Group research

All living organisms have evolved mechanisms to defend themselves against viruses. In plants and invertebrates, RNA interference (RNAi) constitutes a major antiviral mechanism, in which long double-stranded RNA (dsRNA) generated during viral replication is cleaved by the enzyme Dicer into small interfering RNAs (siRNAs). These are then loaded onto Argonaute (Ago) proteins to form the RNA-induced silencing complex that recognizes and cleaves complementary viral RNAs to block viral replication. Importantly, the RNAi pathway is conserved in vertebrates and is involved in the generation and function of micro-RNAs (miRNAs), essential for the regulation of gene expression.

However, in vertebrates, long double-stranded RNA is sensed by cytosolic RIG-I like receptors to initiate a signalling cascade that culminates in secretion of interferons (IFN) and expression of hundreds of antiviral IFN-stimulated genes that inhibit virus replication.

Recent evidence has emerged for a functional role of antiviral RNAi in mammals opening-up a new area of research into characterising when, where and how this ancestral antiviral mechanism plays a role in mammals.

The Maillard Lab aims to characterise:

the cell types and contexts in which RNAi plays a role in the mammalian antiviral defence system
the cellular mechanisms that regulate the IFN response.

IFN response and antiviral RNAi triggered by viral dsRNA.

In the cytoplasm of mammalian cells, the RIG‐I‐like receptors (RLRs) RIG‐I and MDA5 detect viral dsRNA and trigger the production of type I interferons, which results in the induction of interferon‐stimulated genes (ISGs) that encode proteins capable of inhibiting viral replication and virus spread. In antiviral RNAi, Dicer cleaves viral dsRNA into viRNAs that are loaded into a RISC complex. As a protein component of this complex, Ago2 degrades viral RNAs with homology to the viRNAs, thereby inhibiting viral replication. RLRs and Dicer share a common DExD/H domain, composed of three helicases (Hel1, Hel2i and Hel2). RIG‐I and MDA5 additionally carry two CARD domains responsible for downstream signalling to MAVS. Dicer possesses two RNase III domains involved in dsRNA dicing.

Figure from Maillard et al., EMBOJ, 2019