One can only imagine the pain and morbidity associated with a disease that is colloquially referred to in many parts of the world as “breakbone fever.” Yet, for the nearly 400 million people infected annually with the dengue virus (DENV), imagination need not be applied as they have experienced the reality of this painful and potentially lethal virus. With no viable vaccine currently in use and a death toll of more than 20,000 per year, mostly children, researchers have continually searched for potentially methods to reduce or eliminate DENV transmission.
Now, investigators from the Johns Hopkins Bloomberg School of Public Health have successfully engineered mosquitoes to resist infection from DENV. The researchers found that it was possible, in the lab, to boost the Aedes aegypti mosquito’s natural ability to fight the DENV as a first step toward suppressing its capacity to spread the disease. The researchers are optimistic that their findings could be a prelude to developing a strategy to eliminate the threat of dengue. Forty percent of the world’s population live in areas where they are at risk of the virus, which is most common in Southeast Asia and the western Pacific islands and has been rapidly increasing in Latin America and the Caribbean.
“If you can replace a natural population of dengue-transmitting mosquitoes with genetically modified ones that are resistant to the virus, you can stop disease transmission,” explained senior study investigator George Dimopoulos, Ph.D., professor in the department of molecular microbiology and immunology and a member of the Johns Hopkins Malaria Research Institute. “This is a first step toward that goal.”
While the newly engineered mosquitoes were able to significantly suppress dengue virus infection, they did not show any resistance to Zika or chikungunya—two other viruses carried by A. aegypti. “This finding, although disappointing, teaches us something about the mosquito’s immune system and how it deals with different viruses,” Dr. Dimopoulos remarked. “It will guide us on how to make mosquitoes resistant to multiple types of viruses. Ideally, you want a mosquito that is resistant to other viruses as well.”
The Hopkins researchers noted that A. aegypti mosquitoes do mount an immune system response when exposed to the dengue virus, but it appears to be too weak to stop transmission. With this knowledge in hand, the research team was able to manipulate a component of the immune system—the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway—that regulates the production of antiviral factors. They did this in a part of the mosquito known as the fat body, its version of the liver.
The findings from this study were published recently in PLOS Neglected Tropical Diseases in an article entitled “Engineered Aedes aegypti JAK/STAT Pathway-Mediated Immunity to Dengue Virus.”
The genetic modification resulted in fewer mosquitoes becoming infected, and most of those that did had very low levels of dengue virus in their salivary glands, the location from which the virus gets transmitted to humans. Still, these experiments didn’t lower the level of virus in all mosquitoes to zero, something that puzzled the scientists. They say more research is needed to understand whether this level of virus suppression would be enough to halt disease transmission. They are working on other experiments to see if they can produce antiviral factors in the gut, which could assist in inducing a stronger immune response and possibly confer resistance to the other viruses.
The researchers found that the dengue-resistant mosquitoes live as long as the wild mosquitoes, though they do produce fewer eggs, most likely because the same mechanism involved in dialing up the immune system to fight dengue also plays a role in egg production.
“It may be possible to achieve improved or total resistance to dengue and other viruses by expressing additional transgenes in multiple tissues that block the virus through different mechanisms,” the authors wrote. “Recently developed powerful mosquito gene-drive systems, used circumspectly, are likely to make it possible to spread pathogen resistance in mosquito populations in a self-propagating fashion, even at a certain fitness cost.”
While genetically modified organisms and gene-drive technology have seen their fair share of controversy over the past several years, scientists acknowledge there are concerns with the release of genetically modified mosquitoes in the environment since they can’t be recaptured. They are there to stay.
“This is why extensive lab and semi-field studies are required to get it right,” Dr. Dimopoulos stated. If investigators can get this to work, however, it could become a very effective way of controlling the disease. It could be done without people having to actively participate. They would get long-lasting protection without having to take medication, get vaccinated, or use bed nets or repellents.