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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Measles virus receptors

Yanagi Y, Takeda M, Ohno S, Hashiguchi T

Current Topics in Microbiology and Immunology   329   13 - 30   2009 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)

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Measles Viruses Possessing the Polymerase Protein Genes of the Edmonston Vaccine Strain Exhibit Attenuated Gene Expression and Growth in Cultured Cells and SLAM Knock-In Mice

Makoto Takeda, Shinji Ohno, Maino Tahara, Hiroki Takeuchi, Yuta Shirogane, Hirofumi Ohmura, Takafumi Nakamura, Yusuke Yanagi

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY )  82 ( 23 ) 11979 - 11984   2008.12 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Live attenuated vaccines against measles have been developed through adaptation of clinical isolates of measles virus (MV) in various cultured cells. Analyses using recombinant MVs with chimeric genomes between wild- type and Edmonston vaccine strains indicated that viruses possessing the polymerase protein genes of the Edmonston strain exhibited attenuated viral gene expression and growth in cultured cells as well as in mice expressing an MV receptor, signaling lymphocyte activation molecule, regardless of whether the virus genome had the wild-type or vaccine-type promoter sequence. These data demonstrate that the polymerase protein genes of the Edmonston strain contribute to its attenuated phenotype.

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Measles virus circumvents the host interferon response by different actions of the C and V proteins

Yuichiro Nakatsu, Makoto Takeda, Shinji Ohno, Yuta Shirogane, Masaharu Iwasaki, Yusuke Yanagi

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY )  82 ( 17 ) 8296 - 8306   2008.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Measles is an acute febrile infectious disease with high morbidity and mortality. The genome of measles virus (MV), the causative agent, encodes two accessory products, V and C proteins, that play important roles in MV virulence. The V but not the C protein of the IC-B strain (a well-characterized virulent strain of MV) has been shown to block the Jak/Stat signaling pathway and counteract the cellular interferon (IFN) response. We have recently shown that a recombinant IC-B strain that lacks C protein expression replicates poorly in certain cell lines, and its growth defect is related to translational inhibition and strong IFN induction. Here, we show that the V protein of the MV IC-B strain also blocks the IFN induction pathway mediated by the melanoma differentiation-associated gene 5 product, thus actively interfering with the host IFN response at two different steps. On the other hand, the C protein per se possesses no activity to block the IFN induction pathway. Our data indicate that the C protein acts as a regulator of viral RNA synthesis, thereby acting indirectly to suppress IFN induction. Since recombinant MVs with C protein defective in modulating viral RNA synthesis or lacking C protein expression strongly stimulate IFN production, in spite of V protein production, both the C and V proteins must be required for MV to fully circumvent the host IFN response.

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Measles virus infects both polarized epithelial and immune cells by using distinctive receptor-binding sites on its hemagglutinin

Maino Tahara, Makoto Takeda, Yuta Shirogane, Takao Hashiguchi, Shinji Ohno, Yusuke Yanagi

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY )  82 ( 9 ) 4630 - 4637   2008.05 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Measles is one of the most contagious human infectious diseases and remains a major cause of childhood morbidity and mortality worldwide. The signaling lymphocyte activation molecule (SLAM), also called CD150, is a cellular receptor for measles virus (MV), presumably accounting for its tropism for immune cells and its immunosuppressive properties. On the other hand, pathological studies have shown that MV also infects epithelial cells at a later stage of infection, although its mechanism has so far been unknown. In this study, we show that wild-type MV can infect and produce syncytia in human polarized epithelial cell lines independently of SLAM and CD46 (a receptor for the vaccine strains of MV). Progeny viral particles are released exclusively from the apical surface of these polarized epithelial cell lines. We have also identified amino acid residues on the W attachment protein that are likely to interact with a putative receptor on epithelial cells. All of these residues have aromatic side chains and may form a receptor-binding pocket located in a different position from the putative SLAM- and CD46-binding sites on the MV attachment protein. Thus, our results indicate that MV has an intrinsic ability to infect both polarized epithelial and immune cells by using distinctive receptor-binding sites on the attachment protein corresponding to each of their respective receptors. The ability of W to infect polarized epithelial cells and its exclusive release from the apical surface may facilitate its efficient transmission via aerosol droplets, resulting in its highly contagious nature.

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A human lung carcinoma cell line supports efficient measles virus growth and syncytium formation via a SLAM- and CD46-Independent mechanism

Makoto Takeda, Maino Tahara, Takao Hashiguchi, Takeshi A. Sato, Fumiaki Jinnouchi, Shoko Ueki, Shinji Ohno, Yusuke Yanagi

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY )  81 ( 21 ) 12091 - 12096   2007.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Measles virus (MV) propagates mainly in lymphoid organs throughout the body and produces syncytia by using signaling lymphocyte activation molecule (SLAM) as a receptor. W also spreads in SLAM-negative epithelial tissues by unknown mechanisms. Ubiquitously expressed CD46 functions as another receptor for vaccine strains of W but not for wild-type strains. We here show that W grows and produces syncytia efficiently in a human lung adenocarcinoma cell line via a SLAM- and CD46-independent mechanism using a novel receptor-binding site on the hemagglutinin protein. This infection model could advance our understanding of MV infection of SLAM-negative epithelial cells and tissues.

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[Measles virus entry and cellular receptors].

Yanagi Y, Takeda M, Ohno S

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme   52 ( 10 Suppl ) 1088 - 1094   2007.08 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)

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Measles virus infection of SLAM (CD150) knockin mice reproduces tropism and immunosuppression in human infection

Shinji Ohno, Nobuyuki Ono, Fumio Seki, Makoto Takeda, Shinobu Kura, Teruhisa Tsuzuki, Yusuke Yanagi

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY )  81 ( 4 ) 1650 - 1659   2007.02 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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The human signaling lymphocyte activation molecule (SLAM, also called CD150), a regulator of antigen-driven T-cell responses and macrophage functions, acts as a cellular receptor for measles virus (MV), and its V domain is necessary and sufficient for receptor function. We report here the generation of SLAM knockin mice in which the V domain of mouse SLAM was replaced by that of human SLAM. The chimeric SLAM had an expected distribution and normal function in the knockin mice. Splenocytes from the SLAM knockin mice permitted the in vitro growth of a virulent MV strain but not that of the Edmonston vaccine strain. Unlike in vitro infection, NW could grow only in SLAM knockin mice that also lacked the type I interferon receptor (IFNAR). After intraperitoneal or intranasal inoculation, MV was detected in the spleen and lymph nodes throughout the body but not in the thymus. Notably, the virus appeared first in the mediastinal lymph node after intranasal inoculation. Splenocytes from MV-infected IFNAR(-/-) SLAM knockin mice showed suppression of proliferative responses to concanavalin A. Thus, MV infection of SLAM knockin mice reproduces lymphotropism and immunosuppression in human infection, serving as a useful small animal model for measles.

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Translational inhibition and increased interferon induction in cells infected with C protein-deficient measles virus

Yuichiro Nakatsu, Makoto Takeda, Shinji Ohno, Ritsuko Koga, Yusuke Yanagi

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY )  80 ( 23 ) 11861 - 11867   2006.12 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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In addition to the phosphoprotein, the P gene of measles virus (MV) also encodes the V and C proteins by an RNA editing process and by alternative initiation of translation in a different reading frame, respectively. Although the W C protein is required for efficient W replication in vivo and in some cultured cells, its exact functions in virus infection are currently unclear. Here, we report that a recombinant W lacking the C protein (MV Delta C) grew poorly in a human cell line possessing the intact interferon (IFN) pathway and that this growth defect was associated with reduced viral translation and genome replication. The translational inhibition was correlated with phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Moreover, increased IFN induction was observed in MV Delta C-infected cells. The NS1 protein of influenza virus, which binds to double-stranded RNA (dsRNA) and consequently inhibits IFN induction and dsRNA-dependent protein kinase activation, complemented the growth defect of MV Delta C. These results indicate that the MV C protein inhibits IFN induction and modulates host antiviral responses, thereby ensuring W growth in host cells.

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Measles virus: cellular receptors, tropism and pathogenesis

Yusuke Yanagi, Makoto Takeda, Shinji Ohno

JOURNAL OF GENERAL VIROLOGY ( SOC GENERAL MICROBIOLOGY )  87 ( Pt 10 ) 2767 - 2779   2006.10 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)

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Measles virus (MV), a member of the genus Morbillivirus in the family Paramyxoviridae, is an enveloped virus with a non-segmented, negative-strand RNA genome. It has two envelope glycoproteins, the haemagglutinin (H) and fusion proteins, which are responsible for attachment and membrane fusion, respectively. Human signalling lymphocyte activation molecule (SLAM; also called CD 150), a membrane glycoprotein of the immunoglobulin superfamily, acts as a cellular receptor for MV. SLAM is expressed on immature thymocytes, activated lymphocytes, macrophages and dendritic cells and regulates production of interleukin (IL)-4 and IL-13 by CD4(+) T cells, as well as production of IL-1 2, tumour necrosis factor alpha and nitric oxide by macrophages. The distribution of SLAM is in accord with the lymphotropism and immunosuppressive nature of MV. Canine distemper virus and Rinderpest virus, other members of the genus Morbillivirus, also use canine and bovine SLAM as receptors, respectively. Laboratory-adapted MV strains may use the ubiquitously expressed CD46, a complement-regulatory molecule, as an alternative receptor through amino acid substitutions in the H protein. Furthermore, MV can infect SLAM(-) cells, albeit inefficiently, via the SLAM- and CD46-independent pathway, which may account for MV infection of epithelial, endothelial and neuronal cells in vivo. MV infection, however, is not determined entirely by the H protein-receptor interaction, and other MV proteins can also contribute to its efficient growth by facilitating virus replication at post-entry steps. Identification of SLAM as the principal receptor for MV has provided us with an important clue for better understanding of MV tropism and pathogenesis.

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[Cellular tropism and adaptation of the measles virus].

Ohno S, Yanagi Y

Uirusu ( The Japanese Society for Virology )  56 ( 1 ) 27 - 34   2006.06 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)

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Measles virus (MV) is a member of the genus Morbillivirus in the family Paramyxoviridae. Clinical isolates of MV use signaling lymphocyte activating molecule (SLAM) as a cellular receptor. SLAM is mainly expressed on immune cells such as immature thymocytes, activated lymphocytes and mature dendritic cells. This distribution of SLAM can account for the lymphotropism of MV. On the other hand, laboratory strains of MV use CD46 as an alternative receptor, through amino acid change(s) in the receptor binding hemagglutinin protein. Recently, several reports imply the existence of the cellular receptor(s) other than SLAM and CD46. In this review, we discuss the receptor usage of MV and its adaptation to cultured cells.

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Generation of measles virus with a segmented RNA genome

M Takeda, Y Nakatsu, S Ohno, F Seki, M Tahara, T Hashiguchi, Y Yanagi

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY )  80 ( 9 ) 4242 - 4248   2006.05 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Viruses classified in the order Mononegavirales have a single nonsegmented RNA molecule as the genome and employ similar strategies for genome replication and gene expression. Infectious particles of Measles virus (MeV), a member of the family Paramyxoviridae in the order Mononegavirales, with two or three RNA genome segments (2 seg- or 3 seg-MeV) were generated using a highly efficient reverse genetics system. All RNA segments of the viruses were designed to have authentic 3' and 5' self-complementary termini, similar to those of negative-stranded RNA viruses that intrinsically have multiple RNA genome segments. The 2 seg- and 3 seg-MeV were viable and replicated well in cultured cells. 3 seg-MeV could accommodate up to six additional transcriptional units, five of which were shown to be capable of expressing foreign proteins efficiently. These data indicate that the MeV genome can be segmented, providing an experimental insight into the divergence of the negative-stranded RNA viruses with nonsegmented or segmented RNA genomes. They also illustrate a new strategy to develop mononegavirus-derived vectors harboring multiple additional transcriptional units.

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Measles virus receptors and tropism

Y Yanagi, M Takeda, S Ohno, F Seki

JAPANESE JOURNAL OF INFECTIOUS DISEASES ( NATL INST INFECTIOUS DISEASES )  59 ( 1 ) 1 - 5   2006.02 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)

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Measles virus (MV) is a member of the Morbillivirus genus in the Paramyxoviridae family. Human signaling lymphocyte activation molecule (SLAM) acts as a cellular receptor for MV. SLAM is expressed on immature thymocytes, activated lymphocytes, macrophages and mature dendritic cells. This distribution of SLAM is in accord with lymphotropism and immubosuppressive nature of MV. Canine distemper and rinderpest viruses, other members of the Morbillivirus genus, also use SLAM as receptors. Laboratory-adapted MV strains often use ubiquitously expressed CD46 as an alternative receptor through the amino acid change(s) in the receptor-binding hemagglutinin. Furthermore, MV can infect various cultured cells, albeit with very low efficiency, via SLAM- and CD46-independent pathway, which may also account for MV infection of SLAM- cells in vivo.

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Long untranslated regions of the measles virus M and F genes control virus replication and cytopathogenicity

M Takeda, S Ohno, F Seki, Y Nakatsu, M Tahara, Y Yanagi

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY )  79 ( 22 ) 14346 - 14354   2005.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Measles is still a major cause of mortality mainly in developing countries. The causative agent, measles virus (MeV), is an enveloped virus having a nonsegmented negative-sense RNA genome, and belongs to the genus Morbillivirus of the family Paramyxoviridae. One feature of the moribillivirus genomes is that the M and F genes have long untranslated regions (UTRs). The M and F mRNAs of MeV have 426-nucleotide-long 3' and 583-nucleotide-long 5' UTRs, respectively. Though these long UTRs occupy as much as similar to 6.4% of the virus genome, their function remains unknown. To elucidate the role of the long UTRs in the context of virus infection, we used the reverse genetics based on the virulent strain of MeV, and generated a series of recombinant viruses having alterations or deletions in the long UTRs. Our results showed that these long UTRs per se were not essential for MeV replication, but that they regulated MeV replication and cytopathogenicity by modulating the productions of the M and F proteins. The long 3' UTR of the M mRNA was shown to have the ability to increase the M protein production, promoting virus replication. On the other hand, the long 5' UTR of the F mRNA was found to possess the capacity to decrease the F protein production, inhibiting virus replication and yet greatly reducing cytopathogenicity. We speculate that the reduction in cytopathogenicity may be advantageous for MeV fitness and survival in nature.

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Efficient rescue of measles virus from cloned cDNA using SLAM-expressing Chinese hamster ovary cells

M Takeda, S Ohno, F Seki, K Hashimoto, N Miyajima, K Takeuchi, Y Yanagi

VIRUS RESEARCH ( ELSEVIER SCIENCE BV )  108 ( 1-2 ) 161 - 165   2005.03 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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We here report a highly efficient reverse genetics system for measles virus (MeV), using Chinese hamster ovary cells constitutively expressing a MeV receptor human signaling lymphocyte activation molecule (CHO/hSLAM cells). The recombinant vaccinia virus vTF7-3 that encodes the T7 RNA polymerase under the control of the early/late promoter was used in the system. Replication of vTF7-3 was highly restricted in CHO/hSLAM cells, but the virus could still drive the T7 promoter, allowing us to recover MeV from the transfected cDNA efficiently. With this system the number of infectious centers, in which MeV replication cycles are initiated from transfected cDNAs, was approximately 100 times higher than that with the previous system (Takeda et al., 2000. J. Virol. 74, 6643-6647), and the recovery rate was 100%. The wild-type MeV that encodes the lac-Z gene of approximately 3.2 kb in length, was easily generated with this CHO/hSLAM system, while such virus could not be recovered with the previous system. Since SLAM acts as a cellular receptor for both MeV vaccine and wild-type strains, the Edmonston vaccine strain was also recovered with this system more efficiently than with any other systems reported previously. Thus, the CHO/hSLAM-based system would expand applications of the MeV reverse genetics by allowing productions of mutant MeVs that have been difficult to generate with less efficient systems. (C) 2004 Elsevier B.V. All rights reserved.

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Genetic evidence linking SAP, the X-linked lymphoproliferative gene product, to Src-related kinase FynT in T(H)2 cytokine regulation.

Davidson D, Shi X, Zhang S, Wang H, Nemer M, Ono N, Ohno S, Yanagi Y, Veillette A

Immunity   21 ( 5 ) 707 - 17   2004.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Dissection of measles virus V protein in relation to its ability to block alpha/beta interferon signal transduction

S Ohno, N Ono, M Takeda, K Takeuchi, Y Yanagi

JOURNAL OF GENERAL VIROLOGY ( SOC GENERAL MICROBIOLOGY )  85 ( Pt 10 ) 2991 - 2999   2004.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Interferon (IFN)-alpha and -beta are the main cytokines for innate immune responses against viral infections. To replicate efficiently in the hosts, viruses have evolved various countermeasures to the IFN response. The V protein of measles virus (MV) has been shown to block IFN-alpha/beta signalling. Here, the wild-type IC-B strain of MV was shown to grow comparably in the presence and absence of IFN-alpha, whereas replication of the Edmonston tag strain recovered from cloned DNA was strongly suppressed in its presence. The V protein of the IC-B strain, but not the Edmonston tag strain, blocked IFN-alpha signalling. The V protein of the Edmonston strain from the ATCC also inhibited IFN-alpha signalling. There were three amino acid differences between the V proteins of the Edmonston ATCC and tag strains, and substitutions of both residues at positions 110 and 272 were required for the Edmonston ATCC V protein to lose IFN-antagonist activity. The P protein of the IC-B strain, which shares the N-terminal 231 aa residues with the V protein, also inhibited IFN-alpha signalling. Indeed, fragments comprising only those 231 residues of the IC-B and Edmonston ATCC V proteins, but not the Edmonston tag V protein, were able to block IFN-alpha signalling. However, the N-terminal region of the Edmonston tag V protein, when attached to the C-terminal region of the Edmonston ATCC V protein, inhibited IFN-alpha signalling. Taken together, our results indicate that both the N- and C-terminal regions contribute to the IFN-antagonist activity of the MV V protein.

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Histidine at position 61 and its adjacent amino acid residues are critical for the ability of SLAM (CD150) to act as a cellular receptor for measles virus

S Ohno, F Seki, N Ono, Y Yanagi

JOURNAL OF GENERAL VIROLOGY ( SOC GENERAL MICROBIOLOGY )  84 ( Pt 9 ) 2381 - 2388   2003.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Signalling lymphocyte activation molecule (SLAM, also known as CD150), a membrane glycoprotein involved in lymphocyte activation, has two extracellular immunoglobulin superfamily domains, V and C2. It has been shown previously that human SLAM is a cellular receptor for measles virus (MV) and that its V domain is necessary and sufficient for receptor function. Although mouse SLAM has functional and structural similarity to human SLAM, it hardly acts as a receptor for MV. By producing human/mouse chimeric molecules and assessing their receptor function with a vesicular stomatitis virus pseudotype assay, the region at amino acid positions 58-67 was found to be critically responsible for the difference in MV receptor function between human and mouse SLAMs. Exchange of this region allowed mouse SLAM to act as a receptor for MV, almost comparable to human SLAM. Among three amino acid differences (positions 60,61 and 63) in this region, histidine 61 present in human SLAM was most significant, but combined substitutions with this residue and one or both of isoleucine 60 and valine 63 increased further the receptor activity of mouse SLAM. On the other hand, converse substitution at position 61 compromised receptor function of human SLAM. Thus, histidine 61 and its adjacent residues at positions 60 and 63 are critical for SLAM to act as a receptor for MV. Notably, the pseudotype assay indicated that residues at these three positions are also critical for the function of SLAM as a receptor for canine distemper virus.

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