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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Strain-to-strain difference of V protein of measles virus affects MDA5-mediated IFN-β-inducing potential
Hiromi Takaki1, Yumi Watanabe, Masashi Shingai
1Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638, Japan.
Abstract:
Laboratory-adapted and vaccine strains of measles virus (MV) induce type I interferon (IFN) in infected cells to a far greater extent than wild-type strains. We investigated the mechanisms for this differential type I IFN production in cells infected with representative MV strains. The overexpression of the wild-type V protein suppressed melanoma differentiation-associated gene 5 (MDA5)-induced IFN-β promoter activity, while this was not seen in A549 cells expressing CD150 transfected with the V protein of the vaccine strain. The V proteins of the wild-type also suppressed poly I:C-induced IFN regulatory factor 3 (IRF-3) dimerization. The V proteins of the wild-type and vaccine strain did not affect retinoic acid-inducible gene 1 (RIG-I)- or toll-IL-1R homology domain-containing adaptor molecule 1 (TICAM-1)-induced IFN-β promoter activation. We identified an amino acid substitution of the cysteine residue at position 272 (which is conserved among paramyxoviruses) to an arginine residue in the V protein of the vaccine strain. Only the V protein possessing the 272C residue binds to MDA5. The mutation introduced into the wild-type V protein (C272R) was unable to suppress MDA5-induced IRF-3 nuclear translocation and IFN-β promoter activation as seen in the V proteins of the vaccine strain, whereas the mutation introduced in the vaccine strain V protein (R272C) was able to inhibit MDA5-induced IRF-3 and IFN-β promoter activation. The other 6 residues of the vaccine strain V sequence inconsistent with the authentic sequence of the wild-type V protein barely affected the IRF-3 nuclear translocation. These data suggested that the structural difference of laboratory-adapted [corrected] MV V protein hampers MDA5 blockade and acts as a nidus for the spread/amplification of type I IFN induction. Ultimately, measles vaccine strains have two modes of IFN-β-induction for their attenuation: V protein mutation and production of defective interference (DI) RNA.
Insights
Measles virus (MV) vaccine strains induce more type I interferon (IFN) than wild-type strains due to V protein mutations that impair melanoma differentiation-associated gene 5 (MDA5) binding and blockade, aiding viral attenuation.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Laboratory-adapted and vaccine strains of measles virus (MV) exhibit significantly higher type I interferon (IFN) induction compared to wild-type strains.
- Understanding the molecular mechanisms behind this differential IFN production is crucial for vaccine development and understanding viral pathogenesis.
Purpose of the Study:
- To investigate the mechanisms responsible for the differential type I IFN production between measles virus (MV) vaccine strains and wild-type strains.
- To elucidate the role of the MV V protein in modulating the host's innate immune response, specifically type I IFN induction.
Main Methods:
- Comparative analysis of V protein function from wild-type and vaccine MV strains in cell culture models (A549 cells).
- Assessment of V protein's ability to suppress melanoma differentiation-associated gene 5 (MDA5)- and retinoic acid-inducible gene 1 (RIG-I)-mediated IFN-β promoter activation.
- Site-directed mutagenesis to identify key amino acid residues in the V protein responsible for differential MDA5 interaction and IFN suppression.
Main Results:
- Wild-type MV V protein suppressed MDA5-induced IFN-β promoter activity, while vaccine strain V protein did not, correlating with an amino acid substitution at position 272 (C272R).
- The C272 residue in the V protein is essential for binding to MDA5; mutations at this site (C272R in wild-type, R272C in vaccine) altered MDA5 interaction and IFN suppression.
- Structural differences in the laboratory-adapted MV V protein, particularly at position 272, hinder MDA5 blockade, promoting type I IFN induction for viral attenuation.
Conclusions:
- The V protein of measles virus vaccine strains possesses altered structural features, specifically at amino acid position 272, which impair its ability to block MDA5-mediated innate immune signaling.
- This impaired blockade of MDA5 by the vaccine strain V protein leads to enhanced type I IFN induction, contributing to viral attenuation.
- Measles vaccine attenuation is achieved through a combination of V protein mutations and the production of defective interference (DI) RNA, both influencing IFN-β induction.
