Genetically Engineered Mosquitoes Show Resistance To Dengue Fever Virus

Anthony James, a UC Irvine vector biologist, is one of a team of researchers who injected DNA into mosquito embryos, creating the first stable transgenic mosquito resistant to Type 2 dengue fever virus, the most prevalent strain of the disease. The mosquitoes that survived the procedure also remained fertile and were able to reproduce, a key factor for any future strategies that may involve replacing mosquito populations with their genetically modified counterparts.

The results were published this week in the early online edition of the Proceedings of the National Academy of Sciences.

“These results are very exciting because they provide us a genetic tool we can use to control mosquito-borne diseases such as dengue fever,” James said. “We have been working for some time on the individual components of creating a genetically modified mosquito that would fend off dengue infection, but this is the first time we have brought all the pieces together to create a stable model that can also reproduce.”

In the study, the researchers exploited a vulnerability of the dengue virus to make the mosquitoes resistant to infection. This vulnerability occurs when the virus replicates and its single strand of RNA – a chemical cousin of DNA – briefly becomes double–stranded. At this point, the virus is vulnerable because of a naturally occurring protein called dicer-2. This protein initially has no effect on a single strand of RNA, but acts like scissors on the double strand, chopping it up and rendering its genetic material useless. Once this process is started, the single-stranded RNA also becomes vulnerable to dicer-2 and is cut up, thereby preventing further virus replication.

On its own, this process of self-destruction happens only after the virus has already replicated and been transmitted; however, the researchers found a way to control and speed up the process. They accomplished this by cloning a section of the virus’ RNA and injected two inverse copies of it into mosquito embryos. The copies formed a double-stranded RNA, which, as expected, bound with dicer-2 and was chopped up. The virus never had the opportunity to replicate. As a result, they could “inoculate” mosquitoes with a form of the virus that would essentially be benign.

Joining James on the study, funded by a 2001 grant from the National Institutes of Health, were researchers from Colorado State University and from Virginia Polytechnic Institute and State University.

James and his colleagues performed tests on a family of mosquitoes descended from one of the original embryos that survived the procedure. They found that the vast majority of that family was highly resistant to dengue infection. They also were able to detect the engineered RNA in the mosquitoes, a sign that the genetic alteration had been successful and passed down through reproduction. Furthermore, when that genetic modification was reversed, the mosquitoes were as susceptible to the virus as they had been before the procedure.

Dengue fever is endemic in more than 100 countries in Africa, the Americas, the Eastern Mediterranean, Southeast Asia and the Western Pacific. The virus is transmitted to people by mosquitoes of the species Aedes aegypti. The World Health Organization estimates 50 million cases of dengue infection each year. Approximately 20,000 people die annually from the disease.

James, a professor of microbiology and molecular genetics, and of molecular biology and biochemistry, has made a number of significant advances on genetic approaches to interrupt malaria parasite and dengue virus transmission by mosquitoes. He has received a number of international awards for his research.

In 2005, he received a $19.7 million grant from the Foundation for the National Institutes of Health to lead an international effort to develop new methods to control the transmission of dengue fever. The project is among 43 groundbreaking research projects to improve health in developing countries, supported by $436 million for the Grand Challenges in Global Health Initiative, launched by the Bill and Melinda Gates Foundation.

According to James, the next step of this research will be to use the FNIH grant to explore population replacement strategies using the genetically modified mosquitoes. He stressed that no genetically altered mosquitoes will be released at any time during these studies.