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Published Papers - Ohno Shinji

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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)

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)

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)

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)

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)

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)

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.)

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.)

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)

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.)

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)

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)

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)

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)

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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Published Papers - Ohno Shinji