14th April 2014
By Mathieu Brochet
Confocal fluorescence micrograph of an ookinete (the "motile zygote") of the malaria parasite Plasmodium berghei. Credit: Katrin Volkmann and Mathieu Brochet
Signalling molecules called second messengers, which trigger physiological changes in cells, have long been known to be crucial to malaria infection and transmission. However, how these messengers are able to regulate the complex lifecycle of Plasmodium
, the parasite that causes malaria, has been a mystery.
During its journey between humans and mosquitos, Plasmodium parasites face extremely diverse environments, from the warmth of red blood cells to the very inside of a mosquito gut. To sense and respond to changing environments, malaria parasites use a complex system of intracellular communication that relies on signalling molecules such as these second messengers and kinase proteins.
Two of the second messengers responsible for enabling the parasite to move between these environments are calcium ions and cyclic guanosine monophosphate or cGMP. By studying the cGMP-dependent protein kinase G, or PKG, we found a crucial role for it in the movement of Plasmodium’s zygote, the form the parasite takes in the early stages of its lifecycle when it invades the mosquito midgut.
Kinases are signalling molecules that convey information through phosphorylation, a process that turns proteins on and off. We analysed the role of PKG protein, on the phosphorylation of more than 2,000 proteins and found that PKG protein activity controls the phosphorylation of important biological pathways, including the metabolism of phosphoinositides, a family of lipids.
A global analysis of cellular lipids confirmed that PKG controls phosphoinositide metabolism, including the production of the lipid precursors which give rise to inositol 1,4,5-trisphosphate (IP3), another messenger molecule that serves as a signal for the release of calcium ions from stores within the parasite. This led us to hypothesise that a major function for PKG is to control intracellular calcium ion levels in malaria parasites.
We were able to show that 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 to enter the human blood stream
2. for the cellular activation that happens when Plasmodium parasites are ingested by a blood-feeding mosquito during its sexual transmission stage, and
3. for the movement of Plasmodium necessary to invade the mosquito midgut.
This is an important discovery as it reveals the crucial role of the second messenger cGMP in calcium ion regulation. This role emerges as a key Plasmodium vulnerability that is conserved throughout the life cycle of the parasite, so understanding the biological process provides a potential target to block both malaria development in the human host and transmission to the mosquito vector.
Mathieu Brochet is a postdoctoral researcher in Oliver Billker's Malaria Programme at the Wellcome Trust Sanger Institute (United Kingdom). His work aims at identifying the molecular links between essential signalling molecules which allow malaria parasites to successfully progress through their life cycle.
- Brochet M et al. (2014) Phosphoinositide Metabolism Links cGMP-Dependent Protein Kinase G to Essential Ca2+ Signals at Key Decision Points in the Life Cycle of Malaria Parasites PLoS Biology. DOI:10.1371/journal.pbio.1001806