Filarial nematode parasites are among the most devastating infections of humans with over 100 million people affected worldwide. The absence of naturally-existing hosts for human filariae and the relative accessibility of Dirofilaria immitis in dogs has made the dog heartworm system a good conceptual model for the study of filarial nematode infections. Filarial nematodes are transmitted by an arthropod intermediate host. While many species of mosquitoes have been shown to be capable of enabling the development of filarid larvae, most of the laboratory-based work on the susceptibility of mosquitoes to filariae has been based upon infections of Aedes aegypti. The yellow fever mosquito, Ae. aegypti, is one of the better genetically characterized mosquito species with 77 markers having been placed on the classical genetic linkage map for the 3 chromosomes (2n=6). In addition, we have placed 79 loci on a RFLP genetic linkage map to date and these RFLP loci cover the entire Ae. aegypti genome with an average spacing of approximately 2 Mb. While filarial susceptibility was identified originally as a sex-linked recessive locus on chromosome I, the gene product(s) associated with the filarial susceptibility f locus has not been identified. We have identified 3 RFLP markers which explain a significant portion of the observed phenotypic variance for filarial worm susceptibility. The results indicate that at least 3 genes (defined by 3 QTL) are involved in determining D. immitis susceptibility. Our long-term objective is to elucidate the molecular basis for vector competency in the transmission of parasitic diseases with the goal to control vector-borne parasitic disease cycles in nature. The system chosen for these studies is the yellow fever mosquito, Ae. aegypti, and the filarial parasite responsible for zoonotic filariasis, dog heartworm, D. immitis. Since the ability of Ae. aegypti to support filarial development through the infective 3rd stage is under the control of multiple genes located across all 3 Ae. aegypti chromosomes, this proposal will produce a physical map of Ae. aegypti genome, integrate this map with our RFLP genetic linkage map, and identify gene(s) responsible for the filarial worm susceptible phenotype.
The specific aims i nclude: l) Fluorescence in situ hybridization physical mapping of the Ae. aegypti mosquito chromosomes; 2) Integration of genetic determinants of filarial vector competence with the physical map; and 3) Construction of contigs spanning loci determining filarial worm susceptibility and identification of gene(s) and products associated with vector competence.
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