Abstract
Author SummaryMalaria, caused by Plasmodium spp. parasites, is a profound human health problem. Plasmodium parasites progress through a complex life cycle as they move between infected humans and blood-feeding mosquitoes. We know that tight regulation of calcium ion levels within the cytosol of the parasite is critical to control multiple signalling events in their life cycle. However, how these calcium levels are controlled remains a mystery. Here, we show that a single protein kinase, the cGMP-dependent protein kinase G (PKG), controls the calcium signals that are critical at three different points of the life cycle: (1) for the exit of the merozoite form of the parasite from human erythrocytes (red blood cells), (2) for the cellular activation that happens when Plasmodium sexual transmission stages are ingested by a blood-feeding mosquito, and (3) for the productive gliding of the ookinete, which is the parasite stage that invades the mosquito midgut. We provide initial evidence that the universal role of PKG relies on the production of lipid precursors which then give rise to inositol (1,4,5)-trisphosphate (IP3), a messenger molecule that serves as a signal for the release of calcium from stores within the parasite. This signalling pathway provides a potential target to block both malaria development in the human host and transmission to the mosquito vector.
Highlights
Malaria is caused by vector-born protozoan parasites of the genus Plasmodium, which cycle between mosquitoes and humans
We show that a single protein kinase, the cyclic guanosine monophosphate (cGMP)-dependent protein kinase G (PKG), controls the calcium signals that are critical at three different points of the life cycle: (1) for the exit of the merozoite form of the parasite from human erythrocytes, (2) for the cellular activation that happens when Plasmodium sexual transmission stages are ingested by a blood-feeding mosquito, and (3) for the productive gliding of the ookinete, which is the parasite stage that invades the mosquito midgut
To ask if in P. berghei gametocytes PKG regulates Ca2+ release in response to xanthurenic acid (XA), we introduced into the dssu or cssu locus of the marker-free PKG-HA and PKGT619Q-HA lines an expression cassette for a reporter protein that is based on the Ca2+-dependent photoprotein, aequorin (Figure S2F) [30]
Summary
Malaria is caused by vector-born protozoan parasites of the genus Plasmodium, which cycle between mosquitoes and humans. Waves of fever arise from the synchronised egress of merozoites from erythrocytes, an event that must be followed by the invasion of fresh red blood cells (RBCs) for the asexual replicative cycle to continue. Egress of gametes from the host erythrocyte occurs within 10 min of gametocyte ingestion by the mosquito and is followed by fertilisation. Within 24 h zygotes transform into ookinetes, which move actively through the blood meal to colonise the epithelial monolayer of the mosquito midgut. Once transmitted back into another human, they first replicate in the liver before invading the blood stream.
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