Unravelling how a bacterium prevents transmission of Dengue and Zika viruses by mosquitoes
Two of the most serious viral diseases transmitted by the Aedes aegypti mosquito – Dengue fever and Zika virus infection – cause untold death and disability globally. New research from Monash University, published last week in the journal Cell Reports, reveals a previously mysterious mechanism for rendering this mosquito harmless.
In a global program led by Monash, researchers have previously found that infecting the Aedes mosquito with the bacterium, Wolbachia, prevents these insects from transmitting Zika or Dengue viruses.
The Monash-led World Mosquito Program, through the release of these Wolbachia-infected mosquitos, has bred the disease-carrying cousins out of existence in areas from Townsville, Australia to Yogyakarta, Indonesia, and beyond.
However, how the Wolbachia bacterium makes deadly virus-infected mosquitoes harmless remains to be fully explained.
In 2017, Professor Christian Doerig and Dr Gholamreza Haqshenas, from the Monash Biomedicine Discovery Institute, established a platform to study global host response to hepatitis C virus appeared in prestigious journal Nature Communications. According to Professor Doerig and Dr Haqshenas, the assay has allowed the researchers to, for instance, identify host cell signalling pathways that are activated when hepatitis C virus infects the liver; since activation of these pathways are necessary for viral replication, this in turn led to the discovery of novel targets for antiviral intervention.
Professor Doerig and Dr Haqshenas, together with former Monash colleague Professor Beth McGraw (now at Pennsylvania State University), have used the assay to monitor signalling pathways in cells from the Aedes mosquitoes that are infected with the Wolbachia bacterium. It was of particular interest to observe that Wolbachia infection appears to turn off the pathway triggered by the Insulin receptor of the mosquito cell.
As Dr Haqshenas points out, “it had been shown by another group that replication of Dengue virus in human cells requires this same insulin receptor”.
Could it be that viruses cannot grow in Wolbachia-infected mosquito cells because their insulin receptor is turned off by the bacterium?
In a series of elegant experiments, outlined in the paper, the team led by Professor Doerig showed in both cell cultures and live mosquito experiments that the insulin receptor gene is indeed crucial for the infectivity of Dengue and Zika viruses in mosquitoes.
Importantly, the research involved Dr Prasad Paradkar, who works with the insectarium at the CSIRO Australian Animal Health Laboratory, where mosquitoes were fed blood containing a specific insulin receptor inhibitor. Mosquitoes without the Wolbachia infection (and thus able to transmit Dengue or Zika viruses), when fed the insulin receptor inhibitor, produced almost no transmissible virus, thus recapitulating the effect of Wolbachia infection.
“This definitely brings insulin signalling into the limelight as at least a contributor to the ‘Wolbachia effect'”, Professor Doerig said.
“This highlights the complex inter-relationships between host cells and the organisms that infect them,” he said.
Read the full paper in Cell Reports titled A role for the Insulin receptor in the suppression of dengue virus and Zika virus in Wolbachia-infected mosquito cells.
Professor Doerig has since left the Monash BDI, taking up a new position at RMIT as the Associate Dean of the Biomedical Sciences Cluster, within the School of Health and Biomedical Sciences at the start of February 2019.
About the Monash Biomedicine Discovery Institute
Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.