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Dancing with the Enemy


Dancing with the Enemy (continued)

Building "Super Immunity"

Protecting humans from malaria is the obvious goal here. But, says George Dimopoulos, PhD, MBA, protecting mosquitoes from malaria accomplishes the same goal. If researchers could successfully create a mosquito that is immune to Plasmodium, then these insects would be unable to continue the parasite's life cycle and pass it back to humans.

One way to shield mosquitoes from Plasmodium is to bump up the power of their own immune systems. Any normal, healthy mosquito already has the capability to kill off the parasite once it gets infected, explains Dimopoulos, MMI associate professor. "Susceptible mosquitoes that get Plasmodium activate their immune system and kill off large numbers of parasites, but a small number [of parasites] make it through," he says. That small number eventually becomes the population that gives people malaria.

If only researchers could make mosquitoes' immune systems stronger and more resistant to Plasmodium, then the insects could kill off all the invading parasites and have complete immunity. Making these super-immune mosquitoes is a major focus for Dimopoulos and his lab.

Last year, he and his colleagues discovered a network of genes that are part of the immune deficiency (IMD) pathway and allow mosquitoes to fight off Plasmodium. This pathway (so-named for the fly in which it was discovered, which had an immune deficiency) controls a protein called Rel2. When the parasite-fighting IMD pathway is turned on, Rel2 binds to a mosquito's DNA and activates production of parasite-killing molecules. Experiments show that's what seems to happen during a natural malaria infection—albeit too late and too weak to catch all the parasites before an infection takes hold. This pathway doesn't stay running all the time, explains Dimopoulos, since it would take too much of a mosquito's resources to maintain.

He and his team also discovered Rel2's shutoff valve, a gene called caspar, which they manipulated to show that strong activation of the IMD pathway can give mosquitoes Plasmodium resistance. Knowing the components that go into running the IMD pathway allowed them to use genetic engineering to construct an elaborate system in which they linked Rel2 to the gene for a digestive enzyme. That means that once mosquitoes take a blood meal and get to work on digesting it, Rel2 is activated, which jump-starts the malaria-fighting pathway. "Once the parasite tries to infect the mosquito, it will encounter a very hostile environment," Dimopoulos explains.

He and his colleagues are currently studying the genetically engineered strain of mosquitoes they created with this modification to better understand exactly where, when and how Plasmodium is killed and to see whether they can optimize this process. In the meantime, they're also examining a different system that mosquitoes use to fight off malaria: their gut bacteria. "Mosquitoes have a significant population of symbiotic microbes in their intestine that play an important role in fighting off infectious invaders. Humans also have an intestinal 'microbiome,'" which fulfills the same function, explains Dimopoulos.

Dimopoulos' lab has painstakingly searched through the various species that inhabit mosquitoes' guts to see if any has especially good Plasmodium-fighting power. They recently discovered one that seems to possess significantly more parasite-inhibiting power than the others. They are currently delving into how this microbe species battles Plasmodium, efforts that could lead to using this bacterium, or the strategy it employs against the parasite, as a key warrior in the fight against malaria.

Gut-Level Investigations

Jacobs-Lorena and MMI assistant professor Jason Rasgon, PhD, are also hoping to capitalize on mosquitoes' gut bacteria, though in completely different ways.

Jacobs-Lorena led one of the first teams working to genetically modify mosquitoes to make them resistant to malaria. He's since switched tactics, focusing now on genetically modifying the gut bacteria instead. This strategy might solve one of the most puzzling problems of genetic modification in general: how to get the desired gene into the target population. Rather than taking a roll of the dice on mosquitoes' somewhat puzzling sex lives, Jacobs-Lorena notes that getting the target genes inside mosquitoes, packaged inside bacteria, could be a significantly easier exercise. Since all mosquitoes eat—and supplement their blood meals with carbohydrates—mixing some modified bacteria with sugar could be enough to do the trick. Some gut bacteria are passed on from mother to offspring, so starting the process with one generation could keep it going indefinitely.

His lab is currently working on perfecting the right mix of anti-Plasmodium genes in gut bacteria. It's important to have several genes that fight the parasite in different ways, he explains: "You can never rely only on one. Then you'd have the same problem that you'd have with antibiotics on bacteria that make people sick—with time, the parasite becomes resistant."

He and his team recently tested this approach in live mosquitoes from the insectaries he directs, infusing them with bacteria whose new genes produced a variety of malaria-combating proteins. For example, some block the parasite from passing into a mosquito's midgut through a mechanism the scientists still don't understand. Regardless, these useful bacteria reduced by 80 to 90 percent the formation of oocysts, pouches filled with the precursors of Plasmodium's motile form that eventually infects humans. The researchers are optimizing those numbers through further modifications.

Rasgon's work with bacteria aims to shorten the insects' life spans so that they don't live long enough to pass on the parasite. His main focus is a genus of bacteria known as Wolbachia. Researchers have long known that these microbes infect insects, with about 70 percent of species affected. More specifically, Wolbachia infects nearly every genus of mosquito—that is, except for those in the genus Anopheles, the one that carries the malaria parasite.

Since a Wolbachia infection can significantly shorten an insect's life span—hastening death but not before the insect breeds, reducing the evolutionary pressure for an insect species to develop resistance—it would be a boon to develop a way to infect Anopheles. Though it takes some effort in the lab, getting the bacteria into the mosquitoes' cells or bodies is a doable feat. However, unlike other insect species, female Anopheles mosquitoes don't transfer Wolbachia to their offspring, making the process of sustaining the infection through successive generations impossible.

After nearly a decade of trying to make sustainable Wolbachia infection a reality for Anopheles, Rasgon is expecting success in a couple of years. "We've been at this a long time—it's become personal now," he says, with a look that combines both hardened determination and a murderous glint, presumably geared toward mosquitoes.

In the course of working on Wolbachia, Rasgon and his colleagues—by accident—found a virus living in a line of mosquito cells. In live mosquitoes, this virus, called AgDNV, doesn't appear to affect the insects in any way, but tests show that it peaks in reproduction right before the insects are old enough to pass on the malaria parasite. His lab is currently working on using the virus to express some kind of mosquito toxin that could work in a similar way to Wolbachia, by shortening the insects' life spans before they can infect people with malaria.

Comments

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  • saswati datta

    india 04/30/2011 10:15:23 AM

    very informative, very interesting

  • Sief Mahagoub

    Lincoln, Nebraska 02/04/2012 06:47:24 PM

    Great article. I was born and raised in Sudan, Africa. I can relate to this study. Thanks for sharing.

  • Gebremeskel Gebremariam

    Addis Ababa University, Ethiopia 03/06/2012 10:06:15 AM

    I am highly facinated the dimension identified to rollback Malaria, one of the top three most killer diseases in developing countries like Ethiopia. This research may clear our fear or atleast may reduce the nightmare to live in mosquito endemic areas. I am eager to read the next thank you?

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