The first malaria-proof mosquito

Jul 15, 2010
Under UV light, this mosquito larva reveals a red fluorescent marker in its nervous system, causing eyes and nerves to glow. The marker's presence tells the researchers in Riehle’s team that this individual carries the genetic construct rendering it immune to the malaria parasite. Credit: M. Riehle, University of Arizona

For years, researchers worldwide have attempted to create genetically altered mosquitoes that cannot infect humans with malaria. Those efforts fell short because the mosquitoes still were capable of transmitting the disease-causing pathogen, only in lower numbers.

Now for the first time, University of Arizona entomologists have succeeded in genetically altering in a way that renders them completely immune to the parasite, a single-celled organism called Plasmodium. Someday researchers hope to replace wild mosquitoes with lab-bred populations unable to act as vectors, i.e. transmit the malaria-causing parasite.

"If you want to effectively stop the spreading of the parasite, you need mosquitoes that are no less than 100 percent resistant to it. If a single parasite slips through and infects a human, the whole approach will be doomed to fail," said Michael Riehle, who led the research effort, the results of which will be published July 15 in the journal Public Library of Science Pathogens. Riehle is a professor of entomology in the UA's College of Agriculture and Life Sciences and is a member of the BIO5 Institute.

Riehle's team used molecular biology techniques to design a piece of genetic information capable of inserting itself into a mosquito's genome. This construct was then injected into the eggs of the mosquitoes. The emerging generation carries the altered genetic information and passes it on to future generations. For their experiments, the scientists used Anopheles stephensi, a mosquito species that is an important malaria vector throughout the Indian subcontinent.

The researchers targeted one of the many inside the mosquito's cells. Specifically, they engineered a piece of acting as a in the complex control of metabolic functions inside the cell. The genetic construct acts like a switch that is always set to "on," leading to the permanent activity of a signaling enzyme called Akt. Akt functions as a messenger molecule in several metabolic functions, including larval development, immune response and lifespan.

When Riehle and his co-workers studied the genetically modified mosquitoes after feeding them malaria-infested blood, they noticed that the Plasmodium parasites did not infect a single study animal.

"We were surprised how well this works," said Riehle. "We were just hoping to see some effect on the mosquitoes' growth rate, lifespan or their susceptibility to the parasite, but it was great to see that our construct blocked the infection process completely."

Of the estimated 250 million people who contract malaria each year, 1 million - mostly children - do not survive. Ninety percent of the number of fatalities, which Riehle suspects to be underreported, occur in Sub-Saharan Africa.

Each new malaria case starts with a bite from a vector - a mosquito belonging to the genus Anopheles. About 25 species of Anopheles are significant vectors of the disease.

Only the female Anopheles mosquitoes feed on blood, which they need to produce eggs. When they bite an infected human or animal, they ingest the malaria parasite.

Once the Plasmodium cells find themselves in the insect's midgut, they spring into action. They leave the insect's digestive tract by squeezing through the midgut lining. The vast majority of Plasmodium cells do not survive this journey and are eliminated by the mosquito's immune cells. A tiny fraction of parasite cells, usually not more than a handful, make it and attach themselves on the outside of the midgut wall where they develop into brooding cells called oocysts.

Within 10-12 days, thousands of new Plasmodium cells, so-called sporozoites, sprout inside the oocyst. After hatching from the oocyst, the sporozoites make their way into the insect's salivary glands where they lie in wait until the mosquito finds a victim for a blood meal. When the mosquito bites, some sporozoites are flushed into the victim's bloodstream.

"The average mosquito transmits about 40 sporozoites when it bites," said Riehle, "but it takes only one to infect a human and make a new malaria victim."

Several species of Plasmodium exist in different parts of the world, all of which are microscopically small single-celled organisms that live in their hosts' red blood cells. Each time the parasites undergo a round of multiplication, their host cells burst and release the progeny into the bloodstream, causing the painful bouts of fever that malaria is known and feared for.

Malaria killed more soldiers in the Civil War than the fighting, according to Riehle. In fact, malaria was prevalent in most parts of the U.S. until the late 1940s and early 1950, when DDT spraying campaigns wiped the vectors off the map. Today, a new case of malaria occurs in the U.S. only on rare occasions.

The severity of the disease depends very largely on the species of the Plasmodium parasite the patient happens to contract.

"Only two species of Plasmodium cause the dreaded relapses of the disease," said Riehle. "One of them, Plasmodium vivax, can lie dormant in the liver for 10 to 15 years, but now drugs have become available that target the parasites in the liver as well as those in the blood cells."

That said, there are no effective or approved malaria vaccines. A few vaccine candidates have gone to clinical trials but they were shown to either be ineffective or provide only short-term protection. If an effective vaccine were to be developed, distribution would be a major problem, Riehle said.

Researchers and health officials put higher hopes into eradication programs, which aim at the disease-transmitting mosquitoes rather than the pathogens that cause it.

"The question is 'What can we do to turn a good vector into a bad vector?'" Riehle said.

"The eradication scenario requires three things: A gene that disrupts the development of the parasite inside the mosquito, a genetic technique to bring that gene into the mosquito genome and a mechanism that gives the modified mosquito an edge over the natural populations so they can displace them over time."

"The third requirement is going to be the most difficult of the three to realize," he added, which is why his team decided to tackle the other two first.

"It was known that the Akt enzyme is involved in the mosquito's growth rate and immune response, among other things," Riehle said. "So we went ahead with this genetic construct to see if we can ramp up Akt function and help the insects' immune system fight off the malaria parasite."

The second rationale behind this approach was to use Akt signaling to stunt the mosquitoes' growth and cut down on its lifespan.

"In the wild, a mosquito lives for an average of two weeks," Riehle explained. "Only the oldest mosquitoes are able to transmit the parasite. If we can reduce the lifespan of the mosquitoes, we can reduce the number of infections."

His research team discovered that mosquitoes carrying two copies of the altered gene had lost their ability to act as malaria vectors altogether.

"In that group of mosquitoes, not a single Plasmodium oocyst managed to form."

At this point, the modified mosquitoes exist in a highly secured lab environment with no chance of escape. Once researchers find a way to replace wild mosquito populations with lab-bred ones, breakthroughs like the one achieved by Riehle's group could pave the way toward a world in which malaria is all but history.

Explore further: The origin of the language of life

More information: Corby-Harris et al. Activation of Akt Signaling Reduces the Prevalence and Intensity of Malaria Parasite Infection and Lifespan in Anopheles stephensi Mosquitoes. Public Library of Science (PLoS) Pathogens, July 2010 issue: www.plospathogens.org

Related Stories

Malaria immunity trigger found for multiple mosquito species

Mar 13, 2009

(PhysOrg.com) -- Researchers at the Johns Hopkins Bloomberg School of Public Health have for the first time identified a molecular pathway that triggers an immune response in multiple mosquito species capable of stopping ...

Recommended for you

The origin of the language of life

Dec 19, 2014

The genetic code is the universal language of life. It describes how information is encoded in the genetic material and is the same for all organisms from simple bacteria to animals to humans. However, the ...

Quest to unravel mysteries of our gene network

Dec 18, 2014

There are roughly 27,000 genes in the human body, all but a relative few of them connected through an intricate and complex network that plays a dominant role in shaping our physiological structure and functions.

EU court clears stem cell patenting

Dec 18, 2014

A human egg used to produce stem cells but unable to develop into a viable embryo can be patented, the European Court of Justice ruled on Thursday.

User comments : 6

Adjust slider to filter visible comments by rank

Display comments: newest first

philosothink
not rated yet Jul 15, 2010
Won't this gene take over eventually any way? If the mosquitoes are not killing off their food sources... :)
jsa09
5 / 5 (1) Jul 15, 2010
@philosothink NO. Two things can happen to the modified mosquito and the unmodified mosquito.

1) They cross breed and merge and without any darwinian survival advantages the new type being lesser in number would die out.

2) They cannot cross breed and the new type becomes another mosquito living alongside the malarial mosquito.

What is needed as the article says is some advantage. Preferable in two parts. They want their modified mosquito to have a dominant gene and to cross breed with unmodified members of the same species. AND, they want it to have greater survival habits without giving the malaria a chance to mutate and put us all back at square one.

The only problem with making a better mosquito is that who wants a better mosquito?
jonlawsb
not rated yet Jul 16, 2010
Is there any information on the success rate of the modified species mating with unmodified?

Will the released version of the modified insect still have the UV marker? As the mosquito uses UV light in it's vision - surely adding a UV fluorescent marker to proteins in the eyes & nevous system radically alters it's appearance to other mosquitoes and therefore it's cross-breeding success.
labtvonline
not rated yet Jul 16, 2010
This could be a huge breakthrough for the people of the developing world. I think that most people don't realize that Malaria still is the most deadly disease in the world killing 1,000,000 a year. It is a little scary to think that we could possibly genetically engineer a wild population through breading. I feel like this is a slippery slope and we need to be careful. Scientist in the past have done ok with fighting malaria but recently have made a huge breakthrough. The have effectively created a cure for Malaria called Artesinate. It is scheduled for FDA approval and could change the game for people inflicted with this horrible disease. I'll post a link to a video all about this new cure. It's truly amazing!

http://www.ndep.u...-Malaria
Djincs
not rated yet Jul 16, 2010
Great idea, but to create something that is better than the wild population, you must be genious, this creatures can evolve really fast they are at great numbers, the change of the generations happens in a matter of monts.....I dont know if that is possible, they can make another thing, like the roundup ready plants, to give this insects a resistance for pesticide and then to sprey the swamps, but they should modify them in terms that they cant crossbread, they can change the numbers of the hromosomes(to murge 2 hcromosomes in 1 or the oposite) of this new insect ..or something else i dont know, i wish them luck, they will need it.
Ethelred
not rated yet Jul 18, 2010
They want their modified mosquito to have a dominant gene and to cross breed with unmodified members of the same species. AND, they want it to have greater survival habits without giving the malaria a chance to mutate and put us all back at square one.


The malaria parasite is hard on the mosquito not just humans. Mosquitoes that cannot carry malaria are mosquitoes that should be better survivors than those that get it. The article stated that the modified mosquito was 100 percent malaria free in which case the malaria cannot adapt to them.

Of course in the wild there might be strains of malaria that COULD infect the modified mosquito.

Ethelred

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.