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Mutations in viral polymerases and virulence changes associated with cultured cell adaptation of negative strand RNA viruses

Research Project

Project/Area Number 18590450
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Virology
Research InstitutionKyushu University

Principal Investigator

TAKEDA Makoto  Kyushu University, Faculty of Medicine, Associate Professor (40311401)

Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsMeasles virus / Polymerase / Virulence / Attenuation / Negative-strand RNA Virus / 細胞馴化
Research Abstract

Measles is an acute febrile infectious disease with high mortality and morbidity.Measles virus (MV), classified in the negative-stranded RNA virus, is the causative agent of the disease. Live attenuated vaccines are available for the disease, but molecular bases for the virus attenuation is poorly understood. In this study, we analyzed molecular bases for the high virulence of MV and attenuation mechanisms of MV vaccine strains, by using reverse genetics techniques, by which MV can be engineered at will by site directed mutagenesis and genetic recombination. One of focuses of this study is to elucidate roles of viral polymerases in determining MV virulence.
MV genome possesses six genes, N, P, M, F, H and L genes. Among them, P and L genes encode small and large subunits of viral polymerase, respectively. We have generated various recombinant MVs possessing chimera genomes between the virulent IC-B and attenuated Edmonston vaccine strains. Reporter protein genes (enhanced green fluorescent protein or luciferase) were inserted into the recombinant virus genomes for efficient monitoring of virus growth or quantification of viral gene expression. A variety of cell lines, including epithelial and immune cell lines, were infected with recombinant MVs possessing various chimera genomes. Signaling lymphocyte activation molecule (SLAM) is a receptor for MV. We have also established a small animal model of measles, by generating SLAM-knockin mice, in which mouse SLAM gene was replaced with the human SLAM gene. Recombinant MVs were also inoculated into SLAM-knockin mice to analyzed virus virulence in vivo.
Our data indicated that the P and L genes are major determinants of MV virulence, and both the P and L genes of the Edmonston vaccine strains greatly contribute to its attenuation phenotype. These data provide useful information to develop vaccines against negative-strand RNA viruses.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (58 results)

All 2008 2007 2006 Other

All Journal Article (35 results) (of which Peer Reviewed: 7 results) Presentation (20 results) Remarks (2 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Measles virus infects both polarized epithelial and immune cells using distinctive receptor-binding sites on its hemagglutinin2008

    • Author(s)
      Tahara, et. al.
    • Journal Title

      Journal of Virology 82(印刷中)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Homogeneous sugar modification improves crystallization of measles virus hemagglutinin2008

    • Author(s)
      Hashiguchi, et. al.
    • Journal Title

      Journal of Virological Methods (印刷中)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Crystal structure of measles virus hemagglutinin provides insight into effective vaccines2007

    • Author(s)
      Hashiguchi, T., et. al.
    • Journal Title

      Proc Natl Acad Sci U S A 104

      Pages: 19535-40

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] A Human Lung Carcinoma Cell Line Supports Efficient Measles Virus Growth and Syncytium Formation via SLAM- and CD46-Independent Mechanism2007

    • Author(s)
      Takeda, M., et. al.
    • Journal Title

      J Virol 81

      Pages: 112091-12096

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Altered interaction of the matrix protein with the cytoplasmic tail of hemagglutinin modulates measles virus growth by affecting virus assembly and cell-cell fusion2007

    • Author(s)
      Tahara, M., et. al.
    • Journal Title

      J Virol 81

      Pages: 6827-36

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Multiple amino acid substitutions in hemagglutinin are necessary for wild-type measles virus to acquire the ability to use receptor CD46 efficiently2007

    • Author(s)
      Tahara, M., et. al.
    • Journal Title

      J Virol 81

      Pages: 2564-72

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Measles virus infection of SLAM (CD150) knockin mice reproduces tropism and immunosuppression in human infection2007

    • Author(s)
      Ohno, S., et. al.
    • Journal Title

      J Virol 81

      Pages: 1650-9

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] 麻疹ウイルス遺伝子操作系の確立と、複製および病原性発現の分子基盤の解析2007

    • Author(s)
      竹田 誠
    • Journal Title

      ウイルス 57

      Pages: 83-90

    • NAID

      10019531002

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] 麻疹ウイルスの細胞侵入と受容体2007

    • Author(s)
      柳雄 介、竹田 誠、大野 真治
    • Journal Title

      蛋白質核酸酵素 52

      Pages: 1088-1094

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] ウイルスの細胞侵入と受容体2007

    • Author(s)
      柳雄 介、竹田 誠
    • Journal Title

      学術月報 60

      Pages: 199-202

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Crystal structure of measles virus hemagglutinin provides insight into effective vaccines2007

    • Author(s)
      Hashiguchi, et. al.
    • Journal Title

      Proc Natl Acad Sci USA. 104

      Pages: 19535-40

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A Human Lung Carcinoma Cell Line Supports Efficient Measles Virus Growth and Syncytium Formation via SLAM-and CD46-Independent Mechanism2007

    • Author(s)
      Takeda, et. al.
    • Journal Title

      Journal of Virology 81

      Pages: 12091-6

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Altered interaction of the matrix protein with the cytoplasmic tail of hemagglutinin modulates measles virus growth by affecting virus assembly and cell-cell fusion2007

    • Author(s)
      Tahara, et. al.
    • Journal Title

      Journal of Virology 81

      Pages: 6827-36

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Multiple amino acid substitutions in hemagglutinin are necessary for wild-type measles virus to acquire the ability to use receptor CD46 efficiently2007

    • Author(s)
      Tahara, et. al.
    • Journal Title

      Journal of Virology 104

      Pages: 2564-72

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Measles virus infection of SLAM(CD150)knockin mice reproduces tropism and immunosuppression in human infection2007

    • Author(s)
      Ohno, et. al.
    • Journal Title

      Journal of Virology 104

      Pages: 1650-9

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Multiple Amino Acid Substitutions in Hemagglutinin Are Necessary for Wild-type Measles Virus to Acquire the Ability to Use Receptor CD46 Efficiently.2007

    • Author(s)
      Tahara et al.
    • Journal Title

      Journal of Virology 81・6

      Pages: 2564-2572

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Measles virus infection of SLAM (CD150) knockin mice reproduces tropism and immunosuppression in human infection.2007

    • Author(s)
      Ohno et al.
    • Journal Title

      Journal of Virology 81・4

      Pages: 1650-1659

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Altered interaction of the matrix protein with the cytoplasmic tail of hemagglutinin modulates measles virus growth by affecting virus assembly and cell-cell fusion2007

    • Author(s)
      Tahara et al.
    • Journal Title

      Journal of Virology 81 (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Translational inhibition and increased interferon induction in cells infected with a C protein-deficient measles virus2006

    • Author(s)
      Nakatsu, Y., et. al.
    • Journal Title

      J Virol 80

      Pages: 11861-11867

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Rescue system for measles virus from cloned cDNA driven by vacciniavirus Lister vaccine strain2006

    • Author(s)
      Nakatsu, Y., et. al.
    • Journal Title

      J Virol Methods 137

      Pages: 152-155

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Generation of measles virus with a segmented RNA genome2006

    • Author(s)
      Takeda, M., et. al.
    • Journal Title

      J Virol 80

      Pages: 4242-4248

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] The recombinant wild-type measles virus containing a single N481Y substitution in its hemagglutinin cannot use a receptor CD46 as efficiently as that having the hemagglutinin of the Edmonston laboratory strain2006

    • Author(s)
      Seki, F., et. al.
    • Journal Title

      J Gen Virol 87

      Pages: 1643-1648

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Measles virus: cellular receptors, tropism and pathogenesis2006

    • Author(s)
      Yanagi, Y., et. al.
    • Journal Title

      J Gen Virol 87

      Pages: 2767-2779

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Measles virus receptors and tropism2006

    • Author(s)
      Yanagi, Y., et. al.
    • Journal Title

      Jpn J Infect Dis 59

      Pages: 1-5

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] リバースジェネティクスと麻疹ウイルス2006

    • Author(s)
      竹田 誠、柳雄 介
    • Journal Title

      福岡医学雑誌 97

      Pages: 140-145

    • NAID

      120002548744

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Rescue system for measles virus from cloned cDNA driven by vaccinia virus Lister vaccine strain2006

    • Author(s)
      Nakatsu, Y., et. al.
    • Journal Title

      J Virol Methods 137

      Pages: 152-155

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Measles virus : cellular receptors, tropism and pathogenesis2006

    • Author(s)
      Yanagi, Y., et. al.
    • Journal Title

      J Gen Virol 87

      Pages: 2767-2779

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Translational inhibition and increased interferon induction in cells infected with a C protein-deficient measles virus.2006

    • Author(s)
      Nakatsu et al.
    • Journal Title

      Journal of Virology 80・23

      Pages: 11861-11867

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Generation of measles virus having segmented RNA genome.2006

    • Author(s)
      Takeda et al.
    • Journal Title

      Journal of Virology 80・9

      Pages: 4242-4248

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Rescue system for measles virus from cloned cDNA driven by vaccinia virus Lister vaccine strain.2006

    • Author(s)
      Nakatsu et al.
    • Journal Title

      Journal of Virological Methods 137・1

      Pages: 152-155

    • Related Report
      2006 Annual Research Report
  • [Journal Article] The recombinant wild-type measles virus containing a single N481Y substitution in its hemagglutinin cannot use a receptor CD46 as efficiently as that having the hemagglutinin of the Edmonston laboratory strain.2006

    • Author(s)
      Seki et al.
    • Journal Title

      Journal of General Virology 87・6

      Pages: 1643-1648

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Measles virus receptors and tropism.2006

    • Author(s)
      Yanagi et al.
    • Journal Title

      Japanese Journal of Infectious Diseases 59・1

      Pages: 1-5

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Measles virus : cellular receptors, tropism and pathogenesis.2006

    • Author(s)
      Yanagi et al.
    • Journal Title

      Journal of General Virology 87・10

      Pages: 2767-2779

    • Related Report
      2006 Annual Research Report
  • [Journal Article] リバースジェネティクスと麻疹ウイルス2006

    • Author(s)
      竹田ら
    • Journal Title

      福岡医学雑誌 97・5

      Pages: 140-145

    • NAID

      120002548744

    • Related Report
      2006 Annual Research Report
  • [Journal Article] リバースジェネティクスを用いたパラミクソウイルス感染の解析2006

    • Author(s)
      竹田ら
    • Journal Title

      実験医学 23

      Pages: 2587-2594

    • Related Report
      2006 Annual Research Report
  • [Presentation] Mechanism of measles virus infection in SLAM-negative cells: A novel pathway to spread efficiently in human lung carcinoma cells2007

    • Author(s)
      Takeda, M., et. al.
    • Organizer
      Workshop on Replication and Cell Biology of Negative Strand RNA Viruses
    • Place of Presentation
      Evanston, Illinois, USA
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Measles virus optimizes the balance of virus assembly and cell-cell fusion to spread well in different cell types2007

    • Author(s)
      Takeda, M., et. al.
    • Organizer
      Measles virus mini-symposium
    • Place of Presentation
      Rochester, Minnesota, USA
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Application of engineered measles virus with a segmented RNA genometo vector development2007

    • Author(s)
      Takeda, M., et. al.
    • Organizer
      ASM 107th general meeting
    • Place of Presentation
      Toronto, Canada
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 肺癌細胞株を用いた麻疹ウイルスの新たな感染機構の解析2007

    • Author(s)
      竹田 誠, ら
    • Organizer
      第55回日本ウイルス学会
    • Place of Presentation
      札幌
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 麻疹ウイルスワクチン株の培養細胞馴化による弱毒化の分子基盤: ポリメラーゼとプロモーターの変異の意義について2007

    • Author(s)
      竹田 誠, ら
    • Organizer
      第44回 日本ウイルス学会九州支部総会
    • Place of Presentation
      長崎
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Mechanism of measles virus infection in SLAM-negative cells : A novel pathway to spread efficiently in human lung carcinoma cells2007

    • Author(s)
      Takeda, M., et. al.
    • Organizer
      Workshop on Replication and Cell Biology of Negative Strand RNA Viruses
    • Place of Presentation
      Evanston, Illinois
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Altered interaction of the matrix protein with the cytoplasmic tail of hemagglutini modulates measles virus growth by affecting virus assembly and cell-cell fusion.2007

    • Author(s)
      Tahara, M., et. al.
    • Organizer
      Workshop on Replication and Cell Biology of Negative Strand RNA Viruses
    • Place of Presentation
      Evanston, Illinois
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Measles virus optimizes the balance of virus assembly and cell-cell fusion to spread well in different cell types2007

    • Author(s)
      Takeda. M., et. al.
    • Organizer
      Measles virus mini-symposium.
    • Place of Presentation
      Rochester, Minnesota
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Application of engineered measles virus with a segmented RNA genome to vector development2007

    • Author(s)
      Takeda, M., Yanagi, Y
    • Organizer
      ASM 107th general meeting
    • Place of Presentation
      Toronto, Canada
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Mechanism of measles virus infection in SLAM-negative cells:A novel pathway to spread efficiently in human lung carcinoma cells2007

    • Author(s)
      Takeda, et. al.
    • Organizer
      Workshop on Replication and Cell Biology of Negative Strand RNA Viruses.
    • Place of Presentation
      米国イリノイ州エバンストン市
    • Related Report
      2007 Annual Research Report
  • [Presentation] Application of engineered measles virus with a segmented RNA genome to vector development2007

    • Author(s)
      Takeda, et. al.
    • Organizer
      ASM 107th general meeting
    • Place of Presentation
      カナダトロント市
    • Related Report
      2007 Annual Research Report
  • [Presentation] 肺癌細胞株を用いた麻疹ウイルスの新たな感染機構の解析2007

    • Author(s)
      竹田 誠, ら
    • Organizer
      第55回日本ウイルス学会
    • Place of Presentation
      札幌市
    • Related Report
      2007 Annual Research Report
  • [Presentation] 麻疹ウイルスワクチン株の培養細胞馴化による弱毒化の分子基盤:ポリメラーゼとプロモーターの変異の意義について2007

    • Author(s)
      竹田 誠, ら
    • Organizer
      第44回日本ウイルス学会九州支部総会
    • Place of Presentation
      長崎市
    • Related Report
      2007 Annual Research Report
  • [Presentation] Generation of measles virus having segmented RNA genome2006

    • Author(s)
      Takeda, M., et. al.
    • Organizer
      13th International Conference on Negative Strand Viruses
    • Place of Presentation
      Salamanca , Spain
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Mononegavirus-derived vectors having genetically engineered three RNA genome segments2006

    • Author(s)
      Takeda, M., et. al.
    • Organizer
      Keystone Symposia, Cell Biology of Virus Entry, Replication and Pathogenesis
    • Place of Presentation
      Santa Fe, New Mexico, USA
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 麻疹ウイルス遺伝子操作系の確立と複製および病原性発現の分子基盤の解析2006

    • Author(s)
      竹田 誠
    • Organizer
      第54回 日本ウイルス学会
    • Place of Presentation
      名古屋
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Generation of measles virus having segmented RNA genome2006

    • Author(s)
      Takeda, M., et. al.
    • Organizer
      13th International Conference on Negative Strand Viruses
    • Place of Presentation
      Salamanca, Spain
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Influenza virus hemagglutinin(H3) requires palmitoylation of its cytoplasmic tail for assembly : M1 proteins of two subtypes differ in their ability to support assembly2006

    • Author(s)
      Chen, B., et. al.
    • Organizer
      Keystone Symposia, Cell Biology of Virus Entry, Replication and Pathogenesis
    • Place of Presentation
      Santa Fe, New Mexico, USA
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Measles virus C protein suppresses interferon induction and modulates host antiviral responses2006

    • Author(s)
      Nakatsu, Y., et. al.
    • Organizer
      The 6th Awaji International Forum on Infection and Immunity
    • Place of Presentation
      Awaji Island, Hyogo, Japan
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Analysis of measles virus infection using human SLAM knock-in mice2006

    • Author(s)
      Ohno, S., et. al.
    • Organizer
      The 6th Awaji International Forum on Infection and Immunity
    • Place of Presentation
      Awaji Island, Hyogo, Japan
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Remarks] 「研究成果報告書概要(和文)」より

    • URL

      http://www.med.kyushu-u.ac.jp/virus/

    • Related Report
      2007 Final Research Report Summary
  • [Remarks]

    • URL

      http://www.med.kyushu-u.ac.jp/virus/

    • Related Report
      2007 Annual Research Report
  • [Patent(Industrial Property Rights)] 分節ゲノム型モノネガウイルスベクター2006

    • Inventor(s)
      竹田誠, 柳雄介
    • Industrial Property Rights Holder
      竹田誠, 柳雄介
    • Filing Date
      2006-07-13
    • Related Report
      2006 Annual Research Report

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Published: 2006-04-01   Modified: 2016-04-21  

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