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Differential Type I IFN-Inducing Abilities of Wild-Type versus Vaccine Strains of Measles Virus¹

Masashi Shingai^2,*, Takashi Ebihara^*, Nasim A. Begum^3,, Atsushi Kato, Toshiki Honma, Kenji Matsumoto, Hirohisa Saito, Hisashi Ogura, Misako Matsumoto^*, and Tsukasa Seya^4,*,

^* Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan; Department of Immunology, Osaka Medical Center for Cancer, Osaka, Japan; Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; and Department of Virology, Osaka City University, Osaka, Japan

Laboratory adapted and vaccine strains of measles virus (MV) induced type I IFN in infected cells. The wild-type strains in contrast induced it to a far lesser extent. We have investigated the mechanism for this differential type I IFN induction in monocyte-derived dendritic cells infected with representative MV strains. Laboratory adapted strains Nagahata and Edmonston infected monocyte-derived dendritic cells and activated IRF-3 followed by IFN- production, while wild-type MS failed to activate IRF-3. The viral IRF-3 activation is induced within 2 h, an early response occurring before protein synthesis. Receptor usage of CD46 or CD150 and nucleocapsid (N) protein variations barely affected the strain-to-strain difference in IFN-inducing abilities. Strikingly, most of the IFN-inducing strains possessed defective interference (DI) RNAs of varying sizes. In addition, an artificially produced DI RNA consisting of stem (the leader and trailer of MV) and loop (the GFP sequence) exhibited potential IFN-inducing ability. In this case, however, cytoplasmic introduction was needed for DI RNA to induce type I IFN in target cells. By gene-silencing analysis, DI RNA activated the RIG-I/MDA5-mitochondria antiviral signaling pathway, but not the TLR3-TICAM-1 pathway. DI RNA-containing strains induced IFN- mRNA within 2 h while the same recombinant strains with no DI RNA required >12 h postinfection to attain similar levels of IFN- mRNA. Thus, the stem-loop structure, rather than full genome replication or specific internal sequences of the MV genome, is required for an early phase of type I IFN induction by MV in host cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by CREST and Innovation, Japan Science and Technology Corporation, and by Grants-in-Aid from the Ministry of Education, Science, and Culture (Specified Project for Advanced Research), and the Hepatitis C Virus Project in National Institutes of Health of Japan, and by the Takeda Foundation, the Uehara Memorial Foundation, the Mitsubishi Foundation, the Akiyama Foundation, and the NorthTec Foundation.

² Current address: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.

³ Current address: Department of Molecular Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

⁴ Address correspondence and reprint requests to Dr. Tsukasa Seya, Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638 Japan. E-mail address: seya-tu{at}pop.med.hokudai.ac.jp

⁵ Abbreviations used in this paper: RIG-I, retinoic acid-inducible gene; MDA5, melanoma differentiation-associated gene 5; IRF, IFN regulatory factor; MV, measles virus; p.i., postinfection; mDC, myeloid DC; DI, defective interference; CHO, Chinese hamster ovary; pAb, polyclonal Ab; MOI, multiplicity of infection; siRNA, small interference RNA; TBK1, TANK-binding kinase 1; IKK, IB kinase-related kinase ; MAVS, mitochondria antiviral signaling; ISRE, IFN-stimulated response element; Q-PCR, quantitative PCR; NAP1, NAK-associated protein 1; CIAP, calf intestine alkaline phosphatase; SeV, Sendai virus; VISA, virus-induced signaling adaptor.

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