In hopes of fighting malaria by interfering with the life cycle of the malaria parasite, scientists have focused on a potential weak point—the part of the cycle in which the parasite, while in human blood, switches from asexual multiplication to sexual development, which involves the formation of gametocytes. Male and female gametocytes are the only forms of the malaria parasite that are infectious to mosquitos. If scientists could find a way to thwart the switch from asexual to sexual development, they might be able to prevent malaria’s spread, which depends on the parasite’s mosquito-borne stage.
The asexual-to-sexual switch, scientists realized, had to depend on molecular mechanisms involving DNA, whether the mechanisms were direct or indirect. That is, scientists were aware that there were variations in gametocyte production, but they were not certain whether these variations were due to mutations in DNA or something outside the genes that affected DNA transcription. Now, however, two teams of scientists have published independent studies indicating that there is indeed something outside the genes—a transcriptional regulator—that controls gametocyte production.
Both teams found that the same regulatory protein acts as a genetic switch. The protein, called AP2-G, activates genes that commit the malaria parasite to sexual development. The teams published their results in separate papers, both of which appeared February 23 in Nature. Members of both teams expressed optimism that knowledge of the genetic switch could be exploited to prevent transmission of the parasite.
One team, led by Manuel Llinás, an associate professor of biochemistry and molecular biology at Penn State University, entitled its paper “A transcriptional switch underlies commitment to sexual development in malaria parasites.” Another team, led by Andy Waters (University of Glasgow) and Oliver Billker (Wellcome Trust Sanger Institute), entitled its paper “A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium.”
The Llinás team worked with Plasmodium falciparum, which causes the most severe form of human malaria; the Waters/Billker team worked with Plasmodium berghei, a commonly used model parasite infecting rodents. And yet the two teams’ results were remarkably similar. According to the Llinás team, “expression levels of the DNA-binding protein PfAP2-G correlate strongly with levels of gametocyte formation.” According to the Waters/Billker team, “PbAP2-G, a conserved member of the apicomplexan AP2 (ApiAP2) family of DNA-binding proteins, is essential for the commitment of asexually replicating forms to sexual development.”
The Llinás team used independent forward and reverse genetics approaches to demonstrate that PfAP2-G function is essential for parasite sexual differentiation. The Waters/Billker team identified PbAP2-G from mutations in its encoding gene, PBANKA_143750. These mutations, they found, account for the loss of sexual development frequently observed in parasites transmitted artificially by blood passage. They confirmed the role of PbAP2-G via systematic gene deletion of conserved ApiAP2 genes in Plasmodium.
Although they studied different species and used different experimental approaches, both research groups demonstrated that cells of the malaria parasite enter sexual development when they produce AP2-G. This result suggests that the parasite's sexual development can be controlled experimentally, opening new research possibilities, including ways "to develop assays to screen for effective drugs that could disable commitment to sexual development and prevent transmission,” commented Waters. Billker added that "the discovery of AP2-G now gives us a new starting point to work out how the complex life cycle of malaria parasites is regulated by proteins within the parasite cells. It may even enable us to control parasite development in the laboratory."
The ability to culture lots of sexual-stage malaria parasites would facilitate efforts to develop a sexual-stage vaccine. Such a vaccine would help an infected person mount an immune response to prevent their malaria parasites from being transmitted to a mosquito—effectively ending the life cycle for that person's batch of malaria parasites. "With the help of the next-generation technologies that we and other malaria researchers now are using, we are optimistic about more discoveries for malaria control that could occur soon—even during the next five years," Llinás said.