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PRIMARY INVESTIGATOR:
Dr. Anthony A. James, University of California at Irvine, California, United States - US
Genetic Strategies for Control of Dengue Virus Transmission
Research ObjectivesProject Progress & Milestones
Publications & Related LinksCollaborators
Project

Approaches to controlling disease-carrying insects might include inhibiting the development of virus in the mosquito or altering the insects' lifespan so that they die before they can transmit disease. A major challenge to this approach, however, is ensuring that such strategies are effective, safe, and socially and environmentally acceptable. 
 
Dr. James is leading an international team of scientists that is seeking to develop methods of controlling the transmission of dengue viruses using genetic techniques, including those that may block virus transmission by mosquitoes and reduce or eliminate populations of mosquitoes that transmit the virus. 
 
Investigators have begun to analyze locally collected mosquitoes to get baseline data on ecology and reproductive rates, survey species breeding within communities, and obtain specimens to assess the structure of local populations. Surveys of mosquito ecology and dengue epidemiology in the Tapachula area show a variety of dengue serotypes detected in Aedes aegypti and Aedes albopictus.  Investigators will mediate developmentally-regulated transposition in mosquitoes, for transposon-based strategies. Alternative gene drive systems are also being assessed, particularly the Medea system developed in Drosophila melanogaster.  The team is also pursuing promoters capable of expressing RNAi in the salivary glands, as a backup to expression in the midgut.

Research Objectives:
Optimize effector genes for population replacement and reduction. The team is researching two major effector gene strategies: Those that would block virus transmission (RNAi suppression of viral gene expression) and those that would reduce or eliminate mosquito populations (dominant lethal genes for pre-adult lethality).
Develop densovirus formulations as agents for population reduction
Develop safe and efficient systems for introducing effector genes into target populations
Develop mathematical models using ecological data from field sites to simulate gene drive and effect on dengue transmission, and to compare the cost-effectiveness of alternative genetic control strategies
Establish a field site for genetic control trials. The team is evaluating several possible sites
Test genetically modified mosquitoes, first in laboratory cages and then in large outdoor cage trials at the field site, to assess the relative fitness of the mosquitoes compared to local wild mosquitoes, spread of effector genes in experimental populations, and potential for disease prevention. The project does not plan the release of any genetically-modified mosquitoes into the field
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Project Progress & Milestones:
Working with Aedes aegypti, investigators found the Aedes aegypti carboxypeptidase (AaCP) and vitellogenin 1 gene (Vg1) promoters direct accumulation of gene products in the midgut and hemolymph, respectively. Unlike AaCp, however, Vg1 promoter-driven effector genes did not reduce dengue virus concentrations well in challenge assays.
Anti-dengue virus type 2 (DV2) double-stranded RNAs (dsRNAs) were highly effective in reducing viral concentrations in whole animals.
Reducing viral concentrations in mosquito-challenge experiments was also successful in denvue virus types 1-4 using this method.
Development of a female-specific flightless phenotypes has been shown using the AeAct4 gene promoter, which are now a priority for further testing.
Investigators are conducting live cage experiments with mosquitoes to measure the ability of viruses to persist in field-derived mosquitoes and to spread among containers. Investigators are defining product applications and intended outcomes for a potential product named “Densovir.”
Progress had been made on development of computer models to predict the outcome of gene drive systems and to perform cost-effectiveness analysis of different genetic control methods to reduce the burden of dengue.
A site in Tapachula, Mexico, has been chosen for conducting contained field trials.  Efforts are underway to obtain all necessary approvals and plans for cage construction are in development.
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Publications and Related Links:
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Collaborators:
Dr Fred Gould, North Carolina State University, North Carolina, United States - US
Dr Luke Alphey, Oxitec Ltd., United Kingdom - GB
Dr Kenneth E Olson, Colorado State University, Colorado, United States - US
Dr Thomas W Scott, University of California, Davis, California, United States - US
Dr David W Severson, University of Notre Dame, Indiana, United States - US
Dr Craig J Coates, Texas A&M, Texas, United States - US
Dr Claudio J Struchiner, Fundacao Oswaldo Cruz, Brazil - BR
Dr Laura C Harrington, Cornell University, New York, United States - US
Dr Bruce Hay, California Institute of Technology, California, United States - US
Dr Zhijian Tu, Virginia Tech, Virginia, United States - US
Dr Jonathan O Carlson, Colorado State University, Colorado, United States - US
Dr William C Black IV, Colorado State University, Colorado, United States - US
Texas A&M, Texas, United States - US
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 Project at a Glance

GOAL:
CHALLENGE:
TECHNOLOGY CATEGORY:
DISEASE MODEL:

 Research Map