Scientists Find Protein That Prevents Transmission Of Malaria To Mosquitos; Discovery Could Aid In Developing Vaccine

By Shweta Iyer on February 24, 2014 2:12 PM EST

malaria protein
Scientists have now identified a single regulatory protein that triggers the development of the male and female sexual forms of malaria in mosquitos. (Photo: Manuel Llinas lab, Penn State )

Malaria, caused by parasitic protozoans, still affects nearly half the world's population.  Close to 3.3 billion people living in 106 countries and territories are at a risk of malaria transmission, according to the U. S. Centers for Disease Control and Prevention (CDC). And the World Health Organization (WHO) estimates that there were 207 million cases of malaria and 627,000 deaths worldwide in 2012 with approximately seventy seven percent of those killed being children under the age of 5. But scientists have now identified a single regulatory protein that triggers the development of the male and female sexual forms of malaria in mosquitos, according to a press release Sunday. The discovery of this protein gives researchers important clues in understanding the life cycle of a malarial parasite, which could possibly lead to vaccines to control it.

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Malaria is caused by single-celled Plasmodium parasite, which has a complex life cycle involving three stages. It starts with a vertebrate host being bitten by a parasite carrying mosquito where there is an initial infection in the liver. This is followed by the long-lasting red blood cell stage, where clinical symptoms of the disease such as intense fevers occur. Then finally, the mosquito stage happens, which is required to transmit the parasites to other people.

All three stages are essential for the parasite to complete its developmental life cycle. But the parasite cannot be transmitted to mosquitos when it multiplies asexually in the blood stream of the host. For mosquito transmission to occur, male and female sexual forms called gametocytes have to form continually in the blood of the host on a two day cycle. The gametocytes are structurally distinct and have a very different program of gene and protein expression than the asexual forms. When a mosquito bites an infected person, the gametocytes enter and mature in the mosquito gut. This mosquito is now capable of transmitting the disease to other hosts. But malarial parasites produce only a small number of sexual parasites per cycle and this potentially vulnerable choke-point is being utilized by researchers.

"Exciting opportunities now lie ahead for finding an effective way to break the chain of

malaria transmission by preventing the malaria parasite from completing its full lifecycle. This sexual-stage bottleneck is an enticing target for interventions to prevent this comparatively small, yet critical number of sexual parasites from forming. If the sexual forms of the parasite never develop in an infected person's blood, then none will get into the mosquito's gut, and the mosquito will not be able to infect anyone else with malaria", said Manuel Llinás, an associate professor of biochemistry and molecular biology at Penn State University.

"The results were surprising because we found huge differences in the number of sexual-stage

parasites produced by the different cell lines," Llinás said. "Our results perfectly correlate the expression of the ap2-g gene with the number of sexual-stage malaria parasites formed."

The ap2-g is the gene responsible for producing the AP2-G protein.

Scientists have long believed that an epigenetic mechanism is responsible for the parasites producing different levels gametocytes, in spite of having the same genetic code. The role of the AP2-G gene was also confirmed in studies done by David Baker and Taane Clark and colleagues at the London School of Hygiene & Tropical Medicine and the Wellcome Trust Sanger Institute.

The Waters and Biiker groups also conducted parallel studies on rodent malaria parasites to confirm the role of the ap2-g. Tests were conducted on parasites where the ap2-gene had been disabled by cutting it out of the parasite's genome. These parasites lost the ability to produce sexual gametocytes. Furthermore, the parasites regained the ability to produce gametocytes when ap2-g was repaired by gene therapy. Combined with other experiments, the results showed that sexual-stage malaria parasites are produced only when the AP2-G protein is in good working order. "Our research has demonstrated unequivocally that the AP2-G transcription factor protein is essential for flipping the switch that initiates the transformation of malaria parasites in the blood from the asexual stage to the critical sexual stage of their life cycle," said

Llinás.

The researchers are now using the discovery of the AP2-G protein to further their efforts in the development of a sexual-stage malaria vaccine, which will prevent the gametocytes from being transmitted to a mosquito, effectively ending the life cycle of a 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 5 years," said Llinás.

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