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Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses

Abstract

The innate immune system senses viral infection by recognizing a variety of viral components (including double-stranded (ds)RNA) and triggers antiviral responses1,2. 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 recognition3,4,5,6,7. 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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Acknowledgements

We thank all colleagues in our laboratory, K. Takeda, T. Shioda, E. Nakayama and K. Kiyotani for helpful discussions, A. Kato, T. Abe, Y. Mori, B. S. Kim and A. Palmenberg for viruses and plasmids, M. Hashimoto for secretarial assistance, and Y. Fujiwara, M. Shiokawa, N. Kitagaki and A. Shibano for technical assistance. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan, and from the 21st Century Center of Excellence Program of Japan.

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Correspondence to Shizuo Akira.

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Supplementary Notes

This file contains Supplementary Methods, Supplementary Figure Legends. (PDF 129 kb)

Supplementary Figures and Supplementary Table 1

This file contains Supplementary Figures 1–8 and Supplementary Table 1. (PDF 400 kb)

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Further reading

Figure 1: Roles of MDA5, RIG-I and TRIF in the recognition of synthesized dsRNAs and dsRNA analogues.
Figure 2: Differential viral recognition by RIG-I and MDA5.
Figure 3: Susceptibility of RIG-I -/- and MDA5 -/- mice to JEV infection.
Figure 4: Role of MDA5 in host defence against EMCV infection.

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