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Malarial Gut Check

By Alexander Gelfand

The words “parasite,” “bacteria” and “digestive system” do not necessarily give comfort when nestled alongside one another—unless, that is, they are being used to describe the work of Marcelo Jacobs-Lorena, PhD.

Ten years ago, Jacobs-Lorena, a professor of Molecular Microbiology and Immunology, began genetically engineering mosquitoes to make them resistant to Plasmodium, the parasite that causes malaria—a disease that kills more than 800,000 people each year. The approach held great promise. Drug and insecticide resistance have stymied efforts to manage both Plasmodium and the female Anopheles mosquito that transmits it, and there is no vaccine.

Unfortunately, while Jacobs-Lorena’s transgenic mosquitoes performed well in the lab, there was convincing evidence that their malaria-fighting genes would be difficult to propagate in the field. So he and his colleagues at the Johns Hopkins Malaria Research Institute began searching for other ways to foil Plasmodium.

Their latest solution, reported in July in the Proceedings of the National Academy of Sciences, involves tinkering not with the mosquitoes but rather with the bacteria that live in their digestive systems—more specifically, in the midgut, a tiny tube that could become ground zero in the war against malaria.

When a female Anopheles mosquito bites an infected human, she ingests both blood and parasites. The latter mate in her midgut, yielding a handful of thick-skinned offspring called ookinetes. These, in turn, cross the midgut and transform into oocysts, each of which then spawns thousands of progeny that migrate to the mosquito’s salivary glands, where they stand ready to infect the next person she bites. Consequently, says Jacobs-Lorena, “the best way to interfere with the parasite is before it becomes an oocyst.”

Fortunately, nature has provided an opportunity to do just that.

“It just turns out that, like us humans, the mosquito carries lots of bacteria in its midgut,” Jacobs-Lorena says. “And every time the mosquito feeds on blood, the bacteria increase tremendously in number.”

Hence the new approach: Rather than genetically modifying the mosquitoes to knock out Plasmodium, modify their midgut bacteria to do the job instead.

Jacobs-Lorena and his team engineered Pantoea agglomerans, a bacterium commonly found in the midgut of Anopheles mosquitoes, to secrete five antimalarial proteins. The two most effective proteins thwarted oocyst formation of Plasmodium falciparum (the parasite that causes the deadliest form of malaria) by 98 percent. The technique also worked well against P. berghei, a species of Plasmodium that infects rodents, suggesting that it might work against any variety of the parasite.

In theory, this new strategy should sidestep the gene propagation problem, since distributing engineered bacteria among wild mosquitoes ought to be easier than replacing an existing mosquito population with a transgenic one. Indeed, spreading the anti-malarial microbes could be as easy as baiting jars with cotton balls that have been soaked in bacteria and sugar water. (Female Anopheles need blood proteins to produce eggs, but also feed on nectar.)

Hurdles remain, such as securing regulatory approval to release genetically modified organisms into the wild. In the meantime, Jacobs-Lorena and his collaborators have already identified a different bacterium that holds even greater promise than Pantoea. And they are trying to engineer a single gene that will enable the microbe to produce several anti-malarial compounds at once.

Jacobs-Lorena suspects that, unlike his transgenic mosquitoes, these Plasmodium-fighting bacteria will work even better in the field than they do in the lab. If so, they will make a potent addition to an antimalarial arsenal that is in sore need of new blood.