A deletion polymorphism in the Caenorhabditis elegans RIG-I homolog disables viral RNA dicing and antiviral immunity

Alyson Ashe,Lise Frézal,Peter Sarkies,Eric A Miska,Tony Bélicard,Nicolas J Lehrbach,Jérémie Le Pen,Marie-Anne Félix

doi:10.7554/elife.00994

Abstract

RNA interference defends against viral infection in plant and animal cells. The nematode Caenorhabditis elegans and its natural pathogen, the positive-strand RNA virus Orsay, have recently emerged as a new animal model of host-virus interaction. Using a genome-wide association study in C. elegans wild populations and quantitative trait locus mapping, we identify a 159 base-pair deletion in the conserved drh-1 gene (encoding a RIG-I-like helicase) as a major determinant of viral sensitivity. We show that DRH-1 is required for the initiation of an antiviral RNAi pathway and the generation of virus-derived siRNAs (viRNAs). In mammals, RIG-I-domain containing proteins trigger an interferon-based innate immunity pathway in response to RNA virus infection. Our work in C. elegans demonstrates that the RIG-I domain has an ancient role in viral recognition. We propose that RIG-I acts as modular viral recognition factor that couples viral recognition to different effector pathways including RNAi and interferon responses. DOI:http://dx.doi.org/10.7554/eLife.00994.001.

Highlights

The arms races between pathogens and their hosts have led to the evolution of sophisticated mechanisms to provide immunity against infection
We suggest that the physical interaction between DRH-1 and DCR-1, and the potential for DRH-1 to recognize the viral genome as foreign, possibly through its well-conserved RIG-I domain, may enable DRH-1 to recruit DCR-1 to the double-stranded replicating viral genome and instigate a hierarchical antiviral siRNA response (Figure 5)
Our data show that the role of DRH-1 in viral recognition is distinct from that of its paralogs

Summary

Introduction

The arms races between pathogens and their hosts have led to the evolution of sophisticated mechanisms to provide immunity against infection. Whilst adaptive immunity is specific to vertebrates, innate mechanisms are present in all multicellular organisms, allowing cells to recognize specific pathogens and instigate appropriate responses. RNA viruses are important pathogens of many multicellular organisms, which replicate without a DNA intermediate using RNA dependent RNA polymerase. The primary innate immune sensors for RNA viruses in mammals are RIG-I and its homolog MDA-5 (Schlee, 2013). Viral recognition by RIG-I and MDA-5 triggers activation of downstream signaling, mediated by the proteins’ N-terminal CARD domains, and results in the activation of the interferon pathway (Yoneyama et al, 2004). Initial recognition of viral RNA is likely to be mediated by the DExD/H-box helicase domain and the C-terminal RIG-I domain. As all known RNA polymerases leave a triphosphate at the 5′ end of newly synthesized RNA, the presence of a 5′ triphosphate is likely to be a signature of RNA virus replication

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