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

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.Most organisms—from bacteria to mammals—have at least a rudimentary immune system that can detect and defend against pathogens, particularly viruses. This defense mechanism, which is known as the innate immune system, uses sensor proteins to recognize viral RNA, and then mobilizes other immune components to attack the invaders.The specific mechanisms used to destroy viruses differ between species. In mammals, a protein called RIG-1 binds to viral RNA and activates a signaling pathway that leads to the production of interferons: immune proteins named after their ability to ‘interfere’ with viral replication. Plants and insects do not use interferons, but instead use a mechanism called RNA interference, in which long double-stranded RNAs are cleaved into shorter fragments.The nematode worm C. elegans also deploys RNA interference against viruses but, in contrast to insects and plants, worms do not possess a specific set of RNA interference enzymes that participate solely in the antiviral response. They do, however, express a protein called DRH-1 that is related to the RIG-I protein found in mammals.To investigate whether DRH-1 contributes to innate immunity in C. elegans, Ashe et al. infected 97 strains of C. elegans from around the world with a virus, and showed that some strains were more sensitive to the virus than others, with certain strains showing complete resistance. By comparing a sensitive strain with a resistant one, Ashe et al. revealed that viral sensitivity was caused by a mutation in the gene encoding DRH-1.Further experiments showed that DRH-1 is required for the first step in RNA interference. Ashe et al. have thus identified a conserved role for RIG-1 in initiating antiviral responses, and propose that the protein couples virus recognition to distinct defense mechanisms in different evolutionary groups.