16 March 2009

Research of the Week

Immune response stops malaria parasite development

This mosquito, which belongs to the genus Anopheles, transmits the malaria parasite.

Researchers in Maryland, for the first time, have identified a molecular pathway that triggers an immune response in several mosquito species that can stop the development of Plasmodium falciparum — the parasite that causes malaria in people.

The work was funded by the U.S. National Institutes of Health, the National Science Foundation and the Johns Hopkins Malaria Research Institute.

Malaria is a mosquito-borne disease caused by the one-celled Plasmodium falciparum parasite and three closely related species. Each parasite lives part of its life in people and part in mosquitoes. The parasites are transmitted to people in the bites of infected female mosquitoes.

Malaria infects 300 million to 500 million people worldwide, causing more than 1 million deaths each year.

By silencing a gene called caspar, researchers at the Johns Hopkins Bloomberg School of Public Health blocked the development of the malaria-causing parasite in Anopheles gambiae, Anopheles stephensi and Anopheles albimanus mosquitoes — three species that spread malaria in Africa, Asia and the Americas.

The researchers found that silencing the caspar gene by manipulating gene expression produced mosquitoes that blocked the development of Plasmodium falciparum in the gut tissue.

Silencing a gene called cactus, which is part of another pathway called Toll, had a similar effect in controlling the development of Plasmodium berghei, which causes malaria in rodents.

When a mosquito is feeding on malaria-infected blood, the mosquito’s immune system recognizes the parasite through receptors that begin the immune response.

In the wild, this response is thought to occur too late to mount an efficient immune defense that kills all parasites. At least a few Plasmodia develop inside the mosquito and enable malaria transmission, said George Dimopoulos, senior study author and associate professor at the Johns Hopkins Malaria Research Institute.

“In the lab,” he said, “we activated this immune response in advance of infection, giving the mosquito a head start in defeating the invading parasite.”

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March 13, 2009
Johns Hopkins Bloomberg School of Public Health
Tim Parsons

Malaria Immunity Trigger Found for Multiple Mosquito Species

Researchers at the Johns Hopkins Bloomberg School of Public Health have for the first time identified a molecular pathway that triggers an immune response in multiple mosquito species capable of stopping the development of Plasmodium falciparum — the parasite that causes malaria in humans.

By silencing the gene, caspar, the researchers were able to block the development of the malaria-causing parasite in Anopheles gambiae, A. stephensi and A. albimanus mosquitoes — three mosquito species that spread malaria in Africa, Asia and the Americas. Their findings were published March 13 in PLoS Pathogens.

According to the study, the transcription factor Rel 2 is a key molecule involved in regulating several potent anti-Plasmodium defense genes that attack the parasite in the mosquito gut. Rel 2 is activated by the immune deficiency pathway (Imd) which, in turn, is negatively regulated by the caspar gene; when caspar is silenced the Rel 2 is activated.

The researchers found that silencing of the caspar gene through the manipulation of gene expression resulted in mosquitoes that successfully blocked the development of Plasmodium falciparum in the gut tissue. Silencing the gene known as cactus, which is part of another pathway called Toll, was shown to have similar effect in controlling the development of Plasmodium berghei, which causes malaria in rodents.

“When a mosquito is feeding on malaria-infected blood, the parasite will be recognized by the mosquito’s immune system through receptors that then start the immune response. In the wild, this response is believed to occur too late to mount an efficient immune defense that would kill all parasites.

“At least a few Plasmodia will successfully develop inside the mosquito and enable transmission of malaria,” explained George Dimopoulos, PhD, senior author of the study and associate professor at the Johns Hopkins Malaria Research Institute. “In the lab we activated this immune response in advance of infection, giving the mosquito a head start in defeating the invading parasite.”

Dimopoulos and his colleagues Lindsey Graver and Yuemei Dong also found that Rel 2 activation did not affect the survival and egg laying fitness of the modified mosquitoes.

“This came as a pleasant surprise since it essentially means that we one day could spread this trait in natural mosquito populations using genetic modification. Furthermore, by activating Rel 2, the genetically modified mosquitoes will attack the malaria parasite with several independent immune factors, and this will make it very difficult for Plasmodium to develop resistance,” said Dimopoulos.

Malaria kills over one million people worldwide each year.

“Caspar controls resistance to Plasmodium falciparum in diverse Anopheline species” was written by Lindsey S. Garver, Yuemei Dong and George Dimopoulos. Funding was provided by National Institutes of Health, the National Science Foundation and the Johns Hopkins Malaria Research Institute.

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