Innate and adaptive immunity mechanisms provide antiviral protection in mammals. In this talk, I shall present recent findings from my lab and collaborators revealing a distinct form of mammalian antiviral response directed by the RNA interference (RNAi) pathway. In the first part of the presentation, I discuss the data published in a joint paper with Dr. Kate Jeffrey reporting the first evidence for a human virus to induce and suppress antiviral RNAi in cultured mammalian cells. In the second part, I present results of our functional and mechanistic studies on antiviral RNAi from a mouse model of infection by Nodamura virus (NoV), a positive-strand RNA virus transmissible by mosquitoes. We show that NoV RNA replication triggers Dicer-dependent production of predominantly 22-nt virus-derived siRNAs, loaded in RNA-induced silencing complex (RISC) to guide specific RNA cleavages by Argonaute-2. We demonstrate that NoV encodes a dsRNA-binding B2 protein as a viral suppressor of RNAi (VSR) essential for infection by inhibiting both Dicer processing and siRNA loading into RISC by sequestering long dsRNA and siRNA duplexes, respectively. Notably, VSR-B2 enhances virus accumulation exclusively by suppressing the RNAi response since it becomes inactive in RNAi-defective mouse fibroblasts. Moreover, we found that expression of a functional VSR-B2 is essential for NoV infection and virulence not only in suckling mice, but also in adult mice either intact or completely defective in the signaling of type I, II and III interferons (IFN). Together, our findings illustrate that the RNAi response confers in vivo antiviral protection in the presence or absence of IFN-regulated antiviral responses and that specific viral suppression of the RNAi response is essential for in vivo infection and virulence. After a brief summary of data published by others on this topic, I discuss the main properties of mammalian RNAi response to virus infection as compared to the known innate and adaptive immunity mechanisms.

 
Learning objectives:

1. Define the main components of the mammalian RNAi response to virus infection

2. Explain the RNA-based specificity mechanism of the RNAi antiviral response.