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Dissecting dsRNA uptake in RNAi-based antiviral immunity

Periodic Reporting for period 1 - DDRR (Dissecting dsRNA uptake in RNAi-based antiviral immunity)

Reporting period: 2015-06-01 to 2017-05-31

Insects have an immune system that allows them 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?
The insect antiviral immune response, named RNA interference, is based on the recognition of foreign nucleic acids, very different from what happens in vertebrates where the recognition is mainly based on foreign proteins. The foreign nucleic acid recognized by the insect immune system is viral dsRNA, which is produced for every virus as part of the viral replication cycle. Once recognized, this dsRNA is sliced in tiny dsRNA molecules, loaded in the RNAi machinery and used to further recognized virus molecules 100% identical to the tiny one. Once the tiny molecule finds the target, the later get cleaved, therefore precluding virus replication.
In the fruit fly, virus-infected cells release viral dsRNAs that are subsequently taken up by non-infected cells to launch an antiviral response that will protect them from further infection. This effect is known as systemic immune response. For systemic immunity to functions, dsRNA must enter and « signal » the virus infection to the non-infected cell. How does dsRNA enter drosophila cells?
During my MSCA fellowship I tried to answer these questions by using the fruit fly Drosophila melanogaster as a model insect and an array of drosophila viruses to explore my research.
I worked with hemocyte-like cell lines that are the main immune cells present in fruit flies. I developed a cellular system were I could induce the internalization of dsRNA without stressing the cell.
Using this system, I demonstrated that dsRNA is internalized into cells by a receptor-mediated mechanism. I developed a unique combination of wet and dry science (tubes and computers) that allowed me to produce a list of candidates for the function of « receptor » or “gate-keeper” for dsRNA entry into cells.
I present my results in the Gordon Research Conference- Viruses and Cells (2017). I also had the opportunity to present my research progress in diverse Departmental Retreats and in internal seminars organized by Institute Pasteur.
The identification of a dsRNA receptor has immediate relevant consequences :
- it will allow us to manipulate the insect immune system to prevent humans from getting infected by insect bites
- because the RNAi response is conserved along plants, invertebrates and vertebrates, the discovery of the receptor will accelerate the promise of RNAi as a therapeutic and as a biotechnological tool. The receptor could be redesigned and optimized and then expressed in different organisms where the tiny dsRNA molecules could be then delivered. For example, it could be possible to deliver dsRNA molecules into insect transmitting viruses to citrus trees. It could be also possible to enhance the uptake of dsRNA molecules by lung cells or kidney cells to treat some human diseases.
Still, the most significant impact of my research is of a fundamental nature: contributing to increase the understanding of antiviral immunity. I expect my scientific results to offer new perspectives on emerging viral disease transmitted by insects and to inspire a new way of thinking about immunity.
fruit flies at work