Published Papers - Ohno Shinji

Analysis of the interaction between the ORF42 and ORF55 proteins encoded by Kaposi's sarcoma-associated herpesvirus.

Kuriyama K, Watanabe T, Ohno S

Archives of virology ( Springer Science and Business Media LLC )  169 ( 5 ) 98   2024.04 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Lysosome-Associated Membrane Proteins Support the Furin-Mediated Processing of the Mumps Virus Fusion Protein.

Ueo A, Kubota M, Shirogane Y, Ohno S, Hashiguchi T, Yanagi Y

Journal of virology   94 ( 12 )   2020.06 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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A comparative epigenome analysis of gammaherpesviruses suggests cis-acting sequence features as critical mediators of rapid polycomb recruitment.

Günther T, Fröhlich J, Herrde C, Ohno S, Burkhardt L, Adler H, Grundhoff A

PLoS pathogens   15 ( 10 ) e1007838   2019.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Both type I and type III interferons are required to restrict measles virus growth in lung epithelial cells.

Taniguchi M, Yanagi Y, Ohno S

Archives of virology     2019.02 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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S100a4 is secreted by alternatively activated alveolar macrophages and promotes activation of lung fibroblasts in pulmonary fibrosis

Wei Zhang, Shinji Ohno, Beatrix Steer, Stephan Klee, Claudia A. Staab-Weijnitz, Darcy Wagner, Mareike Lehmann, Tobias Stoeger, Melanie Königshoff, Heiko Adler

Frontiers in Immunology ( Frontiers Media S.A. )  9   1216   2018.06 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease, characterized by damage of lung epithelial cells, excessive deposition of extracellular matrix in the lung interstitium, and enhanced activation and proliferation of fibroblasts. S100a4, also termed FSP-1 (fibroblast-specific protein-1), was previously considered as a marker of fibroblasts but recent findings in renal and liver fibrosis indicated that M2 macrophages are an important cellular source of S100a4. Thus, we hypothesized that also in pulmonary fibrosis, M2 macrophages produce and secrete S100a4, and that secreted S100a4 induces the proliferation and activation of fibroblasts. To prove this hypothesis, we comprehensively characterized two established mouse models of lung fibrosis: infection of IFN-γR-/- mice with MHV-68 and intratracheal application of bleomycin to C57BL/6 mice. We further provide in vitro data using primary macrophages and fibroblasts to investigate the mechanism by which S100A4 exerts its effects. Finally, we inhibit S100a4 in vivo in the bleomycin-induced lung fibrosis model by treatment with niclosamide. Our data suggest that S100a4 is produced and secreted by M2 polarized alveolar macrophages and enhances the proliferation and activation of lung fibroblasts. Inhibition of S100a4 might represent a potential therapeutic strategy for pulmonary fibrosis.

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Cell-to-cell measles virus spread between human neurons is dependent on hemagglutinin and hyperfusogenic fusion protein

Yuma Sato, Shumpei Watanabe, Yoshinari Fukuda, Takao Hashiguchi, Yusuke Yanagi, Shinji Ohno

Journal of Virology ( American Society for Microbiology )  92 ( 6 )   2018.03 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Measles virus (MV) usually causes acute infection but in rare cases persists in the brain, resulting in subacute sclerosing panencephalitis (SSPE). Since human neurons, an important target affected in the disease, do not express the known MV receptors (signaling lymphocyte activation molecule [SLAM] and nectin 4), how MV infects neurons and spreads between them is unknown. Recent studies have shown that many virus strains isolated from SSPE patients possess substitutions in the extracellular domain of the fusion (F) protein which confer enhanced fusion activity. Hyperfusogenic viruses with such mutations, unlike the wild-type MV, can induce cell-cell fusion even in SLAM- and nectin 4-negative cells and spread efficiently in human primary neurons and the brains of animal models. We show here that a hyperfusogenic mutant MV, IC323-F(T461I)-EGFP (IC323 with a fusionenhancing T461I substitution in the F protein and expressing enhanced green fluorescent protein), but not the wild-type MV, spreads in differentiated NT2 cells, a widely used human neuron model. Confocal time-lapse imaging revealed the cell-to-cell spread of IC323-F(T461I)-EGFP between NT2 neurons without syncytium formation. The production of virus particles was strongly suppressed in NT2 neurons, also supporting cell-to-cell viral transmission. The spread of IC323- F(T461I)-EGFP was inhibited by a fusion inhibitor peptide as well as by some but not all of the anti-hemagglutinin antibodies which neutralize SLAM- or nectin-4- dependent MV infection, suggesting the presence of a distinct neuronal receptor. Our results indicate that MV spreads in a cell-to-cell manner between human neurons without causing syncytium formation and that the spread is dependent on the hyperfusogenic F protein, the hemagglutinin, and the putative neuronal receptor for MV.

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Annexin A2 Mediates the Localization of Measles Virus Matrix Protein at the Plasma Membrane.

Koga R, Kubota M, Hashiguchi T, Yanagi Y, Ohno S

Journal of virology     2018.02 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Trisaccharide containing α2,3-linked sialic acid is a receptor for mumps virus.

Kubota M, Takeuchi K, Watanabe S, Ohno S, Matsuoka R, Kohda D, Nakakita SI, Hiramatsu H, Suzuki Y, Nakayama T, Terada T, Shimizu K, Shimizu N, Shiroishi M, Yanagi Y, Hashiguchi T

Proceedings of the National Academy of Sciences of the United States of America   113 ( 41 ) 11579 - 11584   2016.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Murine gammaherpesvirus 68 ORF35 is required for efficient lytic replication and latency

Shin-ichi Hikita, Yusuke Yanagi, Shinji Ohno

JOURNAL OF GENERAL VIROLOGY ( SOC GENERAL MICROBIOLOGY )  96 ( 12 ) 3624 - 3634   2015.12 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Murine gammaherpesvirus (MHV) 68, a natural pathogen of field mice, is related to human gammaherpesviruses, Epstein-Barr virus (EBV; human herpesvirus 4) and Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8). The ORF35 of MHV-68 and its homologues of EBV and KSHV are located in the gene cluster composed of ORF34-ORF38 in which each gene overlaps with adjacent genes. Although MHV-68 ORF35 was reported to be an essential gene, its function during infection is presently unknown. In this study, we show, by analysing ORF35-transfected cells, that three serine residues in the C terminus are responsible for the phosphorylation and that the ORF35 protein forms homo-oligomers via a predicted coiled-coil motif. The ORF35 protein expressed by transfection was preferentially located in the cytoplasm of cells uninfected or infected with MHV-68. The recombinant virus lacking ORF35 (35S virus) exhibited genome replication and expression of lytic proteins comparable to those of the WT virus, but reduced levels of virus production, suggesting that the ORF35 protein acts at the virion assembly and/or egress step. Lytic replication in the lung after intranasal infection and the frequency of ex vivo reactivation from latency after intraperitoneal infection were lower in 35S virus-infected mice than in mice infected with the WT or marker-reverted virus. Our results indicate that ORF35 is not essential for MHV-68 lytic replication, but plays an important role in efficient viral replication and reactivation from latency.

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Actin-Modulating Protein Cofilin Is Involved in the Formation of Measles Virus Ribonucleoprotein Complex at the Perinuclear Region

Ritsuko Koga, Yukihiko Sugita, Takeshi Noda, Yusuke Yanagi, Shinji Ohno

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY )  89 ( 20 ) 10524 - 10531   2015.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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In measles virus (MV)-infected cells, the ribonucleoprotein (RNP) complex, comprised of the viral genome and the nucleocapsid (N) protein, phosphoprotein (P protein), and large protein, assembles at the perinuclear region and synthesizes viral RNAs. The cellular proteins involved in the formation of the RNP complex are largely unknown. In this report, we show that cofilin, an actin-modulating host protein, interacts with the MV N protein and aids in the formation of the RNP complex. Knockdown of cofilin using the short hairpin RNA reduces the formation of the RNP complex after MV infection and that of the RNP complex-like structure after plasmid-mediated expression of MV N and P proteins. A lower level of formation of the RNP complex results in the reduction of viral RNA synthesis. Cofilin phosphorylation on the serine residue at position 3, an enzymatically inactive form, is increased after MV infection and the phosphorylated form of cofilin is preferentially included in the complex. These results indicate that cofilin plays an important role in MV replication by increasing formation of the RNP complex and viral RNA synthesis. IMPORTANCE Many RNA viruses induce within infected cells the structure called the ribonucleoprotein (RNP) complex in which viral RNA synthesis occurs. It is comprised of the viral genome and proteins that include the viral RNA polymerase. The cellular proteins involved in the formation of the RNP complex are largely unknown. In this report, we show that cofilin, an actin-modulating host protein, binds to the measles virus (MV) nucleocapsid protein and plays an important role in the formation of the MV RNP complex and MV RNA synthesis. The level of the phosphorylated form of cofilin, enzymatically inactive, is increased after MV infection, and the phosphorylated form is preferentially associated with the RNP complex. Our findings determined with cofilin will help us better understand the mechanism by which the RNP complex is formed in virus-infected cells and develop new antiviral drugs targeting the RNP complex.

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Regulation of Immunoproteasome Function in the Lung

Ilona E. Keller, Oliver Vosyka, Shinji Takenaka, Alexander Kloss, Burkhardt Dahlmann, Lianne I. Willems, Martijn Verdoes, Hermen S. Overkleeft, Elisabeth Marcos, Serge Adnot, Stefanie M. Hauck, Clemens Ruppert, Andreas Guenther, Susanne Herold, Shinji Ohno, Heiko Adler, Oliver Eickelberg, Silke Meiners

SCIENTIFIC REPORTS ( NATURE PUBLISHING GROUP )  5   10230   2015.05 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Impaired immune function contributes to the development of chronic obstructive pulmonary disease (COPD). Disease progression is further exacerbated by pathogen infections due to impaired immune responses. Elimination of infected cells is achieved by cytotoxic CD8(+) T cells that are activated by MHC I-mediated presentation of pathogen-derived antigenic peptides. The immunoproteasome, a specialized form of the proteasome, improves generation of antigenic peptides for MHC I presentation thereby facilitating anti-viral immune responses. However, immunoproteasome function in the lung has not been investigated in detail yet. In this study, we comprehensively characterized the function of immunoproteasomes in the human and murine lung. Parenchymal cells of the lung express low constitutive levels of immunoproteasomes, while they are highly and specifically expressed in alveolar macrophages. Immunoproteasome expression is not altered in whole lung tissue of COPD patients. Novel activity-based probes and native gel analysis revealed that immunoproteasome activities are specifically and rapidly induced by IFN gamma treatment in respiratory cells in vitro and by virus infection of the lung in mice. Our results suggest that the lung is potentially capable of mounting an immunoproteasome-mediated efficient adaptive immune response to intracellular infections.

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Measles Virus Mutants Possessing the Fusion Protein with Enhanced Fusion Activity Spread Effectively in Neuronal Cells, but Not in Other Cells, without Causing Strong Cytopathology

Shumpei Watanabe, Shinji Ohno, Yuta Shirogane, Satoshi O. Suzuki, Ritsuko Koga, Yusuke Yanagi

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY )  89 ( 5 ) 2710 - 2717   2015.03 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Subacute sclerosing panencephalitis (SSPE) is caused by persistent measles virus (MV) infection in the central nervous system (CNS). Since human neurons, its main target cells, do not express known MV receptors (signaling lymphocyte activation molecule [SLAM] and nectin 4), it remains to be understood how MV infects and spreads in them. We have recently reported that fusion- enhancing substitutions in the extracellular domain of the MV fusion (F) protein (T461I and S103I/ N462S/ N465S), which are found in multiple SSPE virus isolates, promote MV spread in human neuroblastoma cell lines and brains of suckling hamsters. In this study, we show that hyperfusogenic viruses with these substitutions also spread efficiently in human primary neuron cultures without inducing syncytia. These substitutions were found to destabilize the prefusion conformation of the F protein trimer, thereby enhancing fusion activity. However, these hyperfusogenic viruses exhibited stronger cytopathology and produced lower titers at later time points in SLAM- or nectin 4-expressing cells compared to the wild-type MV. Although these viruses spread efficiently in the brains of SLAM knock-in mice, they did not in the spleens. Taken together, the results suggest that enhanced fusion activity is beneficial for MV to spread in neuronal cells where no cytopathology occurs, but detrimental to other types of cells due to strong cytopathology. Acquisition of enhanced fusion activity through substitutions in the extracellular domain of the F protein may be crucial for MV's extensive spread in the CNS and development of SSPE. IMPORTANCE Subacute sclerosing panencephalitis (SSPE) is a fatal disease caused by persistent measles virus (MV) infection in the central nervous system (CNS). Its cause is not well understood, and no effective therapy is currently available. Recently, we have reported that enhanced fusion activity of MV through the mutations in its fusion protein is a major determinant of efficient virus spread in human neuronal cells and brains of suckling hamsters. In this study, we show that those mutations render the conformation of the fusion protein less stable, thereby making it hyperfusogenic. Our results also show that enhanced fusion activity is beneficial for MV to spread in the CNS but detrimental to other types of cells in peripheral tissues, which are strongly damaged by the virus. Our findings provide important insight into the mechanism for the development of SSPE after MV infection.

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Sensitive detection of measles virus infection in the blood and tissues of humanized mouse by one-step quantitative RT-PCR

Shota Ikeno, Moto-omi Suzuki, Mahmod Muhsen, Masayuki Ishige, Mie Kobayashi-Ishihara, Shinji Ohno, Makoto Takeda, Tetsuo Nakayama, Yuko Morikawa, Kazutaka Terahara, Seiji Okada, Haruko Takeyama, Yasuko Tsunetsugu-Yokota

FRONTIERS IN MICROBIOLOGY ( FRONTIERS RESEARCH FOUNDATION )  4   298   2013.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Live attenuated measles virus (MV) has long been recognized as a safe and effective vaccine, and it has served as the basis for development of various MV-based vaccines. However, because MV is a human-tropic virus, the evaluation of MV-based vaccines has been hampered by the lack of a small-animal model. The humanized mouse, a recently developed system in which an immunodeficient mouse is transplanted with human fetal tissues or hematopoietic stem cells, may represent a suitable model. Here, we developed a sensitive one-step quantitative reverse transcription (qRT)-PCR that simultaneously measures nucleocapsid (N) and human RNase P mRNA levels. The results can be used to monitor MV infection in a humanized mouse model. Using this method, we elucidated the replication kinetics of MV expressing enhanced green fluorescent protein both in vitro and in humanized mice in parallel with flow-cytometric analysis. Because our qRT-PCR system was sensitive enough to detect MV expression using RNA extracted from a small number of cells, it can be used to monitor MV infection in humanized mice by sequential blood sampling.

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Measles Virus Nonstructural C Protein Modulates Viral RNA Polymerase Activity by Interacting with Host Protein SHCBP1

Minako Ito, Masaharu Iwasaki, Makoto Takeda, Takanori Nakamura, Yusuke Yanagi, Shinji Ohno

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY )  87 ( 17 ) 9633 - 9642   2013.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Most viruses possess strategies to circumvent host immune responses. The measles virus (MV) nonstructural C protein suppresses the interferon response, thereby allowing efficient viral growth, but its detailed mechanism has been unknown. We identified Shc Src homology 2 domain-binding protein 1 (SHCBP1) as one of the host proteins interacting with the C protein. Knockdown of SHCBP1 using a short-hairpin RNA greatly reduced MV growth. SHCBP1 was found to be required for viral RNA synthesis in the minigenome assay and to bind to the MV phosphoprotein, a subunit of the viral RNA polymerase. A stretch of 12 amino acid residues in the C protein were sufficient for SHCBP1 binding, and the peptide containing these 12 residues could suppress MV RNA synthesis, like the full-length C protein. The central region of SHCBP1 was found to bind to the C protein, as well as the phosphoprotein, but the two viral proteins did not compete for SHCBP1 binding. Our results indicate that the C protein modulates MV RNA polymerase activity by binding to the host protein SHCBP1. SHCBP1 may be exploited as a target of antiviral compounds.

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The Receptor-Binding Site of the Measles Virus Hemagglutinin Protein Itself Constitutes a Conserved Neutralizing Epitope

Maino Tahara, Shinji Ohno, Kouji Sakai, Yuri Ito, Hideo Fukuhara, Katsuhiro Komase, Melinda A. Brindley, Paul A. Rota, Richard K. Plemper, Katsumi Maenaka, Makoto Takeda

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY )  87 ( 6 ) 3583 - 3586   2013.03 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Here, we provide direct evidence that the receptor-binding site of measles virus (MV) hemagglutinin protein itself forms an effective conserved neutralizing epitope (CNE). Several receptor-interacting residues constitute the CNE. Thus, viral escape from neutralization has to be associated with loss of receptor-binding activity. Since interactions with both the signaling lymphocyte activation molecule (SLAM) and nectin4 are critical for MV pathogenesis, its escape, which results from loss of receptor-binding activity, should not occur in nature.

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Murine gammaherpesvirus 68 glycoprotein 150 does not contribute to latency amplification in vivo

Romana Ruiss, Shinji Ohno, Beatrix Steer, Reinhard Zeidler, Heiko Adler

VIROLOGY JOURNAL ( BIOMED CENTRAL LTD )  9   107   2012.06 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Background: Murine gammaherpesvirus 68 (MHV-68) is used as a model to study the function of gammaherpesvirus glycoproteins. gp150 of MHV-68, encoded by open reading frame M7, is a positional homolog of gp350/220 of EBV and of gp35/37 of KSHV. Since it had been proposed that gp350/220 of EBV might be a suitable vaccine antigen to protect from EBV-associated diseases, gp150 has been applied as a model vaccine in the MHV-68 system. When analyzing the function of gp150, previous studies yielded conflicting results on the role of gp150 in latency amplification, and disparities between the mutant viruses which had been analyzed were blamed for the observed differences. Results: To further develop MHV-68 as model to study the function of gammaherpesvirus glycoproteins in vivo, it is important to know whether gp150 contributes to latency amplification or not. Thus, we re-evaluated this question by testing a number of gp150 mutants side by side. Our results suggest that gp150 is dispensable for latency amplification. Furthermore, we investigated the effect of vaccination with gp150 using gp150-containing exosomes. Vaccination with gp150 induced a strong humoral and cellular immune response, yet it did not affect a subsequent MHV-68 challenge infection. Conclusions: In this study, we found no evidence for a role of gp150 in latency amplification. The previously observed contradictory results on the role of gp150 in latency amplification were not related to differences between the mutant viruses which had been used.

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ORF23 of murine gammaherpesvirus 68 is non-essential for in vitro and in vivo infection.

S Ohno, B Steer, C Sattler, H Adler

The Journal of general virology   93 ( Pt 5 ) 1076 - 1080   2012.05 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Although ORF23 is conserved among gammaherpesviruses, its role during infection is unknown. Here, we studied the expression of ORF23 of murine gammaherpesvirus 68 (MHV-68) and its role during infection. ORF23 mRNA was detected in infected cells as a late transcript. The ORF23 protein product could be expressed and detected as an N-terminally FLAG-tagged protein by Western blot and indirect immunofluorescence. To investigate the role of ORF23 in the infection cycle of a gammaherpesvirus, we constructed an ORF23 deletion mutant of MHV-68. The analysis of the ORF23 deletion mutant suggested that ORF23 of MHV-68 is neither essential for replication in cell culture nor for lytic or latent infection in vivo. A phenotype of the ORF23 deletion mutant, reflected by a moderate reduction in lytic replication and latency amplification, was only detectable in the face of direct competition to the parental virus.

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The 3 ' Enhancer CNS2 Is a Critical Regulator of Interleukin-4-Mediated Humoral Immunity in Follicular Helper T Cells

Yohsuke Harada, Shinya Tanaka, Yasutaka Motomura, Yasuyo Harada, Shin-ichiro Ohno, Shinji Ohno, Yusuke Yanagi, Hiromasa Inoue, Masato Kubo

IMMUNITY ( CELL PRESS )  36 ( 2 ) 188 - 200   2012.02 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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A main role for interleukin-4 (IL-4) is in humoral immunity, and follicular helper CD4(+) T (Tfh) cells may be an intrinsic IL-4 source. Here we demonstrate that conserved noncoding sequence 2 (CNS2) is an essential enhancer element for IL-4 expression in Tfh cells but not in Th2 cells. Mice with a CNS2 deletion had a reduction in IgG1 and IgE production and in IL-4 expression in Tfh cells. Tracking of CNS2 activity via a GFP reporter mouse demonstrated that CNS2-active cells expressed several markers of Tfh cells: CXCR5, PD-1, and ICOS; the transcriptional master regulator Bcl6; and the cytokines IL-21 and IL-4. These CNS2-active cells were mainly localized in B cell follicles and germinal centers. The GFP(+) Tfh cells were derived from GFP(-) naive T cells after in vivo systemic immunization. These results indicate that CNS2 is an essential enhancer element required for IL-4 expression in Tfh cells controlling humoral immunity.

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Measles Virus-Induced Immunosuppression in SLAM Knock-In Mice

Ritsuko Koga, Shinji Ohno, Satoshi Ikegame, Yusuke Yanagi

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY )  84 ( 10 ) 5360 - 5367   2010.05 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Measles virus (MV) causes transient severe immunosuppression in patients, which may lead to secondary viral and bacterial infections, largely accounting for measles-related morbidity and mortality. MV is known to infect immune cells by using the human signaling lymphocyte activation molecule (SLAM; also called CD150) as a cellular receptor, but the mechanism by which MV causes immunosuppression is not well understood. We show that MV infection of SLAM knock-in mice, in which the V domain of mouse SLAM was replaced by the V domain of human SLAM, crossed with alpha/beta-interferon receptor knockout mice, reproduced many immunological alterations observed in human patients. These included lymphopenia, inhibition of T-cell proliferation and antibody production, increased production of the Th2 cytokine interleukin-4 (IL-4) and the immunosuppressive cytokine IL-10, and suppression of contact hypersensitivity. Gross redistribution of lymphocytes among lymphoid tissues was not apparent in infected mice, nor was an increase of regulatory T cells. The numbers of lymphocytes in lymph nodes remained almost unchanged after MV infection, despite enhanced apoptosis, suggesting that lymph nodes were replenished with lymphocytes from the peripheral blood, which may have contributed to the observed lymphopenia in the spleen. Blocking of IL-10 by use of an anti-IL-10 receptor antibody ameliorated suppression of contact hypersensitivity in infected mice. These results indicate that SLAM knock-in mice lacking the expression of the alpha/beta-interferon receptor serve as a useful small animal model with which to elucidate MV-induced immunosuppression.

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Both RIG-I and MDA5 RNA Helicases Contribute to the Induction of Alpha/Beta Interferon in Measles Virus-Infected Human Cells

Satoshi Ikegame, Makoto Takeda, Shinji Ohno, Yuichiro Nakatsu, Yoichi Nakanishi, Yusuke Yanagi

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY )  84 ( 1 ) 372 - 379   2010.01 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Measles virus (MV), a member of the family Paramyxoviridae, is a nonsegmented negative-strand RNA virus. The RNA helicases retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are differentially involved in the detection of cytoplasmic viral RNAs and induction of alpha/beta interferon (IFN-alpha/beta). RIG-I is generally believed to play a major role in the recognition of paramyxoviruses, whereas many viruses of this family produce V proteins that can inhibit MDA5. To determine the individual roles of MDA5 and RIG-I in IFN induction after MV infection, small interfering RNA-mediated knockdown of MDA5 or RIG-I was performed in the human epithelial cell line H358, which is susceptible to wild-type MV isolates. The production of IFN-beta mRNA in response to MV infection was greatly reduced in RIG-I knockdown clones compared to that in H358 cells, confirming the importance of RIG-I in the detection of MV. The IFN-beta mRNA levels were also moderately reduced in MDA5 knockdown clones, even though these clones retained fully functional RIG-I. A V protein-deficient recombinant MV (MV Delta V) induced higher amounts of IFN-beta mRNA at the early stage of infection in H358 cells compared to the parental virus. The reductions in the IFN-beta mRNA levels in RIG-I knockdown clones were less pronounced after infection with MV Delta V than after infection with the parental virus. Taken together, the present results indicate that RIG-I and MDA5 both contribute to the recognition of MV and that the V protein promotes MV growth at least partly by inhibiting the MDA5-mediated IFN responses.

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