1. Department of Host Defense,
2. Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, and
3. ERATO, Japan Science and Technology Agency, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
4. Department of Genetics and Molecular Biology, Institute for Virus Research, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
5. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
6. Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
7. Department of Medical Technology, Shinshu University School of Allied Medical Sciences, 3-1-1 Asahi, Matsumoto 390-8621, Japan
8. Immunobiology Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
9. *These authors contributed equally to this work

Correspondence to: Shizuo Akira^1,3 Correspondence and requests for materials should be addressed to S.A. (Email: sakira@biken.osaka-u.ac.jp).

Abstract

The innate immune system senses viral infection by recognizing a variety of viral components (including double-stranded (ds)RNA) and triggers antiviral responses^{1, 2}. The cytoplasmic helicase proteins RIG-I (retinoic-acid-inducible protein I, also known as Ddx58) and MDA5 (melanoma-differentiation-associated gene 5, also known as Ifih1 or Helicard) have been implicated in viral dsRNA recognition^{3, 4, 5, 6, 7}. In vitro studies suggest that both RIG-I and MDA5 detect RNA viruses and polyinosine-polycytidylic acid (poly(I:C)), a synthetic dsRNA analogue³. Although a critical role for RIG-I in the recognition of several RNA viruses has been clarified⁸, the functional role of MDA5 and the relationship between these dsRNA detectors in vivo are yet to be determined. Here we use mice deficient in MDA5 (MDA5^-/-) to show that MDA5 and RIG-I recognize different types of dsRNAs: MDA5 recognizes poly(I:C), and RIG-I detects in vitro transcribed dsRNAs. RNA viruses are also differentially recognized by RIG-I and MDA5. We find that RIG-I is essential for the production of interferons in response to RNA viruses including paramyxoviruses, influenza virus and Japanese encephalitis virus, whereas MDA5 is critical for picornavirus detection. Furthermore, RIG-I^-/- and MDA5^-/- mice are highly susceptible to infection with these respective RNA viruses compared to control mice. Together, our data show that RIG-I and MDA5 distinguish different RNA viruses and are critical for host antiviral responses.

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