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Humans and mosquitoes have been coexisting on Earth for all of human history – happily for the mosquitoes, certainly not for the humans. Despite countless attempts at mosquito control, these members of the Culicidae family continue to plague humans as envoys of death and disease. Researchers at the Arthropod-borne and Infectious Diseases Laboratory (AIDL) at Colorado State University are hoping that their investigations into genetic modification will one day engineer a mosquito incapable of spreading disease.
“We are seeking to develop methods that control the transmission of dengue viruses using genetic techniques, including those that may block virus transmission by mosquitoes,” said Dr. Ken Olson, a Professor in the Department of Microbiology, Immunology and Pathology, and Director of AIDL. “Our research offers promising results for halting the spread of this disease by disarming the mosquito’s ability to contract and transmit the dengue type-2 virus, stopping the virus in its tracks. It demonstrates that it’s possible to develop a mosquito that won’t transmit disease to people by genetically triggering the RNA interference pathway.”Researchers manipulated the DNA of mosquito embryos by introducing the DNA of a dengue-resistant gene into the embryo. The research team cuts the mosquito DNA in embryonic germ line cells and pastes in the effector gene linked to a midgut-specific promoter. Activity of the promoter is dependent on ingestion of a blood meal. Germ line transformation makes the effector gene heritable by future generations.
Dr. Olson’s research group is developing transgenic mosquitoes that are pathogen-resistent as well as new methods to identify components of the RNAi pathway, studying the molecular epidemiology of dengue viruses, and identifying and characterizing important interactions between the vector and the virus. One challenge facing the researchers is that there are four distinct dengue virus serotypes, and they can make the mosquito resistant to one serotype. What they are searching for is a piece of genetic material common to all four serotypes that will still produce resistance to infection.
“We’ve started the transgenic work in that area and have a couple of lines that may be promising,” said Dr. Olson. “Once we have the transgenic material in our weakened mosquito line, we’ll take it into a number of wild lines, which are more fit. These tests should reflect more accurately what’s happening in the wild.”
As a part of the work, researchers are developing a site in Tapachula, Mexico, for conducting contained field trails. Efforts are underway to obtain all necessary approvals and plans for cage construction are in development. Once constructed, researchers will be able to use the cage system to see how fit the mosquitoes are in the wild and how well they adapt to the environment, as well as how the environment adapts to the transgenic mosquitoes. The ultimate goal of the project is a population replacement strategy, moving the transgenic mosquito into the wild population, eliminating the mosquitoes’ ability to transmit dengue viruses. Drs. Alexander Franz, Imma Sanchez-Vargas, and Corey Campbell, all working with Dr. Olson at AIDL, have been critical to the population development strategies being developed at CSU.
Dengue fever is endemic to about 100 countries including the United States, Cuba, Africa, Columbia, Brazil, Puerto Rico, and the Caribbean Islands. Dengue fever infects 100 million people each year and has a case-fatality rate of about 5 percent if left untreated, primarily in children and young adults. Dengue hemorrhagic fever is the most severe form of dengue and can be fatal if not properly and promptly treated.
Dr. Olson’s work in dengue fever is part of the Bill and Melinda Gates Foundation Grand Challenges in Global Health, which funded 43 grants for $436 million in 2005. Dr. Olson is part of global team led by Dr. Anthony James, the project’s Principal Investigator, from the University of California at Irvine. Other research partners include North Carolina State University, Oxitec Ltd. in the United Kingdom, University of California at Davis, University of Notre Dame, Texas A&M, Fundacao Oswaldo Cruz in Brazil, Cornell University, California Institute of Technology, and Virginia Tech. At CSU, other collaborators include Dr. William C. Black and Dr. Jonathan O. Carlson, both in the Department of Microbiology, Immunology and Pathology. The stated goal of the grant is to control insect vectors by developing a genetic strategy to deplete or incapacitate a disease-transmitting insect population.
“The exciting thing about being a part of the Grand Challenges is the opportunity to work with others around the world to develop novel genetic strategies for stopping transmission of dengue viruses,” said Dr. Olson, whose initial work in transgenics was funded by the National Institutes of Health. “By sharing our experiences and expertise, we are able to move the work forward to meet the goal of new approaches to controlling vector-borne diseases.”