Of the four species of Plasmodium (protozoan parasites) that can cause malaria in humans, Plasmodium falciparum is the most dangerous. It is transmitted when an infected human is bitten by an Anopheles mosquito that goes on to bite another person. The pathogen’s life cycle has two distinct phases. In the human, it invades red blood cells, divides clonally, and causes the symptoms of disease. Sexual forms of the parasite also develop in the bloodstream, but only when they are taken up by the mosquito can the second phase of the life cycle proceed. Within the mosquito stomach a conversion occurs: the sexual forms change from crescent-shaped to round before fertilization can occur. This transition is referred to as “rounding up” and the signalling system underlying it, which reacts to the change in host (human to mosquito), has previously been poorly characterized. New work, by David Baker and colleagues from the London School of Hygiene & Tropical Medicine, and the Wellcome Trust Sanger Institute in Cambridge, has identified one of the molecules required for the activation of the sexual cycle within the mosquito: PKG.
The new paper, published this week in the open-access journal PLoS Biology, identifies a protein crucial for the reproductive stages of the pathogen’s lifecycle, called cGMP-dependent protein kinase, or PKG. PKG is an enzyme produced by the malaria parasite. The authors have shown that it is essential for induction of “rounding up.” Normal pathogens are unable to respond to the change in host if PKG is experimentally blocked with an inhibitor; thus, PKG is necessary for the pathogen to become sexually mature. Further, the authors genetically modified the parasite so that PKG was insensitive to the inhibitor, and in these mutants, “rounding up” could proceed normally in the presence of the inhibitor. It is, therefore, PKG specifically (rather than another enzyme) that is the target of the inhibitor.
This work suggests a new potential target for anti-malarial drugs. As Dr. Baker comments, “Our work has demonstrated that it is feasible to block a key phase of the malaria parasite life cycle using a selective inhibitor. The findings may have important implications for fighting the spread of drug resistance and malaria control,” for if you could block PKG activity in the pathogen, which the authors have done using a specific inhibitor, then you have a means of controlling transmission of malaria between individuals.
Citation: McRobert L, Taylor CJ, Deng W, Fivelman QL, Cummings RM, et al. (2008) Gametogenesis in malaria parasites is mediated by the cGMP-dependent protein kinase. PLoS Biol 6(6): e139. doi:10.1371/journal.pbio.0060139
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CONTACT:
David Baker
London School of Hygiene & Tropical Medicine
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