Curing Mosquitoes of Dengue

Why does Aedes aegypti transmit the dengue virus, while other mosquitoes do not?

One of the theories pursued by scientists is that cells in the mosquito’s gut may contain unique factors that are necessary for virus replication and permit dengue to establish infection. Another possibility is that the virus can circumvent the immune system of specific mosquito species and strains.

George Dimopoulos, an MMI associate professor, suggests that if these factors could be pinpointed, they could be manipulated to prevent the virus from propagating. Last year he and other dengue experts broke new ground in this area. Oddly, they made their discoveries with the help of an old and much-studied insect friend of researchers: the Drosophila fruit fly.
   
Because scientists lack some molecular tools and a detailed body of mosquito immune system research, they haven’t been able to fully understand the workings of cellular pathways in a mosquito that trigger an immune response. Instead, they used fruit flies, which have a large number of genes similar to mosquitoes, suggesting their immune systems would function similarly.

Funded by the NIH, the researchers began scouring the 14,000 genes of the fruit fly for counterparts to the mosquito factors involved in dengue virus infection.

“Our collaborators deactivated every fruit fly gene in the cell line one by one,” says Dimopoulos. Then, one by one, they infected the cell line with dengue virus to identify which genes were either necessary for dengue infection (host factors) or for acting against dengue infection (restriction factors). When they were finished, scientists had identified 116 specific characteristics of the fruit fly genes that responded either for or against the infection. Only five of those 116 had been previously suspected by researchers.

Dimopoulos and his team then deactivated the same suspected genes in live mosquitoes and injected them with the dengue virus. “In this way we could identify the genes that, when inactivated, would either make the cell more resistant or more susceptible to an infection.” As hoped, they found that the very same genes that reacted to dengue in the fruit fly reacted to it in the mosquito.

In parallel work, the Dimopoulos Group showed that two other immune pathways are key players in the mosquito’s defense against dengue, putting science one step closer to a dengue “cure” for the mosquito.