Updated on 2023/10/19

写真a

 
MATSUMOTO Yuusuke
 
Organization
Research Field in Veterinary Medicine, Agriculture, Fisheries and Veterinary Medicine Area Joint faculty of Veterinary Medicine Transboundary Animal Disease Research Center Associate Professor
Title
Associate Professor

Research Interests

  • Virology

Research Areas

  • Life Science / Virology

  • Life Science / Molecular biology

  • Life Science / Veterinary medical science

Education

  • Osaka University   Graduate School of Medicine

    2009.4 - 2012.9

  • Kyoto University   Institute for Virus Research

    2011.4 - 2012.9

  • University of Miyazaki   Faculty of Agriculture   Department of Veterinary Sciences

    2003.4 - 2009.3

Research History

  • Kagoshima University   Associate Professor

    2022.10

  • Kagoshima University   Joint faculty of Veterinary Medicine Transboundary Animal Disease Research Center   Associate Professor

    2022.10

  • Tokyo Metropolitan Institute of Medical Science   Department of Microbiology and Cell Biology   Researcher

    2020.9 - 2022.9

  • Wakayama Medical University   Department of Microbiology, School of Medicine   Assistant Professor

    2014.4 - 2020.8

  • Kyoto University   Institute for Virus Research

    2013.11 - 2014.3

  • Case Western Reserve University   Department of Molecular Biology & Microbiology   Post Doctoral Scholar

    2013.7 - 2013.10

  • Cleveland Clinic   Lerner Research Institute   Post Doctoral Fellow

    2012.10 - 2013.6

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Professional Memberships

  • The Japanese Society of Veterinary Science

    2022.10

  • The RNA Society of Japan.

    2022.6

  • THE JAPANESE SOCIETY FOR VIROLOGY

    2008.8

 

Papers

  • Sakiko Toyama, Tomoko Honda, Sadahiro Iwabuchi, Shinichi Hashimoto, Kenzaburo Yamaji, Yuko Tokunaga, Yusuke Matsumoto, Hideya Kawaji, Takashi Miyazaki, Yoshiaki Kikkawa, Michinori Kohara .  Application of spatial transcriptomics analysis using the Visium system for the mouse nasal cavity after intranasal vaccination. .  Frontiers in immunology14   1209945 - 1209945   2023Application of spatial transcriptomics analysis using the Visium system for the mouse nasal cavity after intranasal vaccination.Invited Reviewed International journal

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    Language:English   Publishing type:Research paper (scientific journal)  

    Intranasal vaccines that elicit mucosal immunity are deemed effective against respiratory tract infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but their ability to induce humoral immunity characterized by immunoglobulin A (IgA) and IgG production is low. It has been reported that vaccination with a mixture of a viscous base carboxyvinyl polymer (CVP) and viral antigens induced robust systemic and mucosal immune responses. In this study, we analyzed the behavior of immunocompetent cells in the nasal cavity over time by spatial transcriptome profiling induced immediately after antigen vaccination using CVP. We established a method for performing spatial transcriptomics using the Visium system in the mouse nasal cavity and analyzed gene expression profiles within the nasal cavity after intranasal vaccination. Glycoprotein 2 (Gp2)-, SRY-box transcription factor 8 (Sox8)-, or Spi-B transcription factor (Spib)-expressing cells were increased in the nasal passage (NP) region at 3-6 hr after SARS-CoV-2 spike protein and CVP (S-CVP) vaccination. The results suggested that microfold (M) cells are activated within a short period of time (3-6 hr). Subsequent cluster analysis of cells in the nasal cavity showed an increase in Cluster 9 at 3-6 hr after intranasal vaccination with the S-CVP. We found that Il6 in Cluster 9 had the highest log2 fold values within the NP at 3-6 hr. A search for gene expression patterns similar to that of Il6 revealed that the log2 fold values of Edn2, Ccl20, and Hk2 also increased in the nasal cavity after 3-6 hr. The results showed that the early response of immune cells occurred immediately after intranasal vaccination. In this study, we identified changes in gene expression that contribute to the activation of M cells and immunocompetent cells after intranasal vaccination of mice with antigen-CVP using a time-series analysis of spatial transcriptomics data. The results facilitated the identification of the cell types that are activated during the initial induction of nasal mucosal immunity.

    DOI: 10.3389/fimmu.2023.1209945

    PubMed

  • Hirohito Ishigaki, Fumihiko Yasui, Misako Nakayama, Akinori Endo, Naoki Yamamoto, Kenzaburo Yamaji, Cong Thanh Nguyen, Yoshinori Kitagawa, Takahiro Sanada, Tomoko Honda, Tsubasa Munakata, Masahiko Higa, Sakiko Toyama, Risa Kono, Asako Takagi, Yusuke Matsumoto, Aya Koseki, Kaori Hayashi, Masanori Shiohara, Koji Ishii, Yasushi Saeki, Yasushi Itoh, Michinori Kohara .  An attenuated vaccinia vaccine encoding the severe acute respiratory syndrome coronavirus-2 spike protein elicits broad and durable immune responses, and protects cynomolgus macaques and human angiotensin-converting enzyme 2 transgenic mice from severe acute respiratory syndrome coronavirus-2 and its variants .  Frontiers in Microbiology13   967019   2022.11Reviewed

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Frontiers Media SA  

    As long as the coronavirus disease-2019 (COVID-19) pandemic continues, new variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) with altered antigenicity will emerge. The development of vaccines that elicit robust, broad, and durable protection against SARS-CoV-2 variants is urgently required. We have developed a vaccine consisting of the attenuated vaccinia virus Dairen-I (DIs) strain platform carrying the SARS-CoV-2  S gene (rDIs-S). rDIs-S induced neutralizing antibody and T-lymphocyte responses in cynomolgus macaques and human angiotensin-converting enzyme 2 (hACE2) transgenic mice, and the mouse model showed broad protection against SARS-CoV-2 isolates ranging from the early-pandemic strain (WK-521) to the recent Omicron BA.1 variant (TY38-873). Using a tandem mass tag (TMT)-based quantitative proteomic analysis of lung homogenates from hACE2 transgenic mice, we found that, among mice subjected to challenge infection with WK-521, vaccination with rDIs-S prevented protein expression related to the severe pathogenic effects of SARS-CoV-2 infection (tissue destruction, inflammation, coagulation, fibrosis, and angiogenesis) and restored protein expression related to immune responses (antigen presentation and cellular response to stress). Furthermore, long-term studies in mice showed that vaccination with rDIs-S maintains S protein-specific antibody titers for at least 6 months after a first vaccination. Thus, rDIs-S appears to provide broad and durable protective immunity against SARS-CoV-2, including current variants such as Omicron BA.1 and possibly future variants.

    DOI: 10.3389/fmicb.2022.967019

  • Yutaro Neriya, Shohei Kojima, Arata Sakiyama, Mai Kishimoto, Takao Iketani, Tadashi Watanabe, Yuichi Abe, Hiroshi Shimoda, Keisuke Nakagawa, Takaaki Koma, Yusuke Matsumoto .  A comprehensive list of the Bunyavirales replication promoters reveals a unique promoter structure in Nairoviridae differing from other virus families. .  Scientific reports12 ( 1 ) 13560 - 13560   2022.8A comprehensive list of the Bunyavirales replication promoters reveals a unique promoter structure in Nairoviridae differing from other virus families.Invited Reviewed International journal

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    Members of the order Bunyavirales infect a wide variety of host species, including plants, animals and humans, and pose a threat to public health. Major families in this order have tri-segmented negative-sense RNA genomes, the 5' and 3' ends of which form complementary strands that serve as a replication promoter. Elucidation of the mechanisms by which viral polymerases recognize the promoter to initiate RNA synthesis is important for understanding viral replication and pathogenesis, and developing antivirals. A list of replication promoter configuration patterns may provide details on the differences in the replication mechanisms among bunyaviruses. By using public sequence data of all known bunyavirus species, we constructed a comprehensive list of the replication promoters comprising 40 nucleotides in both the 5' and 3' ends of the genome that form a specific complementary strand. Among tri-segmented bunyaviruses, members of the family Nairoviridae, including the highly pathogenic Crimean-Congo hemorrhagic fever virus, have evolved a GC-rich promoter structure differing from that of other families. The unique promoter structure might be related to the large genome size of the family Nairoviridae among bunyaviruses, and the large genome architecture might confer pathogenic advantages. The promoter list provided in this report is useful for predicting the virus family-specific replication mechanisms of bunyaviruses.

    DOI: 10.1038/s41598-022-17758-z

    PubMed

  • Hirohito Ishigaki, Fumihiko Yasui, Misako Nakayama, Akinori Endo, Naoki Yamamoto, Kenzaburo Yamaji, Cong Thanh Nguyen, Yoshinori Kitagawa, Takahiro Sanada, Tomoko Honda, Tsubasa Munakata, Masahiko Higa, Sakiko Toyama, Risa Kono, Asako Takagi, Yusuke Matsumoto, Kaori Hayashi, Masanori Shiohara, Koji Ishii, Yasushi Saeki, Yasushi Itoh, Michinori Kohara .  An attenuated vaccinia vaccine encoding the SARS-CoV-2 spike protein elicits broad and durable immune responses, and protects cynomolgus macaques and human ACE2 transgenic mice from SARS-CoV-2 and its variants .      2022.6

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    Language:English   Publisher:Cold Spring Harbor Laboratory  

    Abstract

    As long as the coronavirus disease 2019 (COVID-19) pandemic continues, new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with altered antigenicity will emerge. The development of vaccines that elicit robust, broad, and durable protection against SARS-CoV-2 variants is urgently needed. We have developed a vaccine (rDIs-S) consisting of the attenuated vaccinia virus DIs strain platform carrying the SARS-CoV-2 S gene. rDIs-S induced neutralizing antibody and T-lymphocyte responses in cynomolgus macaques and human angiotensin converting enzyme 2 (hACE2) transgenic mice, and showed broad protection against SARS-CoV-2 isolates ranging from the early-pandemic strain (WK-521) to the recent Omicron BA. 1 variant (TY38-839). Using a tandem mass tag (TMT) -based quantitative proteomic analysis of lung homogenates from hACE2 transgenic mice, we found that, among mice subjected to challenge infection with WK-521, vaccination with rDIs-S prevented protein expression related to the severe pathogenic effects of SARS-CoV-2 infection (tissue destruction, inflammation, coagulation, fibrosis, and angiogenesis) and restored protein expression related to immune responses (antigen presentation and cellular response to stress). Furthermore, long-term studies in mice showed that rDIs-S maintains S protein-specific antibody titers for at least 6 months after a 1<sup>st</sup> vaccination. Thus, rDIs-S appears to provide broad and durable protective immunity against SARS-CoV-2, including current and possibly future variants.

    DOI: 10.1101/2022.06.12.495779

  • Fumihiko Yasui, Yusuke Matsumoto, Naoki Yamamoto, Takahiro Sanada, Tomoko Honda, Tsubasa Munakata, Yasushi Itoh, Michinori Kohara .  Infection with the SARS-CoV-2 B.1.351 variant is lethal in aged BALB/c mice. .  Scientific reports12 ( 1 ) 4150 - 4150   2022.3Infection with the SARS-CoV-2 B.1.351 variant is lethal in aged BALB/c mice.Invited Reviewed International journal

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    Models of animals that are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can usefully evaluate the efficacy of vaccines and therapeutics. In this study, we demonstrate that infection with the SARS-CoV-2 B.1.351 variant (TY8-612 strain) induces bodyweight loss and inflammatory cytokine/chemokine production in wild-type laboratory mice (BALB/c and C57BL/6 J mice). Furthermore, compared to their counterparts, BALB/c mice had a higher viral load in their lungs and worse symptoms. Importantly, infecting aged BALB/c mice (older than 6 months) with the TY8-612 strain elicited a massive and sustained production of multiple pro-inflammatory cytokines/chemokines and led to universal mortality. These results indicated that the SARS-CoV-2 B.1.351 variant-infected mice exhibited symptoms ranging from mild to fatal depending on their strain and age. Our data provide insights into the pathogenesis of SARS-CoV-2 and may be useful in developing prophylactics and therapeutics.

    DOI: 10.1038/s41598-022-08104-4

    PubMed

  • Naoki Saka, Yusuke Matsumoto, Keisuke Ohta, Daniel Kolakofsky, Machiko Nishio .  A Point Mutation in the Human Parainfluenza Virus Type 2 Nucleoprotein Leads to Two Separate Effects on Virus Replication. .  Journal of virology96 ( 4 ) e0206721   2022.2A Point Mutation in the Human Parainfluenza Virus Type 2 Nucleoprotein Leads to Two Separate Effects on Virus Replication.Invited Reviewed International journal

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    Paramyxovirus genomes, like that of human parainfluenza virus type 2 (hPIV2), have lengths of precisely multiples-of-six nucleotides ("rule of six"), where each nucleoprotein subunit (NP) binds exactly six nucleotides. Ten residues of its RNA binding groove contact the genome RNA; but only one, Q202, directly contacts a nucleotide base. The mutation of NPQ202 leads to two phenotypes: the ability of the viral polymerase to replicate minigenomes with defective bipartite promoters where NPwt is inactive, and the inability to rescue rPIV2 carrying this point mutation by standard means. The absence of an rPIV2 NPQ202A prevented further study of the latter phenotype. By extensive and repeated cocultivation of transfected cells, an rPIV2 carrying this mutation was finally recovered, and this virus was apparently viable due to the presence of an additional NP mutation (I35L). Our results suggest that these two phenotypes are due to separate effects of the Q202 mutation, and that the problematic rescue phenotype may be due to the inability of the transfected cell to incorporate viral nucleocapsids during virus budding. IMPORTANCE Paramyxovirus genomes are contained within a noncovalent homopolymer of its nucleoprotein (NP) and form helical nucleocapsids (NC) whose 3' ends contain the promoters for the initiation of viral RNA synthesis. This work suggests that these NC 3' ends may play another role in the virus life cycle via their specific interaction with virus-modified cell membranes needed for the incorporation of viral NCs into budding virions.

    DOI: 10.1128/JVI.02067-21

    PubMed

  • Takahiro Sanada, Tomoko Honda, Fumihiko Yasui, Kenzaburo Yamaji, Tsubasa Munakata, Naoki Yamamoto, Makoto Kurano, Yusuke Matsumoto, Risa Kohno, Sakiko Toyama, Yoshiro Kishi, Takuro Horibe, Yudai Kaneko, Mayumi Kakegawa, Kazushige Fukui, Takeshi Kawamura, Wang Daming, Chungen Qian, Fuzhen Xia, Fan He, Syudo Yamasaki, Atsushi Nishida, Takayuki Harada, Masahiko Higa, Yuko Tokunaga, Asako Takagi, Masanari Itokawa, Tatsuhiko Kodama, Michinori Kohara .  Serologic Survey of IgG Against SARS-CoV-2 Among Hospital Visitors Without a History of SARS-CoV-2 Infection in Tokyo, 2020-2021. .  Journal of epidemiology32 ( 2 ) 105 - 111   2022.2Serologic Survey of IgG Against SARS-CoV-2 Among Hospital Visitors Without a History of SARS-CoV-2 Infection in Tokyo, 2020-2021.Invited Reviewed

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    BACKGROUND: Tokyo, the capital of Japan, is a densely populated city of >13 million people, so the population is at high risk of epidemic severe acute respiratory coronavirus 2 (SARS-CoV-2) infection. A serologic survey of anti-SARS-CoV-2 IgG would provide valuable data for assessing the city's SARS-CoV-2 infection status. Therefore, this cross-sectional study estimated the anti-SARS-CoV-2 IgG seroprevalence in Tokyo. METHODS: Leftover serum of 23,234 hospital visitors was tested for antibodies against SARS-CoV-2 using an iFlash 3000 chemiluminescence immunoassay analyzer (Shenzhen YHLO Biotech, Shenzhen, China) with an iFlash-SARS-CoV-2 IgG kit (YHLO) and iFlash-SARS-CoV-2 IgG-S1 kit (YHLO). Serum samples with a positive result (≥10 AU/mL) in either of these assays were considered seropositive for anti-SARS-CoV-2 IgG. Participants were randomly selected from patients visiting 14 Tokyo hospitals between September 1, 2020 and March 31, 2021. No participants were diagnosed with coronavirus disease 2019 (COVID-19), and none exhibited COVID-19-related symptoms at the time of blood collection. RESULTS: The overall anti-SARS-CoV-2 IgG seroprevalence among all participants was 1.83% (95% confidence interval [CI], 1.66-2.01%). The seroprevalence in March 2021, the most recent month of this study, was 2.70% (95% CI, 2.16-3.34%). After adjusting for population age, sex, and region, the estimated seroprevalence in Tokyo was 3.40%, indicating that 470,778 individuals had a history of SARS-CoV-2 infection. CONCLUSIONS: The estimated number of individuals in Tokyo with a history of SARS-CoV-2 infection was 3.9-fold higher than the number of confirmed cases. Our study enhances understanding of the SARS-CoV-2 epidemic in Tokyo.

    DOI: 10.2188/jea.JE20210324

    PubMed

  • Keisuke Ohta, Yusuke Matsumoto, Machiko Nishio .  Common and unique mechanisms of filamentous actin formation by viruses of the genus Orthorubulavirus. .  Archives of virology165 ( 4 ) 799 - 807   2020.4Common and unique mechanisms of filamentous actin formation by viruses of the genus Orthorubulavirus.Invited Reviewed International journal

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    We previously found that infection with human parainfluenza virus type 2 (hPIV-2), a member of the genus Orthorubulavirus, family Paramyxoviridae, causes filamentous actin (F-actin) formation to promote viral growth. In the present study, we investigated whether similar regulation of F-actin formation is observed in infections with other rubulaviruses, such as parainfluenza virus type 5 (PIV-5) and simian virus 41 (SV41). Infection with these viruses caused F-actin formation and RhoA activation, which promoted viral growth. These results indicate that RhoA-induced F-actin formation is important for efficient growth of these rubulaviruses. Only SV41 and hPIV-2 V and P proteins bound to Graf1, while the V and P proteins of PIV-5, mumps virus, and hPIV-4 did not bind to Graf1. In contrast, the V proteins of these rubulaviruses bound to both inactive RhoA and profilin 2. These results suggest that there are common and unique mechanisms involved in regulation of F-actin formation by members of the genus Orthorubulavirus.

    DOI: 10.1007/s00705-020-04565-y

    PubMed

  • Keisuke Ohta, Yusuke Matsumoto, Machiko Nishio .  Inhibition of Cavin3 Degradation by the Human Parainfluenza Virus Type 2 V Protein Is Important for Efficient Viral Growth. .  Frontiers in microbiology11   803 - 803   2020Inhibition of Cavin3 Degradation by the Human Parainfluenza Virus Type 2 V Protein Is Important for Efficient Viral Growth.Invited Reviewed International journal

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    Cavin proteins have important roles in the formation of caveolae in lipid raft microdomains. Pulse-chase experiments of cells infected with human parainfluenza virus type 2 (hPIV-2) showed decreased proteasomal degradation of Cavin3. Overexpression of hPIV-2 V protein alone was sufficient to inhibit Cavin3 degradation. Immunoprecipitation analysis revealed that V protein bound to Cavin3. Trp residues within C-terminal region of V protein, as well as the N-terminal region of Cavin3, are important for V-Cavin3 interaction. Cavin3 knockdown suppressed hPIV-2 growth without affecting its entry, replication, transcription, or translation. Higher amounts of Cavin3 were observed in V protein-overexpressing cells than in control cells in lipid raft microdomains. Our data collectively suggest that hPIV-2 V protein binds to and stabilizes Cavin3, which in turn facilitates assembly and budding of hPIV-2 in lipid raft microdomains.

    DOI: 10.3389/fmicb.2020.00803

    PubMed

  • Keisuke Ohta, Yusuke Matsumoto, Machiko Nishio .  Profilin2 is required for filamentous actin formation induced by human parainfluenza virus type 2. .  Virology533   108 - 114   2019.7Profilin2 is required for filamentous actin formation induced by human parainfluenza virus type 2.Invited Reviewed International journal

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    We previously reported that human parainfluenza virus type 2 (hPIV-2) promoted RhoA activation and subsequent filamentous actin (F-actin) formation. Actin-binding proteins, such as profilin and cofilin, are involved in the regulation of F-actin formation by RhoA signaling. In the present study, we identified profilin2 as a key molecule that is involved in hPIV-2-induced F-actin formation. Immunoprecipitation assays demonstrated that hPIV-2 V protein binds to profilin2 but not to profilin1. Mutation of Trp residues within C-terminal region of V protein abolished the binding capacity to profilin2. Depletion of profilin2 resulted in the inhibition of hPIV-2-induced F-actin formation and the suppression of hPIV-2 growth. Overexpression of wild type V but not Trp-mutated V protein reduced the quantity of actin co-immunoprecipitated with profilin2. Taken together, these results suggest that hPIV-2 V protein promotes F-actin formation by affecting actin-profilin2 interaction through its binding to profilin2.

    DOI: 10.1016/j.virol.2019.05.013

    PubMed

  • Matsumoto Y, Ohta K, Nishio M .  Importance of tyrosine in the RNA-binding domain of human parainfluenza virus type 2 nucleoprotein for polymerase activity. .  Archives of virology164 ( 7 ) 1851 - 1855   2019.5Importance of tyrosine in the RNA-binding domain of human parainfluenza virus type 2 nucleoprotein for polymerase activity.Reviewed International journal

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    The RNA genome of human parainfluenza virus type 2 (hPIV2) is encapsidated by nucleoprotein (NP) to act as a template for RNA synthesis. We examined the importance of individual amino acids in the RNA-binding domain of hPIV2 NP for polymerase activity using a mini-replicon assay. We showed that substitution of tyrosine at amino acid position 260, located in the RNA-binding pocket of NP, severely reduced polymerase activity. The aromatic side-chain of Y260 may be required for the formation of stable contacts between nucleotides and basic amino acids, thereby affecting promoter recognition by the viral polymerase.

    DOI: 10.1007/s00705-019-04240-x

    PubMed

  • Yumine N, Matsumoto Y, Ohta K, Fukasawa M, Nishio M .  Claudin-1 inhibits human parainfluenza virus type 2 dissemination. .  Virology531   93 - 99   2019.5Claudin-1 inhibits human parainfluenza virus type 2 dissemination.Reviewed International journal

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    Tight junctions enable epithelial cells to form physical barriers that act as an innate immune defense against respiratory infection. However, the involvement of tight junction molecules in paramyxovirus infections, which include various respiratory pathogens, has not been examined in detail. Human parainfluenza virus type 2 (hPIV2) infects airway epithelial cells and causes respiratory illness. In the present study, we found that hPIV2 infection of cultured cells induces expression of claudin-1 (CLDN1), an essential component of tight junctions. This induction seemed to be intrinsically restricted by V, an accessory protein that modulates various host responses, to enable efficient virus propagation. By generating CLDN1 over-expressing and knockout cell lines, we showed that CLDN1 is involved in the restriction of hPIV2 spread via cell-to-cell contact. Taken together, we identified CLDN1 an inhibitory factor for hPIV2 dissemination, and that its V protein acts to counter this.

    DOI: 10.1016/j.virol.2019.01.031

    PubMed

  • Matsumoto Y, Nouchi T, Ohta K, Nishio M .  Regulation of Hazara virus growth through apoptosis inhibition by viral nucleoprotein. .  Archives of virology164 ( 6 ) 1597 - 1607   2019.4Regulation of Hazara virus growth through apoptosis inhibition by viral nucleoprotein.Reviewed International journal

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    Hazara virus (HAZV) is closely related to Crimean-Congo hemorrhagic fever virus (CCHFV), but differs in that it is non-pathogenic to humans. Since HAZV was isolated for the first time in 1954, the biological characteristics of this virus, particularly its behavior within culture cells, have not been well-studied, despite its importance as a surrogate model for CCHFV. Nucleoprotein (N) is the main component of viral nucleocapsid and is the most abundant virion protein, it is believed to play a pivotal role in the viral lifecycle. Generation of a series of anti-HAZV N monoclonal antibodies has enabled us to directly examine the involvement of this protein on viral growth. Observation of HAZV-infected cells revealed that this infection caused apoptosis, which was further characterized by DNA ladder and elevated caspase-3/7 activity. HAZV titers initially increased in cell culture, but after reaching the peak titer began to rapidly decline. HAZV particles were found to be very unstable in culture medium at 37 °C, and virus particles tend to lose infectivity at that point. HAZV N appears to inhibit apoptosis, thus can potentially support efficient viral propagation.

    DOI: 10.1007/s00705-019-04236-7

    PubMed

  • Matsumoto Y, Ohta K, Kolakofsky D, Nishio M .  A Minigenome Study of Hazara Nairovirus Genomic Promoters. .  Journal of virology93 ( 6 )   2019.3A Minigenome Study of Hazara Nairovirus Genomic Promoters.Reviewed International journal

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    Hazara nairovirus (HAZV) is a trisegmented RNA virus most closely related to Crimean-Congo hemorrhagic fever virus (CCHFV) in the order Bunyavirales The terminal roughly 20 nucleotides (nt) of its genome ends are highly complementary, similar to those of other segmented negative-strand RNA viruses (sNSV), and act as promoters for RNA synthesis. These promoters contain two elements: the extreme termini of both strands (promoter element 1 [PE1]) are conserved and virus specific and are found bound to separate sites on the polymerase surface in crystal structures of promoter-polymerase complexes. The following sequences (PE2) are segment specific, with the potential to form double-stranded RNA (dsRNA), and the latter aspect is also important for promoter activity. Nairovirus genome promoters differ from those of peribunyaviruses and arenaviruses in that they contain a short single-stranded region between the two regions of complementarity. Using a HAZV minigenome system, we found the single-stranded nature of this region, as well as the potential of the following sequence to form dsRNA, is essential for reporter gene expression. Most unexpectedly, the sequence of the PE2 dsRNA appears to be equally important for promoter activity. These differences in sNSV PE2 promoter elements are discussed in light of our current understanding of the initiation of RNA synthesis.IMPORTANCE A minigenome system for HAZV, closely related to CCHFV, was used to study its genome replication. HAZV genome ends, like those of other sNSV, such as peribunyaviruses and arenaviruses, are highly complementary and serve as promoters for genome synthesis. These promoters are composed of two elements: the extreme termini of both 3' and 5' strands that are initially bound to separate sites on the polymerase surface in a sequence-specific fashion and the following sequences with the potential to anneal but whose sequence is not important. Nairovirus promoters differ from the other sNSV cited in that they contain a short single-stranded RNA (ssRNA) region between the two elements. The single-stranded nature of this region is an essential element of the promoter, whereas its sequence is unimportant. The sequence of the following complementary region is unexpectedly also important, a possible rare example of sequence-specific dsRNA recognition.

    DOI: 10.1128/JVI.02118-18

    PubMed

  • Ohtsuka J, Matsumoto Y, Ohta K, Fukumura M, Tsurudome M, Nosaka T, Nishio M .  Nucleocytoplasmic shuttling of the human parainfluenza virus type 2 phosphoprotein. .  Virology528   54 - 63   2019.2Nucleocytoplasmic shuttling of the human parainfluenza virus type 2 phosphoprotein.Reviewed International journal

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    Human parainfluenza virus type 2 phosphoprotein (P) is an essential component of viral polymerase. The P gene encodes both P and accessory V proteins by a specific gene editing mechanism. Therefore, the N-terminal 164 amino acids of P protein are common to V protein. Interestingly, while P protein is located in the cytoplasm, V protein is found mainly in the nucleus. Using deletion mutants, we show the presence of a nuclear localization signal (NLS) in the P/V common domain, and a nuclear export signal (NES) in the C-terminal P specific region. The NLS region makes a complex with importin α5 or 7. In the presence of leptomycin B, P protein is retained in the nucleus, indicating that it contains a CRM1-dependent NES. We identified the NLS (65PVKPRRKK72) and the NES (225IIELLKGLDL234) using β-galactosidase fusion proteins. Moreover, nucleocytoplasmic shuttling of P protein appears to be important for efficient viral polymerase activity.

    DOI: 10.1016/j.virol.2018.12.005

    PubMed

  • Ohta K, Matsumoto Y, Yumine N, Nishio M .  The V protein of human parainfluenza virus type 2 promotes RhoA-induced filamentous actin formation. .  Virology524   90 - 96   2018.11The V protein of human parainfluenza virus type 2 promotes RhoA-induced filamentous actin formation.Reviewed International journal

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    We previously demonstrated that human parainfluenza virus type 2 (hPIV-2) induces RhoA activation, which promotes its growth. RhoA controls the equilibrium between globular and filamentous actin (F-actin). We found that F-actin formation is induced by wild type (wt) hPIV-2 infection, and that inhibition of F-actin formation by cytochalasin D decreases hPIV-2 growth. In wt RhoA-expressing cells, F-actin formation occurs and hPIV-2 growth is promoted. Overexpression of T19N RhoA, a dominant negative (DN) form of RhoA, inhibits hPIV-2-induced F-actin formation, and suppresses hPIV-2 growth. Immunoprecipitation assays reveal that hPIV-2 V protein binds only to DN RhoA, and this interaction requires its C-terminal Trp residues. F-actin formation is not observed during infection of recombinant hPIV-2 expressing Trp-mutated V protein (VW178H/W182E/W192A). Overexpression of V protein, but not that of VW178H/W182E/W192A, causes F-actin formation. Our results suggest that hPIV-2 V protein enhances hPIV2 growth through RhoA-induced F-actin formation, by selectively binding to inactive RhoA.

    DOI: 10.1016/j.virol.2018.08.015

    PubMed

  • Keisuke Ohta, Yusuke Matsumoto, Machiko Nishio .  Rab27a facilitates human parainfluenza virus type 2 growth by promoting cell surface transport of envelope proteins .  Medical Microbiology and Immunology207 ( 2 ) 141 - 150   2018.4Rab27a facilitates human parainfluenza virus type 2 growth by promoting cell surface transport of envelope proteinsReviewed International journal

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Springer Verlag  

    Human parainfluenza virus type 2 (hPIV-2) proteins and genomes newly synthesized in the cytoplasm need to be transported to the plasma membrane where budding occurs. This mechanism, where Rab proteins regulate intracellular traffic by switching between GTP-bound active form and GDP-bound inactive form, is not fully understood. mRNA and protein expression levels of Rab8a, Rab11a, and Rab27a are not altered by hPIV-2 infection. hPIV-2 growth is affected by depletion of Rab27a but not Rab8a and Rab11a. Overexpression of a constitutively active mutant of Rab27a Q78L promotes the cell surface levels of fusion (F) and hemagglutinin-neuraminidase (HN) proteins in hPIV-2-infected cells without affecting viral mRNA levels. Increase in the cell surface level of F and HN proteins by Rab27a Q78L is noticeable when these proteins are coexpressed independent of hPIV-2 infection. Our results collectively suggest that the active form of Rab27a enhances hPIV-2 growth by promoting transport of F and HN proteins to the plasma membrane.

    DOI: 10.1007/s00430-018-0536-3

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  • Yusuke Matsumoto, Keisuke Ohta, Daniel Kolakofsky, Machiko Nishio .  The control of paramyxovirus genome hexamer length and mRNA editing .  RNA24 ( 4 ) 461 - 467   2018.4The control of paramyxovirus genome hexamer length and mRNA editingReviewed International journal

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    The unusual ability of a human parainfluenza virus type 2 (hPIV2) nucleoprotein point mutation (NPQ202A) to strongly enhance minigenome replication was found to depend on the absence of a functional, internal element of the bipartite replication promoter (CRII). This point mutation allows relatively robust CRII-minus minigenome replication in a CRII-independent manner, under conditions in which NPwt is essentially inactive. The nature of the amino acid at position 202 apparently controls whether viral RNA-dependent RNA polymerase (vRdRp) can, or cannot, initiate RNA synthesis in a CRII-independent manner. By repressing genome synthesis when vRdRp cannot correctly interact with CRII, gln202 of N, the only residue of the RNA-binding groove that contacts a nucleotide base in the N-RNA, acts as a gatekeeper for wild-type (CRII-dependent) RNA synthesis. This ensures that only hexamer-length genomes are replicated, and that the critical hexamer phase of the cis-acting mRNA editing sequence is maintained.

    DOI: 10.1261/rna.065243.117

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  • Keisuke Ohta, Yusuke Matsumoto, Machiko Nishio .  Human parainfluenza virus type 2 V protein inhibits caspase-1 .  Journal of General Virology99 ( 4 ) 501 - 511   2018.4Human parainfluenza virus type 2 V protein inhibits caspase-1Reviewed International journal

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    The multifunctional V protein of human parainfluenza virus type 2 (hPIV2) plays important roles in controlling viral genome replication, inhibiting the host interferon response and promoting virus growth. We screened a yeast two-hybrid library using V protein as bait to identify host factors that are important for other functions of V. One of several positive clones isolated from HeLa cell-derived cDNA library encodes caspase-1. We found that the C-terminal region of V interacts with the C-terminal region of caspase-1 in mammalian cells. Moreover, the V protein repressed caspase-1 activity and the formation of interleukin1β (IL-1 β) in a dose-dependent manner. IL-1 β secretion induced by wild-type hPIV2 infection in human monocytic THP-1 cells was significantly lower than that induced by recombinant hPIV2 lacking V protein or having a mutant V. These data suggest that hPIV2 V protein inhibits caspase-1-mediated maturation of IL-1 β via its interaction with caspase-1.

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  • Yusuke Matsumoto, Keisuke Ohta, Machiko Nishio .  Lethal infection of embryonated chicken eggs by Hazara virus, a model for Crimean-Congo hemorrhagic fever virus .  Archives of Virology163 ( 1 ) 219 - 222   2018.1Lethal infection of embryonated chicken eggs by Hazara virus, a model for Crimean-Congo hemorrhagic fever virusReviewed International journal

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    Hazara virus (HAZV) is a member of the genus Orthonairovirus of the family Nairoviridae. HAZV is closely related to Crimean-Congo hemorrhagic fever virus but differs in that it is non-pathogenic to humans. To establish an infection model system, we tested whether embryonated chicken eggs, which are classically used for evaluating viral pathogenicity, are susceptible to HAZV infection. We demonstrated that HAZV replicates well in embryonated chicken eggs and kills 100% of the embryos. This can be a valuable tool to evaluate the lethality of nairoviruses in a biosafety level 2 laboratory.

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  • Yusuke Matsumoto, Keisuke Ohta, Machiko Nishio .  Human parainfluenza virus type 2 polymerase complex recognizes leader promoters of other species belonging to the genus Rubulavirus .  MEDICAL MICROBIOLOGY AND IMMUNOLOGY206 ( 6 ) 441 - 446   2017.12Human parainfluenza virus type 2 polymerase complex recognizes leader promoters of other species belonging to the genus RubulavirusReviewed International journal

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    Leader sequence, located at the 3' terminus of paramyxovirus genomes, determines the degree of viral transcription and replication. The essential nucleotides in the leader sequence that influence viral propagation, however, have not been investigated in detail. In the present study, we show that polymerase complex of human parainfluenza virus type 2 (hPIV2) uses a luciferase-encoding hPIV2 mini-genome possessing the leader sequence from other closely related viruses as a template. Furthermore, we demonstrate that although hPIV2 polymerase complex can recognize the leader sequence of hPIV4B, mumps virus (MuV) and PIV5 as well as Newcastle disease virus (NDV), it cannot recognize measles virus, hPIV1, Sendai virus (SeV) or hPIV3. We could obtain the chimeric hPIV2 possessing the leader sequence from hPIV4B, MuV and PIV5, but not from other species, including NDV and SeV. These results reveal that although hPIV2 polymerase complex can recognize the leader sequence from rubulaviruses to achieve efficient viral infection, this does not apply to viruses belonging to other genus. A comparison of leader sequence nucleotides among paramyxoviruses highlights the importance of the conservation in the first 13 nucleotides for infectious hPIV2 growth.

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  • Keisuke Ohta, Yusuke Matsumoto, Morihiro Ito, Machiko Nishio .  Tetherin antagonism by V proteins is a common trait among the genus Rubulavirus .  MEDICAL MICROBIOLOGY AND IMMUNOLOGY206 ( 4 ) 319 - 326   2017.8Tetherin antagonism by V proteins is a common trait among the genus RubulavirusReviewed International journal

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    Tetherin (BST-2/CD317/HM1.24) is an anti-viral factor that restricts the budding of several enveloped viruses. Most of these viruses have evolved to encode tetherin antagonists. Our previous study demonstrated that the growth of human parainfluenza virus type 2 (hPIV-2), a member of the genus Rubulavirus in the family Paramyxoviridae, was inhibited by tetherin, and its V protein decreases the amount of cell surface tetherin by the interaction. In the present study, we investigated whether tetherin inhibits the growth of other rubulaviruses including PIV-5, mumps virus (MuV), simian virus 41, and hPIV-4, and whether their V proteins act as tetherin antagonists. Plaque assay demonstrated that the growth of PIV-5 and MuV was inhibited by tetherin. Flow cytometry and immunoblot analyses revealed that the infection of PIV-5 and MuV caused reduction of cell surface tetherin without affecting total amount of tetherin. Immunoprecipitation analysis showed that all V proteins of rubulaviruses tested bound to tetherin. These results suggest that tetherin antagonism by V proteins is common among the genus Rubulavirus.

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  • Keisuke Ohta, Yusuke Matsumoto, Natsuko Yumine, Machiko Nishio .  Human parainfluenza virus type 2 V protein inhibits induction of tetherin .  MEDICAL MICROBIOLOGY AND IMMUNOLOGY206 ( 4 ) 311 - 318   2017.8Human parainfluenza virus type 2 V protein inhibits induction of tetherinReviewed International journal

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    Tetherin is an anti-viral factor that restricts viral budding through tethering virions to the cell surface. The human parainfluenza virus type 2 (hPIV-2) V protein decreases cell surface tetherin in HeLa cells, which constitutively express endogenous tetherin. However, the role of the hPIV-2 V protein in tetherin induction remains unclear. Here, we examined whether hPIV-2 infection itself induces tetherin in HEK293 cells that have no basal expression of tetherin. Unlike influenza A virus (IAV) infection, hPIV-2 infection induced neither tetherin mRNA nor protein expression. In contrast, robust tetherin induction was observed by infection of rPIV-2s carrying V mutants, in which either three Trp residues (W178H/W182E/W192A) or Cys residues (C209/211/214A) that are important for decreasing cell surface tetherin are mutated. hPIV-2 infection also inhibited the induction of tetherin expression by IFN-alpha and IAV infection. Furthermore, hPIV-2 V protein but not P and V-W178H/W182E/W192A suppressed tetherin induction. Our data collectively suggest that the hPIV-2 V protein inhibits tetherin expression induced by several external stimuli.

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  • Yusuke Matsumoto, Keisuke Ohta, Daniel Kolakofsky, Machiko Nishio .  A Point Mutation in the RNA-Binding Domain of Human Parainfluenza Virus Type 2 Nucleoprotein Elicits Abnormally Enhanced Polymerase Activity .  JOURNAL OF VIROLOGY91 ( 9 )   2017.5A Point Mutation in the RNA-Binding Domain of Human Parainfluenza Virus Type 2 Nucleoprotein Elicits Abnormally Enhanced Polymerase ActivityReviewed

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    The genome RNA of human parainfluenza virus type 2 (hPIV2) that acts as the template for the polymerase complex is entirely encapsidated by the nucleoprotein (NP). Recently, the crystal structure of NP of PIV5, a virus closely related to hPIV2, was resolved in association with RNA. Ten amino acids that contact the bound RNA were identified and are strictly conserved between PIV5 and hPIV2 NP. Mutation of hPIV2 NP Q202 (which contacts a base rather than the RNA backbone) to various amino acids resulted in an over 30-fold increase of polymerase activity as evidenced by a minireplicon assay, even though the RNA-binding affinity was unaltered. Using various modified minireplicons, we found that the enhanced reporter gene expression could be accounted for by increased minigenome replication, whereas mRNA synthesis itself was not affected by Q202 mutation. Moreover, the enhanced activities were still observed in minigenomes partially lacking the leader sequence and which were not of hexamer genome length. Unexpectedly, recombinant hPIV2 possessing the NP Q202A mutation could not be recovered from cDNA.
    IMPORTANCE We examined the importance of amino acids in the putative RNAbinding domain of hPIV2 NP for polymerase activity using minireplicons. Abnormally enhanced genome replication was observed upon substitution mutation of the NP Q202 position to various amino acids. Surprisingly, this mutation enabled polymerase to use minigenomes that were partially lacking the leader sequence and not of hexamer genome length. This mutation does not affect fundamental properties of NP, e.g., recognition of gene junctional and editing signals. However, the strongly enhanced polymerase activity may not be viable for the infectious life cycle. This report highlights the potential of the polymerase complex with point mutations in NP and helps our detailed understanding of the molecular basis of gene expression.

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  • Keisuke Ohta, Hideo Goto, Yusuke Matsumoto, Natsuko Yumine, Masato Tsurudome, Machiko Nishio .  Graf1 Controls the Growth of Human Parainfluenza Virus Type 2 through Inactivation of RhoA Signaling .  JOURNAL OF VIROLOGY90 ( 20 ) 9394 - 9405   2016.10Graf1 Controls the Growth of Human Parainfluenza Virus Type 2 through Inactivation of RhoA SignalingReviewed

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    Rho GTPases are involved in a variety of cellular activities and are regulated by guanine nucleotide exchange factors and GTPase-activating proteins (GAPs). We found that the activation of Rho GTPases by lysophosphatidic acid promotes the growth of human parainfluenza virus type 2 (hPIV-2). Furthermore, hPIV-2 infection causes activation of RhoA, a Rho GTPase. We hypothesized that Graf1 (also known as ARHGAP26), a GAP, regulates hPIV-2 growth by controlling RhoA signaling. Immunofluorescence analysis showed that hPIV-2 infection altered Graf1 localization from a homogenous distribution within the cytoplasm to granules. Graf1 colocalized with hPIV-2 P, NP, and L proteins. Graf1 interacts with P and V proteins via their N-terminal common region, and the C-terminal Src homology 3 domain-containing region of Graf1 is important for these interactions. In HEK293 cells constitutively expressing Graf1, hPIV-2 growth was inhibited, and RhoA activation was not observed during hPIV-2 infection. In contrast, Graf1 knockdown restored hPIV-2 growth and RhoA activation. Overexpression of hPIV-2 P and V proteins enhanced hPIV-2-induced RhoA activation. These results collectively suggested that hPIV-2 P and V proteins enhanced hPIV-2 growth by binding to Graf1 and that Graf1 inhibits hPIV-2 growth through RhoA inactivation.
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    Robust growth of hPIV-2 requires Rho activation. hPIV-2 infection causes RhoA activation, which is suppressed by Graf1. Graf1 colocalizes with viral RNP (vRNP) in hPIV-2-infected cells. We found that Graf1 interacts with hPIV-2 P and V proteins. We also identified regions in these proteins which are important for this interaction. hPIV-2 P and V proteins enhanced the hPIV-2 growth via binding to Graf1, while Graf1 inhibited hPIV-2 growth through RhoA inactivation.

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  • Hideo Goto, Keisuke Ohta, Yusuke Matsumoto, Natsuko Yumine, Machiko Nishio .  Evidence that Receptor Destruction by the Sendai Virus Hemagglutinin-Neuraminidase Protein Is Responsible for Homologous Interference .  JOURNAL OF VIROLOGY90 ( 17 ) 7640 - 7646   2016.9Evidence that Receptor Destruction by the Sendai Virus Hemagglutinin-Neuraminidase Protein Is Responsible for Homologous InterferenceReviewed

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    Receptor destruction has been considered one of the mechanisms of homologous Sendai virus (SeV) interference. However, direct evidence of receptor destruction upon virus infection and its relevance to interference is missing. To investigate a precise mechanism of homologous interference, we established SeV persistently infected cells. The persistently infected cells inhibited superinfection by homologous SeV but supported replication of human parainfluenza virus 2 (hPIV2) and influenza A virus (IAV). We confirmed that SeV particles could not attach to or penetrate the infected cells and that the hemagglutinin-neuraminidase (HN) protein of SeV was involved in the interference. Lectin blot assays showed that the alpha 2,3-linked sialic acids were specifically reduced in the SeV-infected cells, but the level of alpha 2,6-linked sialic acids had not changed. As infection with IAV removed both alpha 2,3- and alpha 2,6-linked sialic acids, especially alpha 2,3-linked sialic acids, IAV-infected cells inhibited superinfection of SeV. These results provide concrete evidence that destruction of the specific SeV receptor, alpha 2,3-linked sialic acids, is relevant to homologous interference by SeV.
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    Viral interference is a classically observed phenomenon, but the precise mechanism is not clear. Using SeV interference, we provide concrete evidence that reduction of the alpha 2,3-linked sialic acid receptor by the HN of SeV is closely related with viral interference. Since SeV infection resulted in decrease of only alpha 2,3-linked sialic acids, IAV, which also utilized alpha 2,6-linked sialic acids to initiate infection, superinfected the SeV-infected cells. In contrast, SeV could not superinfect the IAV-infected cells because both alpha 2,3- and alpha 2,6-linked sialic acids were removed. These results indicate that receptor destruction critically contributes to viral interference.

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  • Yusuke Matsumoto, Keisuke Ohta, Hideo Goto, Machiko Nishio .  Parainfluenza virus chimeric mini-replicons indicate a novel regulatory element in the leader promoter .  JOURNAL OF GENERAL VIROLOGY97 ( 7 ) 1520 - 1530   2016.7Parainfluenza virus chimeric mini-replicons indicate a novel regulatory element in the leader promoterReviewed

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    Gene expression of paramyxoviruses is regulated by genome-encoded cis-acting elements; however, whether all the required elements for viral growth have been identified is not clear. Using a mini-replicon system, it has been shown that human parainfluenza virus type 2 (hPIV2) polymerase can recognize the promoter elements of parainfluenza virus type 5 (PIV5), but reporter activity is lower in this case. We constructed a series of luciferase-encoding chimeric PIV2/5 mini-genomes that are basically hPIV2, but whose leader (le), mRNA start signal and trailer sequence are partially replaced with those of PIV5. Studies of the chimeric PIV2/5 mini-replicons demonstrated that replacement of hPIV2 le with PIV5 le results in remarkably weak luciferase expression. Further mutagenesis identified the responsible region as positions 25-30 of the PIV5 le. Using recombinant hPIV2, the impact of this region on viral life cycles was assessed. Insertion of the mutation at this region facilitated viral growth, genomic replication and mRNA transcription at the early stage of infection, which elicited severe cell damage. In contrast, at the late infection stage it caused a reduction in viral transcription. Here, we identify a novel cis-acting element in the internal region of an le sequence that is involved in the regulation of polymerase, and which contributes to maintaining a balance between viral growth and cytotoxicity.

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  • Tomoyuki Honda, Yusuke Yamamoto, Takuji Daito, Yusuke Matsumoto, Akiko Makino, Keizo Tomonaga .  Long-term expression of miRNA for RNA interference using a novel vector system based on a negative-strand RNA virus .  SCIENTIFIC REPORTS6   26154   2016.5Long-term expression of miRNA for RNA interference using a novel vector system based on a negative-strand RNA virusReviewed

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    RNA interference (RNAi) has emerged as a promising technique for gene therapy. However, the safe and long-term expression of small RNA molecules is a major concern for the application of RNAi therapies in vivo. Borna disease virus (BDV), a non-segmented, negative-strand RNA virus, establishes a persistent infection without obvious cytopathic effects. Unique among animal non-retroviral RNA viruses, BDV persistently establishes a long-lasting persistent infection in the nucleus. These features make BDV ideal for RNA virus vector persistently expressing small RNAs. Here, we demonstrated that the recombinant BDV (rBDV) containing the miR-155 precursor, rBDV-miR-155, persistently expressed miR-155 and efficiently silenced its target gene. The stem region of the miR-155 precursor in rBDV-miR-155 was replaceable by any miRNA sequences of interest and that such rBDVs efficiently silence the expression of target genes. Collectively, BDV vector would be a novel RNA virus vector enabling the long-term expression of miRNAs for RNAi therapies.

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  • Yusuke Matsumoto, Keisuke Ohta, Natsuko Yumine, Hideo Goto, Machiko Nishio .  Identification of two essential aspartates for polymerase activity in parainfluenza virus L protein by a minireplicon system expressing secretory luciferase .  MICROBIOLOGY AND IMMUNOLOGY59 ( 11 ) 676 - 683   2015.11Identification of two essential aspartates for polymerase activity in parainfluenza virus L protein by a minireplicon system expressing secretory luciferaseReviewed

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    Gene expression of nonsegmented negative-strand RNA viruses (nsNSVs) such as parainfluenza viruses requires the RNA synthesis activity of their polymerase L protein; however, the detailed mechanism of this process is poorly understood. In this study, a parainfluenza minireplicon assay expressing secretory Gaussia luciferase (Gluc) was established to analyze large protein (L) activity. Measurement of Gluc expression in the culture medium of cells transfected with the minigenome and viral polymerase components enabled quick and concise calculation of L activity. By comparing the amino acid sequences in conserved region III (CRIII), a putative polymerase-active domain of the L protein, two strictly conserved aspartates were identified in all families of nsNSV. A series of L mutants from human parainfluenza virus type 2 and parainfluenza virus type 5 showed that these aspartates are necessary for reporter gene expression. It was also confirmed that these aspartates are important for the production of viral mRNA and antigenome cRNA, but not for a polymerase-complex formation. These findings suggest that these two aspartates are key players in the nucleotidyl transfer reaction using two metal ions.

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  • Shohei Kojima, Tomoyuki Honda, Yusuke Matsumoto, Keizo Tomonaga .  Heat stress is a potent stimulus for enhancing rescue efficiency of recombinant Borna disease virus .  MICROBIOLOGY AND IMMUNOLOGY58 ( 11 ) 636 - 642   2014.11Heat stress is a potent stimulus for enhancing rescue efficiency of recombinant Borna disease virusReviewed

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    Recently developed vector systems based on Borna disease virus (BDV) hold promise as platforms for efficient and stable gene delivery to the central nervous system (CNS). However, because it currently takes several weeks to rescue recombinant BDV (rBDV), an improved rescue procedure would enhance the utility of this system. Heat stress reportedly enhances the rescue efficiency of other recombinant viruses. Here, heat stress was demonstrated to increase the amount of BDV genome in persistently BDV-infected cells without obvious cytotoxicity. Further analyses suggested that the effect of heat stress on BDV infection is not caused by an increase in the activity of BDV polymerase. More cells in which BDV replication occurs were obtained in the initial phase of rBDV rescue by using heat stress than when it was not used. Thus, heat stress is a useful improvement on the published rescue procedure for rBDV. The present findings may accelerate the practical use of BDV vector systems in basic science and the clinic and thus enable broader adoption of this viral vector, which is uniquely suited for gene delivery to the CNS.

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  • Kan Fujino, Masayuki Horie, Tomoyuki Honda, Shoko Nakamura, Yusuke Matsumoto, Ivo M. B. Francischetti, Keizo Tomonaga .  Evolutionarily Conserved Interaction between the Phosphoproteins and X Proteins of Bornaviruses from Different Vertebrate Species .  PLOS ONE7 ( 12 ) e51161   2012.12Evolutionarily Conserved Interaction between the Phosphoproteins and X Proteins of Bornaviruses from Different Vertebrate SpeciesReviewed

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    Bornavirus, a non-segmented, negative-strand RNA viruses, is currently classified into several genetically distinct genotypes, such as Borna disease virus (BDV) and avian bornaviruses (ABVs). Recent studies revealed that bornavirus genotypes show unique sequence variability in the putative 5' untranslated region (5' UTR) of X/P mRNA, a bicistronic mRNA for the X protein and phosphoprotein (P). In this study, to understand the evolutionary relationship among the bornavirus genotypes, we investigated the functional interaction between the X and P proteins of four bornavirus genotypes, BDV, ABV genotype 4 and 5 and reptile bornavirus (RBV), the putative 5' UTRs of which exhibit variation in the length. Immunofluorescence and immunoprecipitation analyses using mammalian and avian cell lines revealed that the X proteins of bornaviruses conserve the ability to facilitate the export of P from the nucleus to the cytoplasm via interaction with P. Furthermore, we showed that inter-genotypic interactions may occur between X and P among the genotypes, except for X of RBV. In addition, a BDV minireplicon assay demonstrated that the X and P proteins of ABVs, but not RBV, can affect the polymerase activity of BDV. This study demonstrates that bornaviruses may have conserved the fundamental function of a regulatory protein during their evolution, whereas RBV has evolved distinctly from the other bornavirus genotypes.

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  • Shoko Nakamura, Masayuki Horie, Kan Fujino, Yusuke Matsumoto, Tomoyuki Honda, Keizo Tomonaga .  Generation of Human Bronchial Epithelial Cell Lines Expressing Inactive Mutants of GALNT3 .  JOURNAL OF VETERINARY MEDICAL SCIENCE74 ( 11 ) 1493 - 1496   2012.11Generation of Human Bronchial Epithelial Cell Lines Expressing Inactive Mutants of GALNT3Reviewed

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    As a tool to understand the role of mucins in the infection of respiratory viruses, we established cell lines stably expressing inactive mutants of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), which initiates O-glycosylation of mucins. We introduced single amino acid mutation into the regions essential for the enzyme activity of GALNT3 using the expression plasmid of human GALNT3 and transfected the mutant constructs into a human bronchial epithelial cell line, BEAS-2B. We showed that although the mutants of GALNT3 exhibit an authentic localization at the Golgi apparatus, the glycosylation pattern of the expressing cell lines appeared to be different from that of the cells expressing wild-type GALNT3. These results suggested that the established cell lines express inactive forms of GALNT3 and might be useful in investigation of the significance of O-glycosylation of mucins in respiratory virus infections.

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  • Yusuke Matsumoto, Yohei Hayashi, Hiroko Omori, Tomoyuki Honda, Takuji Daito, Masayuki Horie, Kazuyoshi Ikuta, Kan Fujino, Shoko Nakamura, Urs Schneider, Geoffrey Chase, Tamotsu Yoshimori, Martin Schwemmle, Keizo Tomonaga .  Bornavirus Closely Associates and Segregates with Host Chromosomes to Ensure Persistent Intranuclear Infection .  CELL HOST & MICROBE11 ( 5 ) 492 - 503   2012.5Bornavirus Closely Associates and Segregates with Host Chromosomes to Ensure Persistent Intranuclear InfectionReviewed

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    Bornaviruses are nonsegmented negative-strand RNA viruses that establish a persistent infection in the nucleus and occasionally integrate a DNA genome copy into the host chromosomal DNA. However, how these viruses achieve intranuclear infection remains unclear. We show that Borna disease virus (BDV), a mammalian bornavirus, closely associates with the cellular chromosome to ensure intranuclear infection. BDV generates viral factories within the nucleus using host chromatin as a scaffold. In addition, the viral ribonucleoprotein (RNP) interacts directly with the host chromosome throughout the cell cycle, using core histones as a docking platform. HMGB1, a host chromatin-remodeling DNA architectural protein, is required to stabilize RNP on chromosomes and for efficient BDV RNA transcription in the nucleus. During metaphase, the association of RNP with mitotic chromosomes allows the viral RNA to segregate into daughter cells and ensure persistent infection. Thus, bornaviruses likely evolved a chromosome-dependent life cycle to achieve stable intranuclear infection.

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  • Takuji Daito, Kan Fujino, Tomoyuki Honda, Yusuke Matsumoto, Yohei Watanabe, Keizo Tomonaga .  A Novel Borna Disease Virus Vector System That Stably Expresses Foreign Proteins from an Intercistronic Noncoding Region .  JOURNAL OF VIROLOGY85 ( 23 ) 12170 - 12178   2011.12A Novel Borna Disease Virus Vector System That Stably Expresses Foreign Proteins from an Intercistronic Noncoding RegionReviewed

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    Borna disease virus (BDV), a nonsegmented, negative- strand RNA virus, infects a wide variety of mammalian species and readily establishes a long- lasting, persistent infection in brain cells. Therefore, this virus could be a promising candidate as a novel RNA virus vector enabling stable gene expression in the central nervous system (CNS). Previous studies demonstrated that the 5&apos; untranslated region of the genome is the only site for insertion and expression of a foreign gene. In this study, we established a novel BDV vector in which an additional transcription cassette has been inserted into an intercistronic noncoding region between the viral phosphoprotein (P) and matrix (M) genes. The recombinant BDV (rBDV) carrying green fluorescent protein (GFP) between the P and M genes, rBDV P/ M- GFP, expressed GFP efficiently in cultured cells and rodent brains for a long period of time without attenuation. Furthermore, we generated a nonpropagating rBDV, Delta GLLP/M, which lacks the envelope glycoprotein (G) and a splicing intron within the polymerase gene (L), by the transcomplementation system with either transient or stable expression of the G gene. Interestingly, rBDV Delta GLLP/M established a persistent infection in cultured cells with stable expression of GFP in the absence of the expression of G. Using persistently infected rBDV Delta GLLP/M-infected cells, we determined the amino acid region in the cytoplasmic tail (CT) of BDV G important for the release of infectious rBDV particles and also demonstrated that the CT region may be critical for the generation of pseudotyped rBDV having vesicular stomatitis virus G protein. Our results revealed that the newly established BDV vector constitutes an alternative tool not only for stable expression of foreign genes in the CNS but also for understanding the mechanism of the release of enveloped virions.

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  • Tomoyuki Honda, Kan Fujino, Daisuke Okuzaki, Naohiro Ohtaki, Yusuke Matsumoto, Masayuki Horie, Takuji Daito, Masayuki Itoh, Keizo Tomonaga .  Upregulation of Insulin-Like Growth Factor Binding Protein 3 in Astrocytes of Transgenic Mice That Express Borna Disease Virus Phosphoprotein .  JOURNAL OF VIROLOGY85 ( 9 ) 4567 - 4571   2011.5Upregulation of Insulin-Like Growth Factor Binding Protein 3 in Astrocytes of Transgenic Mice That Express Borna Disease Virus PhosphoproteinReviewed

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:AMER SOC MICROBIOLOGY  

    In a previous study, we demonstrated that transgenic mice that express Borna disease virus (BDV) phosphoprotein (P) in astrocytes show striking neurobehavioral abnormalities resembling those in BDV-infected animals. To understand the molecular disturbances induced by the expression of P in astrocytes, we performed microarray analysis with cultured astroglial cells transiently expressing P. We showed that expression of insulin-like growth factor binding protein 3 mRNA increases not only in P-expressing cultured cells but also in astrocytes from the cerebella of P transgenic mice (P-Tg). Furthermore, we demonstrated that insulin-like growth factor signaling is disturbed in the P-Tg cerebellum, a factor that might be involved in the increased vulnerability of Purkinje cell neurons in the brain.

    DOI: 10.1128/JVI.01817-10

    Web of Science

    PubMed

  • 松本祐介, 藤野寛, 朝長啓造 .  ボルナウイルスの基本性状 .  臨床獣医.29:12-16. 2011   2011ボルナウイルスの基本性状Reviewed

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    Language:Japanese  

  • Yusuke Matsumoto, Tomoyuki Miura, Hirofumi Akari, Yoshitaka Goto, Takeshi Haga .  Peripheral Blood CD4 and CD8 Double-Positive T Cells of Rhesus Macaques Become Vulnerable to Simian Immunodeficiency Virus by In Vitro Stimulation Due to the Induction of CCR5 .  JOURNAL OF VETERINARY MEDICAL SCIENCE72 ( 8 ) 1057 - 1061   2010.8Peripheral Blood CD4 and CD8 Double-Positive T Cells of Rhesus Macaques Become Vulnerable to Simian Immunodeficiency Virus by In Vitro Stimulation Due to the Induction of CCR5Reviewed

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:JAPAN SOC VET SCI  

    In vivo Simian Immunodeficiency Virus (SIV) challenge of macaques demonstrated the earlier disappearance of CD4 and CD8 double-positive (DP) T cells than CD4 single-positive T cells, although its mechanism remains unclear. Here we found that peripheral DP T cells were readily induced to express CCR5, a secondary receptor for SIV, by in vitro stimulation with either concanavalin A or anti-CD3/CD28 monoclonal antibodies. Activated DP T cells were more vulnerable to SIV infection, indicating that the ability of DP T cells to readily express CCR5 after activation may hasten DP T cell death by SIV infection in vivo.

    Web of Science

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MISC

  • A novel RNA virus vector system for small RNA deliery based on Borna disease virus

    T. Honda, Y. Yamamoto, Y. Matsumoto, A. Makino, K. Tomonaga

    HUMAN GENE THERAPY   26 ( 10 )   A102 - A102   2015.10

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    Language:English   Publishing type:Research paper, summary (international conference)   Publisher:MARY ANN LIEBERT, INC  

    Web of Science

  • 内在性ボルナウイルスEBLN の発現によるボルナ病ウイルスの感染阻害 Reviewed

    藤野 寛, 堀江真行, 本田知之, 大東卓史, 松本祐介, 朝長啓造

    第153 回日本獣医学会学術集会. 埼玉2012 年3月27-29日   153rd   2012

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    Language:Japanese  

    J-GLOBAL

  • Intranuclear persistence of Borna disease virus shows a novel life cycle of RNA virus using host chromosome. Reviewed

    Matsumoto Y, Fujino K, Horie M, Nakamura S, Honda T, Schwemmle M, Tomonaga K

    The 10th International Student Seminar. Kyoto, 5-8 March 2012   2012

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  • Characterization of Borna disease virus-induced RNA speckles in the nucleus. Reviewed

    Honda T, Matsumoto Y, Makino A, Fujino K, Sofiiku K, Nakamura S, Tomonaga K

    The 11th Awaji International Forum on Infection and Immunity. 11-14 September 2012   2012

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  • ボルナウイルス 感染細胞における核内ウイルスRNP の制御機構の解明 Reviewed

    本田知之, 松本祐介, 牧野晶子, 藤野 寛, 惣福 梢, 中村祥子, 朝長啓造

    第35回日本分子生物学会年会. 福岡 2012 年12月11-14日   35th   2012

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    J-GLOBAL

  • ボルナ病ウイル ス核内構造物の存在意義の解明 Reviewed

    本田知之, 松本祐介, 牧野晶子, 藤野 寛, 惣福 梢, 中村祥子, 朝長啓造

    第60回日本ウイルス学会学術集会. 大阪 2012 年 11月13-15日   60th   2012

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    Language:Japanese  

    J-GLOBAL

  • Chromatin-dependent transcriptional regulation of Borna disease virus. Reviewed

    Matsumoto Y, Horie M, Daito T, Fujino K, Omori H, Tomonaga K

    The 18th East-Asia Joint Symposium on Biomedical Research. Shanghai China. 7-9 December 2011.   2011

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  • 鳥ボルナウイルス感染状況の調査

    堀江真行, 大東卓史, 藤野寛, 松本祐介, 朝長啓造

    日本獣医学会学術集会講演要旨集   150th   2010

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  • わが国における鳥ボルナウイルスの持続感染

    堀江真行, 上田謙吾, 上田亜希子, 大東卓史, 藤野寛, 松本祐介, 朝長啓造

    日本ウイルス学会学術集会プログラム・抄録集   58th   2010

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  • ボルナウイルスを用いた新規RNAウイルスベクターの開発

    大東卓史, 堀江真行, 藤野寛, 松本祐介, 本田知之, 朝長啓造

    日本RNA学会年会要旨集   12th   2010

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  • ボルナ病ウイルスのインテグレーションに関する研究

    堀江真行, 本田知之, 大東卓史, 藤野寛, 松本祐介, 朝長啓造

    日本ウイルス学会学術集会プログラム・抄録集   58th   2010

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  • ボルナ病ウイルスの核内寄生メカニズムの解明

    松本祐介, 堀江真行, 大東卓史, 藤野寛, 朝長啓造

    日本ウイルス学会学術集会プログラム・抄録集   58th   2010

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  • ボルナ病ウイルス膜糖蛋白質と粒子形成機構の解析

    大東卓史, 堀江真行, 藤野寛, 松本祐介, 朝長啓造

    日本ウイルス学会学術集会プログラム・抄録集   58th   2010

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  • マトリックス及びエンベロープ遺伝子欠損型ボルナウイルスベクターの構築

    藤野寛, 大東卓史, 堀江真行, 松本祐介, 朝長啓造

    日本ウイルス学会学術集会プログラム・抄録集   58th   2010

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  • 膜遺伝子欠損型ボルナ病ウイルスベクターの開発

    大東卓史, 松本祐介, 藤野寛, 堀江真行, 本田知之, 朝長啓造

    日本獣医学会学術集会講演要旨集   149th   2010

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  • 鳥ボルナウイルスXおよびP遺伝子の相互作用の解析

    藤野寛, 堀江真行, 上田謙吾, 本田知之, 大東卓史, 松本祐介, 朝長啓造

    日本獣医学会学術集会講演要旨集   148th   2009

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  • ボルナウイルス属ウイルスのXおよびP蛋白質の相互作用の解析

    藤野寛, 堀江真行, 本田知之, 大東卓史, 松本祐介, 生田和良, 朝長啓造

    日本ウイルス学会学術集会プログラム・抄録集   57th   2009

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  • ボルナ病ウイルスのクロマチン結合に関与するウイルス因子の同定

    堀江真行, 松本祐介, 本田知之, 大東卓史, 藤野寛, 生田和良, 朝長啓造

    日本ウイルス学会学術集会プログラム・抄録集   57th   2009

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  • 毛引き症のオオハナインコにおける鳥ボルナウイルス遺伝子の検出

    堀江真行, 上田謙吾, 藤野寛, 松本祐介, 大東卓史, 朝長啓造

    日本獣医学会学術集会講演要旨集   148th   2009

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Awards

  • Sugiura Award

    2023.9   Japanese Society for Virology   Elucidation of the molecular basis of negative-strand RNA virus genome replication

Research Projects

  • 牛パラミクソウイルスベクターワクチン改良・開発基盤の構築

    2023.8 - 2024.3

    令和5年度 鹿児島大学地域活性化研究支援事業 

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    Authorship:Principal investigator 

  • 全てのパラミクソウイルスに対応する弱毒ワクチン開発機構と新規ワクチンベクターへの応用

    2023.4 - 2025.3

    AMED  新興・再興感染症に対する革新的医薬品等開発推進研究事業 

    松本祐介, 加藤文博, 一戸猛志

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  • エボラウイルスゲノムの塩基数はなぜ6の倍数でなければならないのか

    2023.4 - 2025.3

    (公財)加藤記念バイオサイエンス振興財団  加藤記念研究助成 

    松本祐介

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  • 牛パラミクソウイルス感染症の革新的ワクチン改良技術の構築

    2023.4 - 2024.3

    (一財)旗影会 2023年度研究助成 

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  • 全てのパラミクソウイルスに対応する弱毒ワクチン開発機構と新規ワクチンベクターへの応用

    2023.4 - 2024.3

    東京大学医科学研究所国際共同利用・共同研究拠点 2023年度共同研究 

    松本祐介, 一戸猛志

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  • RNAウイルスのゲノム塩基数が複製におよぼす影響の解析

    2023.4 - 2024.3

    京都大学医生物学研究所  ウイルス・幹細胞システム医生物学共同研究拠点 共同研究 

    松本祐介, 朝長啓造

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  • Elucidation of the significance of the "rule of six" for Ebola virus replication

    2022.10 - 2024.3

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  • 新型コロナウイルス感染予防ワクチン作用機序の解明

    2021.4 - 2022.3

    公益財団法人東京生化学研究会  2020年度研究奨励金(I) 

    松本祐介

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  • モデルウイルスを用いたクリミア・コンゴ出血熱ウイルスの病原性解析

    2020.10 - 2021.9

    武田科学振興財団  医学系研究継続助成 

    松本祐介

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  • The reason why paramyxovirus genome should be a multiple of six.

    Grant number:20K16266  2020.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Early-Career Scientists  Grant-in-Aid for Early-Career Scientists

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    Authorship:Principal investigator 

    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

  • モデルウイルスを用いたクリミア・コンゴ出血熱ウイルスの病原性解析

    2018.4 - 2019.3

    武田科学振興財団  医学系研究助成 

    松本 祐介

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    Authorship:Principal investigator  Grant type:Competitive

  • Analysis of Hazara virus growth machanism as a surrogate medel for Crimean-Congo hemarrhagic fever virus

    Grant number:20K07528  2017.4 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Nishio Machiko

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    Authorship:Principal investigator  Grant type:Competitive

    Hazara virus(HAZV) is closely related to Crimean-Congo hemorrhagic fever virus(CCHFV). However, it is non-pathogenic to humans, making it a suitable model to study CCHFV. We first generated monoclonal antibodies against HAZV. In this study, we found that HAZV infection caused apoptosis, and N protein prevented it. We also established an infection model system in vivo, using embryonate chicken eggs. Furthermore, we made a minigenome system for HAZV to study the contributions of promoter elemetens within the genomic ends for viral RNA synthesis.

  • Mechanism of viral cytotoxicity regulated by the leader promoter in paramyxovirus genome

    Grant number:16K19143  2016.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    Matsumoto Yusuke

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    To study the mechanism of human parainfluenza virus type 2 growth, I focused on viral transcription and replication. I found that genomic leader promoter regulates the balance of transcription and replication, thereby affects viral cytotoxicity in the infected cells. Moreover, I revealed that an amino acid in the RNA binding domain of nucleoprotein, which encapsidates viral genome, is involved in the recognition of viral replication promoters.

  • Study on a role of receptor destruction in homologous viral interference by Sendai virus using persistently infected cells.

    Grant number:15K08500  2015.4 - 2016.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    GOTO Hideo

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    Authorship:Principal investigator  Grant type:Competitive

    To develop a novel strategy to control virus infection, we studied on a mechanism of viral interference. Interference of Sendai virus infection was established at an early stage of infection such as attachment or penetration. Additionally, viral interference was dependent on the HN protein expression that releases sialic acids (a receptor molecule for Sendai virus) by the sialidase activity and decrease of sialic acid molecules on the cell surface. Rabies virus also showed viral interference at an early stage of infection in spite of lack of a receptor destruction factor similar to that of the HN protein.
    From these results, we concluded that a receptor destruction by virus infection is one of a major factor for viral interference.

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