By John Timmer, Ars Technica

Although public health efforts have eradicated some diseases and helped limit the impact of many others, malaria continues to present a massive public health issue. A large fraction of the world's population lives in areas where the parasite poses a risk, and it kills a million people annually, most of them in the developing world.

[partner id="arstechnica" align="right"] The malarial parasite, Plasmodium, has proven tough to tackle for a variety of reasons. Once in a human, it manages to change the proteins that cover its surface often enough that our immune systems have trouble mounting a successful response. Unlike a bacteria or virus, the parasite is a eukaryote, just like humans, which means that it's harder to find unique biochemical properties that would let us target it with drugs. Plasmodium has also been able to evolve resistance to the few drugs that we've been using to treat it. That evolution of resistance extends to its vectors, a few species of mosquitoes, which have also evolved resistance to many of the pesticides we have used to keep them in check.

All of that might seem to be enough to make tackling malaria seem like an intractable problem. But some researchers are reporting some success with a new approach to limiting its spread: engineering a mosquito parasite to attack it before it can reach humans.

The species of mosquitoes that transmit malaria are themselves vulnerable to parasites, including some forms of fungus. This has led to interest in using these fungi as a form of biological insecticide. But the fungus doesn't always kill quickly enough, and if it did, it might end up facing the same sorts of problems that chemical insecticides do: the mosquitoes would simply evolve resistance to the fungus as well.

The solution the researchers arrived at is to use a form of fungus that doesn't kill the mosquitoes until late in their lives, after they've had a chance to reproduce. This keeps them from evolving resistance, but wouldn't keep them from spreading Plasmodium. To do that, they turned to a bit of genetic engineering, creating fungi that produce various proteins that attack the parasite.

The authors tried a variety of approaches. These parasites exit the mosquito through its salivary gland, so the authors created a modified protein that coated the glands, blocking Plasmodium's attempts to latch on to them. They also used a fragment of an antibody that binds directly to Plasmodium's, as well as a toxin present in scorpion venom that kills it. They merged two of the approaches, fusing the venom protein to the one that coats the salivary gland.

To a degree, all of them worked. The fungus alone had a weak effect on the invasion of the salivary glands by Plasmodium, dropping it by 15 percent. But the engineered fungi dropped it by anywhere from 75 to 90 percent. Two of the combined approaches dropped it by 97 and 98 percent. Thus, in the presence of these modified parasites, Plasmodium had a hard time getting to where it could infect humans.

Depending on the precise timing of fungal infection, the authors estimate that it could reduce transmission by 75-90 percent if it reaches the mosquitoes within 11 days of their picking up the Plasmodium. And that's a conservative estimate, given that this estimate was based simply on the presence or absence of the malarial parasite in the salivary glands. The levels in the fungus-infected animals were greatly reduced, which should limit transmission even further.

Although this shouldn't select for resistant mosquitoes, it still has the potential to drive the evolution of Plasmodium that can resist the scorpion toxin. There are two reasons the authors think this might not be a huge problem. For one, the fungus can obviously express a number of toxins at the same time, which makes it much more difficult for Plasmodium to evolve a way around it. The other thing is that there are many proteins that could potentially be used to target it; this is especially appealing, given that an antibody fragment was one of the proteins used in this experiment, suggesting that it should be possible to create a large panel of interfering molecules.

The other nice thing about this approach is that this fungus (or its relatives) can attack other mosquito species, including the ones that spread Dengue fever. This is a very promising fungus.

The general approach holds promise as well, since we reported on another use of an engineered, disease-fighting pathogen already this month. There have been millions of years of evolution that help pathogens target specific species and tissues, something that we're rarely able to do with drugs. If it's possible to take advantage of that specificity, it can be a powerful tool.

Image: A mosquito drawing blood. (James Gathany/CDC)

Citation: "Development of Transgenic Fungi That Kill Human Malaria Parasites in Mosquitoes." Weiguo Fang, Joel Vega-Rodríguez, Anil K. Ghosh, Marcelo Jacobs-Lorena, Angray Kang, and Raymond J. St. Leger. Science, Vol. 331, No. 6020, Feb. 25, 2011. DOI: 10.1126/science.1199115

*Source: Ars Technica.

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