Our studies clearly demonstrate the functional role of two RNA helicases, RIG-I and MDA5 as RNA virus sensors. RIG-I and MDA5 sense the invasion of distinct viral species and individually trigger antiviral responses, such as the production of type I IFNs and inflammatory cytokines.

We also found that two different types of double-stranded (ds) RNAs, poly I:C and in vitro transcribed dsRNAs, are differentially recognized by MDA5 and RIG-I. Previous in vitro studies showed that these two cytoplasmic RNA helicases function redundantly in antiviral responses; however, we clarified using gene-targeting techniques that MDA5 and RIG-I have ligand specificities, leading to differential viral recognition. These findings have a profound impact on many researchers, especially on immunologists and virologists.

At first, we described the phenotypes of MDA5-deficient mice. Our finding that RIG-I and MDA5 sense the invasion of distinct viral species was unexpected and is one of the key discoveries in the mechanism of virus sensing by hosts.

A podcast audio interview with Hiroki Kato discussing the functional role of two RNA helicases, RIG-I and MDA5 as RNA virus sensors. Podcast formats: mp3 | wma

So far there are several reported candidates as viral detectors, which sense viral invasion and trigger antiviral responses such as the induction of type 1 IFNs. However, which molecule is the major player remained to be determined. Here in our paper, we clearly show that two molecules called RIG-I and MDA5 are the real viral detectors. Mice lacking RIG-I or MDA5 are highly susceptible to several viral infections because they cannot produce type 1 IFNs. We also found that RIG-I and MDA5 recognize different types of viruses because these two molecules recognize a different motif of viral components.

In particular, the picornavirus family is recognized by MDA5, but not by RIG-I, and contains several viruses that are highly pathogenic for humans, including poliovirus, rhinovirus, and foot-and-mouth-disease virus. If we can develop the therapeutic agents to modify MDA5 and/or RIG-I, we will have a new antiviral strategy to use against these viruses.

Our main focus is to find out which molecules are involved in innate immunity. Toll-like receptors (TLRs) have been one of the targets for us and are shown to be involved in antiviral as well as antibacterial responses.

While we found that plasmacytoid DCs (dendritic-cells) utilize the TLR system to elicit antiviral responses, RIG-I, a cytoplasmic RNA helicase, was discovered and also suggested to be a viral detector. Thus, we assessed the functional role of RIG by gene targeting, and found that both RIG-I and TLRs are real viral detectors, but their involvement in antiviral responses is cell type-specific.

Since MDA5, which has a high homology with RIG-I, was also expected to be involved in antiviral responses, we investigated the functional role of MDA5 by gene targeting and clearly show in this paper that RIG-I and MDA5 sense the invasion of distinct viral species.

The picornavirus family, recognized by MDA5, contains several viruses that are pathogenic for humans, including poliovirus, rhinovirus, and foot-and-mouth-disease virus. From a medical point of view, our studies suggest that human MDA-5 also recognizes picornavirus; thus, identification of therapeutic agents that modify MDA5 may provide antiviral strategies against the picornavirus family.

Hiroki Kato
Department of Host Defense
Research Institute for Microbial Diseases
Osaka University

Shizuo Akira, M.D., Ph.D.
Professor
Department of Host Defense
Research Institute for Microbial Diseases
Osaka University
and Director, AKIRA Innate Immunity Project
ERATO (Exploratory Research for Advanced Technology)
Japanese Science Technology
Osaka, Japan

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