March 29, 2004
Genetically Engineered Mosquitoes Could Stop Malaria

Researchers in the European Molecular Biology Laboratory located in Heidelberg, Germany have discovered mosquito proteins that determine how well the malaria parasite falciparum plasmodium reproduces in mosquitoes.

EMBL scientists have identified four mosquito proteins that affect the ability of the malaria parasite (Plasmodium) to survive and develop in the malaria-carrier mosquito (Anopheles). This breakthrough, featured in recent issues of Cell (March 5, 2004) and Science (March 26, 2004), could be used to block the transmission of malaria from mosquitoes to humans.

"Many researchers focus on the direct effects of Plasmodium on the human body but the mosquito is an equally important battleground in fighting the disease," notes Prof. Fotis C. Kafatos, EMBL's Director-General and leader of the group focusing on malaria research. "We now see a way to potentially stop the parasite in its tracks."

The malaria parasite has to be able to reproduce in the mosquito in order to be able to infect humans.

When a blood-feeding Anopheles mosquito bites an infected organism, the insect feeds on its blood - taking in the malaria-causing Plasmodium. After three weeks of developing within the mosquito, the Plasmodium moves from the insect gut into the salivary glands and is ready for transmission: at the next bloodmeal it will be injected into the bloodstream along with the mosquito's saliva, initiating a new infection cycle.

But one fact that had continued to puzzle malaria researchers is why within one mosquito species, some mosquitoes transmit malaria (termed "susceptible"), whereas others do not ("refractory"). It was suspected that protein factors of the mosquito's immune system might be responsible for this difference. EMBL scientists have now shown this to be the case - with a new twist.

Two of these mosquito proteins, TEP1 and LRIM1, were shown to be true defenders of the mosquito - killing the parasite in the insect's gut.

"The TEP1 and LRIM1 studies proved that the mosquito's immune system has the ability to defend itself against malaria. By enhancing these natural defenders, we may be able to block the parasite-mosquito cycle," says EMBL PhD student Stephanie Blandin, who worked on the TEP1 studies with CNRS researcher (and EMBL alumna) Elena Levashina and collaborators from the University of Leiden (The Netherlands).

"Our studies on TEP1 represent an important step because they show that TEP1 specifically locks onto the Plasmodium and it is this binding that mediates the killing of the parasite," notes Levashina. "Different forms of this protein are present in susceptible and refractory mosquitoes, potentially accounting for the fact that refractory mosquitoes do not sustain parasite development."

In the Kafatos Group, a collaboration between postdoctoral fellow Mike Osta and Staff Scientist George Christophides revealed a new twist: in addition to the mosquito defender protein LRIM1, they discovered two proteins, CTL4 and CTLMA2, which have an opposite effect, actually protecting the parasite as it develops in the mosquito gut. If these proteins were eliminated, the parasites died.

One way to use this new information would be to develop chemicals aimed at these proteins to strip away protection that these proteins provide to falciparum plasmodium. The chemicals would be used in a fashion analogous to pesticides but with the aim of allowing mosquito immune systems to kill the malaria parasite rather than killing the mosquitoes.

"It is now clear that if we strip away protective proteins, the parasite becomes vulnerable to the mosquito's immune system," Christophides notes. "Developing novel chemicals to inhibit the ability of such proteins to protect the parasite is a promising avenue to decrease the prevalence of malaria."

Prof. Kafatos agrees. "These studies are the first to show the power of the mosquito's immune system and give us some very real options for fighting the disease in the insect before it even has a chance to be passed to a human," he explains. "There is no single 'magic bullet' for controlling this ancient scourge of humanity, but we want to exploit this new lead to contribute to the defeat of malaria."

If the protein made by the CTL4 gene could be deactivated or simply not made then 97% of the parasites would be killed.

When one gene, called CTL4, is inactivated, the mosquitoes destroy up to 97% of the parasites developing inside their bodies. When the other, called LRIM1, is removed, it has the opposite effect: the parasites multiply readily.

The more radical approach to stopping the malaria parasite would be to make genetically engineered mosquitoes that are highly resistant to falciparum plasmodium infection and release those mosquitoes into the wild to displace existing wildtype mosquitoes.

The discoveries have raised new possibilities for stopping mosquitoes from spreading the parasite. For example, genetically engineering mosquitoes with extra genes to attack the parasites, or lacking the genes that protect them, could help.

One objection raised to this approach is that it would be difficult to displace all wildtype mosquitoes. But repeated releases of genetically engineered mosquitoes could make a large dent in the population of wildtype and at the very least decrease the rate of human infection by malaria. Consider the number of lives at stake. Currently every year 300-500 million people are infected and 1.5-2.7 million people die from malaria. Malaria causes damage to livers, kidneys, and other parts of the body. Even the people who do not die and who are not permanently damaged still suffer and are far less able to work and provide for themselves and their families. Those numbers represent a great deal of human suffering.

This is an idea that could be applied to a number of other diseases by making analogous discoveries in other insects and bugs to find out how to make them resistant to pathogens that they pass on to humans. Genetic engineering of ticks, mosquitoes, and other bugs could protect humans against Lyme Disease, West Nile Virus, and other pathogens transmitted by various sorts of creatures. This idea could even be extended as far as genetically engineering chickens, pigs, and other organisms to be more resistant to influenza infection in order to reduce the risk of virulent influenza strains jumping from other species into humans.

Many of the usual suspects who are opposed to genetically modified food crops can be expected to oppose genetic engineering of mosquitoes and other bugs. But the potential number of lives saved could run into the millions and even the tens of millions over a longer period of time. One big advantage of genetic engineering is that it avoids the costs, potential human health risks, and potential environmental harm that would come from repeated application of chemicals in areas where malaria or some other disease is being spread by insects into the human population.

Share |      Randall Parker, 2004 March 29 04:19 PM  Biotech Pathogen Control

Robert Cowger said at March 30, 2004 4:18 PM:

I acquired Malaria while I was in Korea during the Korean War.
Don't ever have malaria. It hurts. I am told that I still have the parasite in my liver, but I rarely ever get a full blown round of malaria requiring medication.

Thank God! for that.

Traverse Davies (logic11) said at March 31, 2004 9:28 AM:

I also have had Malaria, but have had no flare ups since.
What about a retrovirus that attacks mosquitoes? I know that tailored viruses are both risky and controversial, but with the right precautions it could work.

T.J.Green said at April 7, 2004 12:24 PM:

The infected mosquito has a reduced life-span,so this will help in our fight against malaria. The mosquito suffers and dies,as our species suffers and dies. I have to fight for my species,but I have to admire lifes neutrality.

chuck ferret said at May 6, 2005 5:47 AM:

I got diagnosed with malaria and two days later I got shot twice in the side. Malaria sucks!

shehu abdulmoumin said at May 13, 2005 1:55 PM:

i'm so impressed with your research and i think it holds a lotof promise.i am currently a student of pharmacy(nigerian) who is so much interested in malaria generally.Ams i think trials like this will open new ways of tackling this killer disease. if not eradicate it alongside its vector altogether.

John Lucas said at September 8, 2005 7:24 PM:

Can this approach work on the Aedes mosquitoe to fight Dangue fever? Is the Dangue virus transmitted to the mosquitoe eggs creating infected offspring?

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