Plasmodium falciparum CRK5 Is Critical for Male Gametogenesis and Infection of the Mosquito.

Cyclin-dependent kinases (CDKs) and cyclins are critical cell cycle regulators in eukaryotes. In this study, we functionally characterized a CDK-related kinase (CRK5) of the human malaria parasite Plasmodium falciparum. P. falciparum CRK5 (PfCRK5) was expressed in asexual blood stages and sexual gametocyte stages, but showed male gametocyte- specific expression. In contrast to previous findings, we showed that gene deletion Pfcrk5(-) parasites grew normally as asexual stages and underwent normal gametocytogenesis to stage V gametocytes. However, Pfcrk5(-) parasites showed a severe defect in male gametogenesis, which was evident by a significant reduction in the emergence of male gametes (exflagellation). This defect caused a severe reduction of parasite transmission to the mosquito. Genetic crosses performed using sex-specific sterile transgenic parasites revealed that Pfcrk5(-) parasites suffered a defect in male fertility but female gametes were fertile. Taken together, these results demonstrate that PfCRK5 is a critical sexual stage kinase which regulates male gametogenesis and transmission to the mosquito. IMPORTANCE Gametocytes are parasite sexual stages which differentiate from asexually replicating parasites. These stages are necessary for the completion of sexual phase of the parasite life cycle. Inside the mosquito midgut, gametocytes rapidly get activated to form fertilization competent gametes. These stages present a bottleneck in the parasite life cycle. In this study, we demonstrate that PfCRK5 is important for male gametogenesis and therefore regulates parasite transmission to the mosquito. Our study identifies PfCRK5 as a potential target for the development of drugs to block malaria transmission.