Associated organisationsLondon School of Hygiene & Tropical Medicine · The Francis Crick InstituteEurope PMC affiliations are not treated as award recipients or mapped locations.
Funding£1.4M
PeriodJul 2020 — Jun 2025
In plain English
AI plain-English summary
Malaria parasites rely on two molecular signals—cGMP and cAMP—to time their escape from blood cells and their invasion of new ones, and this project will map the proteins that control that switch. The parasite’s ability to cause disease depends entirely on its asexual blood-stage cycle, while its transmission to mosquitoes requires a separate sexual stage; both are governed by these cyclic nucleotide signals. The researchers have already identified a key binding partner for one of the signalling enzymes and a set of targets for the other, but they do not yet understand how the signals interact with calcium, how phosphorylation drives invasion, or which proteins regulate the enzymes that balance the signals. This is fundamental science—there is no immediate practical application. But because the signalling pathways are essential for parasite survival and transmission, a mechanistic understanding could eventually reveal vulnerable points for new antimalarial drugs, which are urgently needed as resistance to existing treatments spreads.
View original technical description
Our research programme will deliver mechanistic understanding of how cyclic nucleotide signalling controls the development of two key phases of the malaria parasite lifecycle: the asexual blood stage that causes pathology, and gametogenesis that is required for transmission to the mosquito vector. We have previously shown that there is a temporal switch from cyclic GMP (cGMP) signalling to cAMP signalling as the asexual parasite progresses from egress (escape from its host erythrocyte) to invasion. Cyclic GMP signalling also controls egress of sexual stage parasites to enable fertilisation in the mosquito. In both lifecycle phases, egress requires cGMP-dependent calcium flux. We have recently identified a unique, essential membrane-bound binding partner of the cGMP-dependent protein kinase (PKG). We have also identified a set of high confidence targets of cAMP signalling required for invasion and subsequent parasite development, and have obtained exciting new insights into how cGMP production is governed. We now want to: (1) determine the mechanisms underlying the interrelationship between cGMP and calcium signalling; (2) dissect the role of cAMP-dependent phosphorylation in erythrocyte invasion; and (3) identify the parasite proteins that interact with cyclase and phosphodiesterase enzymes (which balance cellular levels of cyclic nucleotide) to understand how the pathways are regulated.
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