Gametogenesis in Malaria Parasites Is Mediated by the cGMP-Dependent Protein Kinase

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Abstract
Malaria parasite transmission requires differentiation of male and female gametocytes into gametes within a mosquito following a blood meal. A mosquito-derived molecule, xanthurenic acid (XA), can trigger gametogenesis, but the signalling events controlling this process in the human malaria parasite Plasmodium falciparum remain unknown. A role for cGMP was revealed by our observation that zaprinast (an inhibitor of phosphodiesterases that hydrolyse cGMP) stimulates gametogenesis in the absence of XA. Using cGMP-dependent protein kinase (PKG) inhibitors in conjunction with transgenic parasites expressing an inhibitor-insensitive mutant PKG enzyme, we demonstrate that PKG is essential for XA- and zaprinast-induced gametogenesis. Furthermore, we show that intracellular calcium (Ca2+) is required for differentiation and acts downstream of or in parallel with PKG activation. This work defines a key role for PKG in gametogenesis, elucidates the hierarchy of signalling events governing this process in P. falciparum, and demonstrates the feasibility of selective inhibition of a crucial regulator of the malaria parasite life cycle. The protozoan parasite Plasmodium falciparum, which causes malaria in humans, is responsible for over 1 million deaths each year. Its life cycle is complex; the asexually replicating forms, which cause disease symptoms, are quite distinct from the sexual forms, which mediate transmission between individuals via the bite of a mosquito. After a period of growth in the human host, these sexual forms (gametocytes) lie dormant until taken up by a mosquito. The change in environment from human to mosquito triggers differentiation into mature gametes. In this study, we have identified a protein kinase from the parasite that is instrumental in mediating this essential differentiation step. We have also gained insight into how this protein kinase might interact with calcium to coordinate these events. By using genetically modified malaria parasites in combination with specific inhibitors of the protein kinase, we have illustrated the feasibility of blocking development of the sexual stage of the parasite's life cycle. Development of a drug that targets this parasite stage, for use in combination with a curative drug, would be an important tool for controlling the spread of drug resistance.