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New microRNA Data Offers Clues on Controlling Dengue Virus

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A team of Australian researchers have reported new data on the role of a specific microRNA in blocking dengue replication in the mosquito Aedes aegypti, providing new insights into how infection by the virus may be combatted through management of its primary vector.

Dengue virus, or DENV, is a principle cause of a potentially lethal hemorrhagic fever and is primarily transmitted by female mosquitos. With no specific antiviral treatments or preventative vaccines available, controlling mosquitos has emerged as a key strategy to prevent infection.

Given the potential hazards of using chemical pesticides, interest has turned to the use of the endosymbiotic bacteria Wolbachia for vector population management.

According to the report, which appeared in this week’s Proceedings of the National Academy of Sciences, mosquitos infected with Wolbachia show strong resistance to a variety of arboviruses including DENV, yellow fever, and Plasmodium.

In 2011, as part of their effort to uncover the mechanisms behind this protective effect, the Australian investigators discovered that Wolbachia infection not only significantly alters the overall mosquito miRNA profile, but also induces expression of the miRNA aae-miR-2940, which is not detected in non-infected mosquitos.

Notably, a target of aae-miR-2940 is the Ae. aegypti metalloprotease gene, and the scientists demonstrated that miRNA and its stabilization of its target are “essential” for the replication/maintenance of Wolbachia in the mosquito.

“Considering the significant abundance of [aae-miR-2940] in Wolbachia-infected mosquitoes, we were interested to find out if the miRNA has other potential targets,” Sassan Asgari, a University of Queensland researcher and senior author of the PNAS paper, told Gene Silencing News in an email.

Using bioinformatics tools, the researchers identified the DNA methyltransferase gene AaDnmt2 as a possible target of aae-miR-2940 — a result that caught the team’s attention in light of research being conducted in a colleague’s lab indicating that the genomes of Wolbachia-infected mosquitoes are hypomethylated, he noted.

Ae. aegypti only has one cytosine methyltransferase — AaDnmt2,” Asgari added. “Therefore, we were interested to find out if this gene is affected by aae-miR-2940, leading to changes in genome methylation.”

Experimentation revealed that the gene was not detectable in Wolbachia-infected mosquitoes, but could be found in those infected insects that had been cured using tetracycline, according to the PNAS paper. In tetracycline-treated mosquitos infected with DENV, meanwhile, AaDnmt2 was expressed at “much higher levels” compared with non-DENV mosquitos.

Additional investigation validated the interaction between aae-miR-2940 and AeDnmt2, and the researchers demonstrated that the miRNA downregulates the gene’s expression, offering one possibility for the “mosquito genome methylation inflicted by Wolbachia, Asgari wrote in his email.

Since aae-miR-2940 was found to upregulate the transcript levels of the host metalloprotease, which is essential for Wolbachia infection, and because the miRNA also downregulates the transcript levels of AaDnmt2, the scientists explored the gene’s effect on the bacteria.

They discovered that overexpression of AaDnmt2 in Wolbachia-infected mosquitos significantly lowers the bacteria’s density, suggesting that suppression of the gene by Wolbachia is essential for infection maintenance.

To examine AaDnmt2’s effect on DENV, the researchers overexpressed the gene in mosquito cell lines that were then infected with the virus, finding that the relative abundance of DENV was significantly higher in cells overexpressing AaDnmt2 versus control cells transfected with an empty vector, they wrote in PNAS.

“It seems suppression of AeDnmt2 by Wolbachia via induction of aae-miR-2940 contributes into resistance of Wolbachia-infected mosquito cells against dengue virus replication,” Asgari explained, although just how this AaDnmt2 facilitates dengue virus replication requires further investigation.

Interestingly, when considered alongside the data from the team’s 2011 paper, the findings in PNAS indicate that a single miRNA can have both repressive and enhancing effects on different targets — in this case, AaDnmt2 and metalloprotease, respectively, he added.

Overall, the work published in PNAS reveals a critical functional link between Wolbachia, miRNAs, and DENV, the study’s authors concluded.

Additionally, a better understanding of the mechanisms that contribute to Wolbachia’s inhibitory effects on DENV may help in the utilization of the endosymbiont in disease prevention and improved management of the mosquito vector, Asgari added.

This is particularly important as Ae. aegypti is a relatively new host to Wolbachia, with many questions remaining about its interaction with the mosquito and its long-term maintenance and inhibitory effects on viral replication, he wrote.

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