", said the first author. "We are now able to engineer genetically-modified parasites that deliver enormous quantities of gametocytes. We predict that these parasites will be useful not only for future basic research, but also for applied research in this area".
Molecular switch between malaria parasite proliferation and transmission stage unraveled
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