Recover from dengue once, and you’re not necessarily free and clear. The mosquito-borne disease marked by fever, rash, and debilitating pain results from any of four genetically distinct versions of the dengue virus. Previously infected people who get hit with a second of these “serotypes” can face more severe, even life-threatening symptoms. Now, by endowing a line of mosquitoes with an antibody against the virus, researchers have for the first time made insects that—at least in lab tests—appear unable to spread any form of the disease. In theory, these mosquitoes could be released into the wild to suppress the circulation of the virus.
“This is right on the money,” says Alexander Franz, a biologist at 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 dengue prevalence.”
Conventional control strategies for dengue, such as removing stagnant water where mosquitoes breed, spraying insecticides, and protecting people with bed nets, have failed to defeat the virus, which infects up to 400 million people a year in regions near the tropics. So some researchers are trying to defeat dengue from inside the mosquito that has just drunk infected blood. The goal is to keep the virus from spreading to the insect’s saliva, where it can be injected into the next person bitten.
One strategy is to fight infection with an infection—give mosquitoes a virus-blocking bacterium called Wolbachia pipientis. Releasing Wolbachia-carrying insects into the wild has reduced rates of human dengue infection in preliminary experiments. Other approaches tinker with the mosquito genome—for example, inserting the gene for a synthetic RNA molecule that destroys the virus’s genetic material. But no approach has effectively combatted all four varieties—or serotypes—of the virus.
In 2013, researchers uncovered a new possibility. In the blood of a person who had been infected with dengue multiple times, researchers at Vanderbilt University found an antibody that could strongly bind to all four dengue serotypes and prevent them from infecting new cells.
Mosquitoes don’t make antibodies to target pathogens like we do, but giving them the ability to make one of these immune proteins could help them fight off an infection that they would otherwise pass on to people. In previous studies, researchers endowed mosquitoes that carry the malaria parasite Plasmodium with an antibody that kept the pathogen out of their saliva.
The new study applies a similar principle to the dengue virus. Molecular biologist Omar Akbari of the University of California, San Diego, and colleagues reengineered the human antidengue antibody to simplify its structure, making its gene easier to insert into the mosquito genome. They injected the slimmed-down antibody gene into the embryos of Aedes aegypti mosquitoes, which spread dengue. Then, they bred the resulting insects to make offspring with two copies of the new gene, which is activated only when blood enters the gut. After the engineered mosquitoes drank blood infected with any one of the four dengue serotypes, they had no detectable dengue virus in their saliva, the researchers report today in PLOS Pathogens.
In the lab, these genetically engineered mosquitoes could mate and produce healthy offspring. They developed slightly slower than typical mosquitoes, and the females had slightly shorter life spans, but it’s hard to gauge from these initial tests how fit these mosquitoes will be compared with their wild counterparts, Akbari says.
Overall, the work is promising, Franz says. But future tests will need to demonstrate that the dengue virus doesn’t quickly mutate and evade the antibody’s grip, and that the inserted gene is stable—able to produce the antibody in the mosquito gut generation after generation. If it does, he says, “I think this is probably a winner.”
Akbari’s team eventually hopes to release the mosquitoes into the wild. To efficiently spread the antidengue antibody gene into native populations, the released insects might be further engineered to bump up the natural likelihood that the gene will be passed from parent to offspring. This “gene drive” approach has never been approved for testing in the wild, and could quickly and irreversibly change the genetic makeup of an entire population.
But in a recent preprint, Akbari’s team described what they suggest would be an easier-to-control “split gene drive” for A. aegypti. That approach inserts the two key genetic components of the gene drive into different parts of the mosquito genome, which means that the gene for the antidengue antibody would spread more slowly and would eventually disappear from the population.
Akbari and his collaborators also plan to investigate other antibodies from human blood that could fight off mosquito-borne human pathogens. They suspect that similar weapons against viruses such as chikungunya and Zika could be re-engineered and slipped into the mosquito genome.