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
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
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.