DDRR · Dissecting dsRNA uptake in RNAi-based antiviral immunity
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-06-01 → 2017-05-31
- EU contribution
- €185,076
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Dissecting dsRNA uptake in RNAi-based antiviral immunity
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.
Data: CORDIS, © European Union
Project objective
Important viral infectious diseases, such as dengue and chikungunya, are transmitted to humans by insectvectors. One of the key factors that modulates whether an insect is competent or not to transmit a givenpathogen is its innate immune response. The major antiviral defense in insects is the RNA interference(RNAi) mechanism that is activated by the detection of viral double-stranded RNA (dsRNA). Duringantiviral RNAi a silencing immune signal is transported from one cell to another to set an antiviral state(systemic RNAi). To be primed, non-infected cells must sense this silencing signal and internalize it.Although dsRNA as a mediator of local antiviral immunity is well established in insects, the effectors of asystemic immune response are not identified. For instance, the identification of the dsRNA receptor ininsects remains elusive. This proposal intends to dissect the mechanism of dsRNA uptake in insects withspecial focus on discovering its receptor. I propose to combine functional (genome wide RNAi screen, invivo dsRNA oral uptake) with binding (electrophoretic mobility shift assay, surface plasmon resonance) andstructural assays (expression, production and studies of complexes receptor/dsRNA) using Drosophilamelanogaster as insect model and an array of viruses in order to identify and characterize the dsRNAreceptor.To be found, the manipulation of this receptor could help control the insect vectors of emergingviral diseases. Understanding how the infection is controlled within the insect before crossover to the humanhost could generate new strategies to disrupt pathogen transmission.
Original text from CORDIS.
Participants
- INSTITUT PASTEUR · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union