After decades of research and countless control attempts, dengue fever--a mosquito-borne viral disease--continues to infect an estimated 390 million people around the world each year. Now, researchers have reported in PLOS Neglected Tropical Diseases that the mosquitos that carry dengue virus (DENV) can be genetically engineered have an increased resistance to infection by the virus.
When a mosquito bites someone infected with DENV, the virus needs to complete its lifecycle in the mosquito's gut, eventually infecting its salivary glands, before it can infect another person. Previous studies have shown that mosquitos rely on a molecular pathway dubbed JAK/STAT to try to fight DENV infection and stop this cycle. Proteins known as Dome and Hop are involved in turning on the JAK/STAT when the mosquito is infected with DENV.
In the new work, George Dimopoulos, of Johns Hopkins University, and colleagues genetically engineered Aedes aegypti mosquitos to turn on expression of either Dome or Hop, in the fatbody tissue, earlier in infection--immediately after ingesting blood--and make more of the proteins.
Mosquitos with engineered versions of Dome or Hop that were then infected with DENV had 78.18% (Dome) and 83.63% (Hop) fewer copies of the virus in their guts, as well as significantly less virus in their salivary glands. Mosquitos with the altered genes had normal lifespans, but produced fewer eggs than normal mosquitos. When the researchers repeated the experiments with Zika virus and chikungunya virus, no impact was seen on infection, suggesting that the importance of the JAK/STAT pathway in the fatbody tissue is unique to DENV.
"It may be possible to achieve improved or total resistance to dengue and other viruses by expressing additional transgenes in multiple tissues that block the virus through different mechanisms," the researchers write. "Recently developed powerful mosquito gene-drive systems, that are under development, are likely to make it possible to spread pathogen resistance in mosquito populations in a self-propagating fashion, even at a certain fitness cost."
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Citation: Jupatanakul N, Sim S, Angleró-Rodríguez YI, Souza-Neto J, Das S, Poti KE, et al. (2017) Engineered Aedes aegypti JAK/STAT Pathway-Mediated Immunity to Dengue Virus. PLoS Negl Trop Dis 11(1): e0005187. doi:10.1371/journal.pntd.0005187
Funding: SS was supported by a fellowship from the Agency for Science, Technology and Research, Singapore. NJ was supported by a fellowship from the Royal Thai Government. The work was supported by grants from the NIH, NIAID: AI101431 (to GD), R21AI090188 (GD), 1R24AI120942 (to NV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.