Nature has published the results of new research that reveals the key role of the protein AP2-G in malaria transmission. The study was carried out by researchers working in ISGlobal's research centre CRESIB and the University of Princeton, who coordinated the study and worked with the London School of Hygiene and Tropical Medicine. The findings show that the protein AP2-G is an essential regulator of sexual reproduction in malaria parasites and that it acts as a developmental switch by activating the transcription of early genes of gametocytes, the sexual form of the parasite. The study has revealed new targets for the interruption of malaria transmission that could be used to prevent the formation and maturation of the parasite's sexual stages, which are essential for the transmission of malaria from humans to mosquitoes.
Alfred Cortés, ICREA Research Professor in CRESIB, who headed up the part of the study undertaken by the Barcelona institute, explains, "Most of the malaria parasites in the bloodstream are in an asexual stage. Sexual differentiation, which is activated in only some parasites, is an essential step in the transmission of malaria from humans to mosquitoes and the infection of other humans. The challenge is not only to cure the patients affected by malaria, but also to block the transmission of the disease to others."
The life cycle of many parasites involves transitions between different host species and this means that the parasites have to go through several stages of development to adapt to each of these niches. The transmission of malaria parasites (Plasmodium falciparum) from humans to the mosquito vector requires differentiation from asexual stages replicating within red blood cells into non-dividing male and female gametocytes.
Cortés goes on to explain how this works. "We discovered that the AP2-G protein plays a key role in the control of sexual differentiation. In the asexual blood-stage parasites, the gene that codes for the AP2-G protein is "turned off" (silenced) in most of the parasites, but is nonetheless prone to spontaneous activation. The parasites in which the expression of this gene is "turned on" (activated) will develop as sexual gametocytes, the only form of the parasite that can survive in the mosquito host and transmit the disease to another person. This means that the AP2-G protein functions as a molecular switch that triggers sexual development and gives rise to the sexual form of the parasite essential to malaria transmission. During the 48-hour cycle following each new invasion of red blood cells, a decision is taken within each malaria parasite whether to continue to replicate asexually and maintain the infection in the current host or whether to activate the expression of AP2-G and commit to differentiating sexually as a male or female gametocyte."
The researchers have shown that AP2-G function is indispensable to sexual differentiation in malaria parasites and that levels of expression of this DNA-binding protein correlate strongly with levels of gametocyte production. Using genetic approaches they have also demonstrated that AP2-G is an essential component of this sexual differentiation. AP2-G expression is regulated epigenetically.
"The AP2-G protein is a powerful new tool for future studies of sexual stage development in malaria parasites and its study is also important to our understanding of the regulation of gene expression in these parasites in general", concludes the CRESIB researcher.