In July, pop singer and “X-Factor” judge Cheryl Cole made headlines not for her new record or impending divorce but for hospitalization due to malarial infection. This infectious disease, caused by the release of the Plasmodium falciparum parasite into the bloodstream from a mosquito bite, is both preventable and treatable. Yet it remains devastating to millions, particularly young children in sub-Saharan Africa and parts of Asia, who develop a form of the disease called cerebral malaria. This type of infection is characterized by severe damage to the blood vessels around the brain. And this damage results in coma, neurological damage and, too often, death (See also the Cerebrum story, Cerebral Malaria, a Wily Foe).
Across the globe, scientists are focusing on different strategies to help combat this destructive parasite, including engineering malaria-free mosquitoes and finding practical new preventive treatments. But it may be that understanding the molecular pathways of the parasite will help us to understand why some infected people develop only flu-like symptoms and others sustain profound damage to the brain.
A new kind of mosquito
Plasmodium falciparum is spread through mosquito bites. In India, the mosquito responsible for most infections is the Anopheles stephensi. Michael Riehle, an entomologist at the University of Arizona, and Shirley Luckhart, a researcher at University of California Davis, successfully genetically re-engineered this species of mosquito to make it immune to malarial infection.
“In a sense, we were basically doing the same thing as you see in breeding programs for dogs,” says Riehle. “We selected for the traits we were interested in and made those changes. But we were very surprised that we were able to block infection completely.”
Riehle had expected for perhaps 80 percent success—but not only did the group completely block malarial infection in the re-engineered insects, by making the changes to a specific enzymatic pathway in embryos, it was able to block it in future generations as well. A paper describing their efforts was published in the July 15 issue of Public Library of Science Pathogens. Riehle hopes to successfully re-engineer other species of mosquitoes and then find ways to release them into the wild to breed with and ultimately replace the indigenous populations.
Antibiotics as a preventive measure
The World Health Organization estimates that more than 1 million people become infected with malaria each year. Preventive treatment with drugs like Mefloquine or Malarone are effective but the malarial parasites are becoming increasingly resistant to them over time. Steffen Borrmann, a researcher with the Department of Infectious Diseases at Heidelberg University in Germany, has found that not only can antibiotics like azithromycin prevent malarial infection but they may also offer lasting protection months later. In a paper published in the July 14 issue of Science Translational Medicine, Borrmann and his colleagues demonstrated that mice infected with malaria parasites develop complete and lasting immunity—even after 6 months—if antibiotics were present in their systems at the time of first infection.
“We found this effect with mice only being given the antibiotics for three days,” says Borrmann. “It’s impossible to give prophylaxis throughout the whole life, it’s not safe. But in endemic populations, we could perhaps given the most susceptible individuals, young children between one and five years, antibiotics for a period of time during the malaria season. It’s possible it will offer lasting protection in the long run.”
A metabolic pathway as sensor
Manuel Llinás, a molecular biologist at Princeton University, is using mass spectrometry to identify novel and interesting metabolic pathways that exist in Plasmodium falciparum.
“If we want to ultimately identify new ways to drug this parasite and treat it with anti-malarial drugs, we need to understand its metabolism,” he says. “If we can find small molecules that parasites make that we don’t make, or enzymes they have that we don’t, we’re looking at excellent candidates for drug approaches down the line.”
Llinás and colleagues found that a major metabolic pathway, the tricarboxylic acid (TCA) cycle, or Krebs cycle, which is involved with the conversion of carbohydrates, fats, and proteins into a usable energy form in cells, takes a very different form in the malaria parasite. In a paper published in the Aug. 5 issue of Nature, he and colleagues demonstrate that the parasite shows a unique branching pathway instead of the classic looping cycle found in humans and other eukaryotic cells.
“We were looking at a pathway we thought we understood very well from other organisms,” says Llinás. “And we found a very different utilization here. In the parasite, the classical cyclical form was highly altered.”
This unique metabolic pathway not only offers new pathways for drug treatments – it may also provide insight into why the parasite can result in cerebral malaria in some individuals and not others.
“We found the cell is sensing external compounds in the host,” says Llinás. “And it’s possible that this modulation by the extracellular environment may have something to do with disease severity.”
Cheryl Cole recovered from her bout with malaria after only a few weeks. She was one of the lucky ones. But millions more may not be as lucky as they weather their own battles with the disease. Llinás says new advances in the field are providing us new direction, insight and hope.
“The thing that surprises me most is how little we understand about malaria even after studying it so long,” says Llinás. “But by looking at newer approaches, we find more interesting things we don’t know about the disease. These are often the harder questions, but they provide the potential for a bigger payoff.”