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Deciphering the mechanisms of antiviral RNA interference in mammals

Project description

RNA interference as an antiviral weapon in mammals

RNA interference (RNAi) is a widely conserved biological mechanism that represses gene expression. It is mediated by small RNA molecules that bind to and degrade target RNAs. RNAi was originally described as a defence mechanism against viruses in worms, plants and insects, but its role in mammals remains controversial. The aim of the EU-funded UncoveRNAi project is to identify where and how the antiviral RNAi mechanism takes place in mammals. Results will provide important insight into the in vivo significance of RNAi as an antiviral mechanism in comparison to type I interferons responsible for orchestrating antiviral responses in mammals.


Organisms such as plants, worms or insects rely on RNA interference (RNAi) to mount an antiviral immune response. On the other hand, it is widely believed that the type I interferon (IFN-I) pathway replaced antiviral RNAi as a primary line of defence against viral infections in chordates. However, recent work from multiple teams, including the host laboratory, has described a possible antiviral role for RNAi in cultured mammalian cells and in mice during infection with different RNA viruses. The importance of RNAi as an antiviral mechanism in mammals remains a matter of great controversy, in part due to a dearth of in vivo studies. In particular, the cell type(s) performing RNAi in vivo remains unknown, as is the relative importance of antiviral RNAi compare to the IFN-I response. I propose to decipher the mechanism and importance of antiviral RNAi in mice, by answering three main questions: 1) Where is antiviral RNAi happening? I will identify cell types implicated in antiviral RNAi using reporter viruses and permanent genetic marking of RNAi-competent cells. In parallel with these unbiased approaches, I will study antiviral immune responses in specific cell types likely to rely on antiviral RNAi, such as stem cells. 2) How is antiviral RNAi happening? I hypothesise that antiviral RNAi relies on truncated isoforms of Dicer expressed in specific cell types, and/or production of viral DNA as a means of boosting the RNAi response. I will explore both possibilities in detail. 3) What is the importance of antiviral RNAi? I will specifically ablate antiviral RNAi in cell niches that use this defence mechanism to assess its importance with respect to IFN-I. Overall, my work aims at dissecting antiviral RNAi pathways in mammals and assessing their in vivo significance. This work will provide answers to important questions in the field of antiviral immunity and will potentially open up new areas of research in human health.



Net EU contribution
€ 212 933,76
1 midland road
NW1 1AT London
United Kingdom

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London Inner London — West Camden and City of London
Activity type
Research Organisations
Other funding
€ 0,00