Dengue (DEN) and dengue hemorrhagic fever (DHF) have emerged as the most important mosquito-borne viral diseases affecting humans. DEN disease control is difficult because traditional vector control measures are becoming less effective and vaccines are not currently available. The molecular genetic manipulation of vector mosquitoes has been proposed as an approach to disrupt the transmission of DEN viruses and control DEN disease. The laboratory group at the Arthropod-borne and Infectious Diseases Laboratory (AIDL; Colorado State University (CSU), Fort Collins, CO) using transient alphavirus expression systems has identified gene-based, virus-specific, effector RNAs that profoundly alter the vector competence of Aedes aegypti for transmission of DEN viruses. The James laboratory (University of California, Irvine, CA) has developed methods for producing transformed mosquitoes using two different class 11 transposable elements, Hermes and mariner. Thus, for the first time, all of the components are in place to produce virus-resistant, stable lines of mosquitoes in the laboratory. Genetic analyses will be required to study gene flow of resistant-gene bearing transposons and determine if resistant genes will move through caged populations of mosquito vectors. The research program we propose has the following specific aims: 1) genetically-alter the vector mosquito, Aedes aegypti, with nonautonomous class 11 transposable elements to express anti-DEN effector genes; 2) evaluate the level of resistance and transmission-blocking potential of transgenic mosquito lines to all four serotypes of DEN viruses and among genetic variants of the viruses; and 3) evaluate the mobility and stability of anti-DEN genes as they are carried by autonomous transposable elements through cage populations of mosquitoes. Information derived in these studies may provide a new paradigm for control of vector borne diseases by interrupting the cycle of transmission at the level of the vector, which may then be directly applicable to other vector-pathogen systems.
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