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Dynamics of the RNAi-mediated antiviral immunity

Periodic Report Summary 2 - RNAIMMUNITY (Dynamics of the RNAi-mediated antiviral immunity)

Like every other organism on Earth, insects are infected with viruses, and they rely on RNA interference (RNAi) mechanisms to circumvent viral infections. A remarkable characteristic of RNAi is that it is both broadly acting, because it is triggered by double-stranded RNA molecules derived from virtually any virus, and extremely specific, because it targets only the particular viral sequence that initiated the process.
Interestingly, this RNAi-immune response allows insects to remain asymptomatic when they are infected with a virus that is deadly when transmitted to humans. How is this possible and how does this immune system work? Can we manipulate this immune system and therefore prevent humans from getting infected by insect bites? With our ERC Consolidator Grant, we aim to answer these questions by using the fruit fly Drosophila melanogaster as a model insect to explore our research. We develop a unique combination of basic science and bioinformatics that allow us to tackle several projects in ill-studied areas of insect antiviral immunity, as well as to investigate key aspects of pre-existing and often incomplete paradigms on host-pathogen biology.
We showed that Drosophila and mosquitoes produced a viral DNA form from the RNA viruses that they are infected with. This viral DNA form amplifies the immune response and allows the establishment of persistent infections, making of insects very efficient vectors to transmit viral diseases to humans. We provided proof of concept on the feasibility of eliminating only infected mosquitoes by interfering with the synthesis of the viral DNA form. In an attempt to understand how the immune response spread throughout the organism, we discovered the existence of nanotubes in Drosophila. These nanotubes increase during infection, communicate infected with non-infected cells and transport the RNAi machinery. We also characterized the remnants of past infections (fossil viruses) present in mosquitoes that transmit Dengue and Zika viruses and we speculated on the capacity of these fossil viruses to confer protection against new modern infections. Finally, we demonstrated that fundamental differences have arisen between the antiviral defenses of flies and mosquitoes since they last shared a common ancestor >200 million years ago.
Our scientific strategy is offering new perspectives on emerging viral disease transmission and will inspire a new way of thinking about immunity.