Recover from dengue once and you are not necessarily free and clear. Mosquito-borne disease characterized by fever, rash and debilitating pain results from one of the four genetically distinct versions of the dengue virus. Previously infected people who are affected by a second of these “serotypes” may face more severe, even life-threatening symptoms. Now, by equipping a mosquito line with an antibody against the virus, the researchers first made insects that – at least in laboratory tests – seem unable to spread any form of the disease. In theory, these mosquitoes could be released in the wild to suppress the circulation of the virus.
“This is fair for the money,” says Alexander Franz, a biologist from the University of Missouri, Columbia, who studies insect-borne viruses. “This is what you need to do if you really want to have a strong effect on the prevalence of dengue.”
Conventional control strategies for dengue, such as removing stagnant water where mosquitoes reproduce, spraying insecticides and protecting people with bed nets, have failed to defeat the virus, which infects up to 400 million people per year in regions close to the tropics. So some researchers are trying to defeat the dengue from inside the mosquito that has just drunk infected blood. The goal is to prevent the virus from spreading into the insect’s saliva, where it can be injected into the next bitten person.
One strategy is to fight the infection with an infection: give mosquitoes a bacteria-blocking virus called Wolbachia pipientis. releasing Wolbachia– insects that carry in the wild have reduced human dengue infection rates in preliminary experiments. Other approaches tinker with the mosquito genome, for example by inserting the gene for a synthetic RNA molecule that destroys the genetic material of the virus. But no approach has effectively battled all four varieties – or serotypes – of the virus.
In 2013, researchers discovered a new possibility. In the blood of a person who had been repeatedly infected with dengue, researchers from Vanderbilt University found an antibody that could bind strongly to all four dengue serotypes and prevent them from infecting new cells.
Mosquitoes don’t make antibodies to target pathogens like us, but giving them the ability to produce one of these immune proteins could help them fight an infection that would otherwise pass on to people. In previous studies, researchers have equipped mosquitoes that carry the malaria parasite Plasmodium with an antibody that kept the pathogen out of its saliva.
The new study applies a principle similar to the dengue virus. Molecular biologist Omar Akbari of the University of California, San Diego, and colleagues redesigned the human anti-dengue antibody to simplify its structure, making it easier to insert its gene into the mosquito genome. They injected the antibody weight loss gene into the embryos of Aedes aegypti mosquitoes, which spread dengue. Then, they bred the resulting insects to produce offspring with two copies of the new gene, which is activated only when blood enters the intestine. After engineered mosquitoes drank blood infected with one of the four dengue serotypes, they did not detect detectable dengue virus in saliva PLOS pathogens.
In the laboratory, these genetically modified mosquitoes could mate and produce healthy offspring. They developed slightly slower than typical mosquitoes, and females had a slightly shorter lifespan, but from these initial tests it is difficult to assess to what extent these mosquitoes will be compared to their wild counterparts, Akbari says.
Overall, the work is promising, says Franz. But future tests will have to show that the dengue virus does not change rapidly and evades the antibody intake and that the inserted gene is stable, capable of producing the antibody in the intestine of mosquitoes generation after generation. If he does, he says, “I think this is probably a winner.”
Akbari’s team eventually hopes to free the mosquitoes freely. To effectively spread the antidengue antibody gene in native populations, the released insects could be further engineered to increase the natural probability that the gene will be passed on from parent to offspring. This “gene drive” approach has never been approved for testing in nature and could rapidly and irreversibly change the genetic structure of an entire population.
But in a recent prepress, the Akbari team described what they suggest would be an easier “split genetic boost” to control for A. aegypti. This approach inserts the two key genetic components of the gene drive into different parts of the mosquito genome, which means that the antidengue antibody gene would spread more slowly and eventually disappear from the population.
Akbari and his associates also plan to investigate other human blood antibodies that could fight human mosquito-borne pathogens. They suspect that similar weapons against viruses like Chikungunya and Zika can be redesigned and introduced into the mosquito genome.