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A innate immune defense system against Mycobacterium avium pulmonary disease based on intracellular pH homeostasis

Research Project

Project/Area Number 20K17205
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53030:Respiratory medicine-related
Research InstitutionNational Institute of Infectious Diseases

Principal Investigator

Yoshida Mitsunori  国立感染症研究所, ハンセン病研究センター 感染制御部, 主任研究官 (70772630)

Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords非結核性抗酸菌症 / 発症機序 / 肺MAC症 / CHP2 / 遺伝子発現解析 / 細胞内pH / 自然免疫
Outline of Research at the Start

肺MAC症は患者数の増加が著しい慢性呼吸器疾患であるが、発症機序は解明されておらず、有効な治療法も確立されていない。申請者らのこれまでの解析から、肺組織において細胞内pH制御に関わるCHP2遺伝子の発現量の低下が肺MAC症の発症に関連していることが示された。本研究では、「CHP2 遺伝子の発現量が低下したことで、MAC感染時における宿主細胞のpH制御に基づいた炎症応答および殺菌機構が阻害される」という仮説を、発現解析や分子生物学的解析により検証する。MACに対する感染・発症防御にとって重要な分子機構を明らかにできれば、新規の治療薬や診断法の開発にも展開でき、国民の公衆衛生に大きく貢献できる。

Outline of Final Research Achievements

The aim of this study was to test the hypothesis that reduced CHP2 gene expression inhibits the inflammatory response and bactericidal mechanisms based on intracellular pH regulation during pulmonary MAC infection. In human alveolar epithelial cell lines, CHP2 knockdown tended to increase the infection efficiency of MAC strains, but no significant difference in intracellular bacterial content after infection was observed. To test the possibility that CHP2 is involved in the bactericidal mechanism of MAC in vivo, CHP2 knockout mice were generated. However, planned tests could not be carried out because the reproductive efficiency of the homozygous individuals was reduced.

Academic Significance and Societal Importance of the Research Achievements

近年の先進国を中心とした肺MAC症患者の急増から、肺MAC症の発症機序の解明と新たな診断方法および治療方法の開発は、今後さらに重要性が増すことが予想される研究分野である。本研究から、CHP2遺伝子がヒトの肺胞上皮細胞におけるMAC菌株の感染効率に関与している可能性が示唆された。将来的に、CHP2遺伝子が関与する肺MAC症の発症機序を証明することができれば、得られた知見に基づいた創薬研究、診断方法や治療法開発などへの展開も十分に期待できる。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (14 results)

All 2024 2022 2021 2020

All Journal Article (10 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 10 results,  Open Access: 9 results) Patent(Industrial Property Rights) (4 results) (of which Overseas: 1 results)

  • [Journal Article] Transcriptome analysis of long non-coding RNAs in Mycobacterium avium complex?infected macrophages2024

    • Author(s)
      Yoshida Mitsunori、Kwon Andrew Taejun、Qin Xian-Yang、Nishimura Hajime、Maeda Shiori、Miyamoto Yuji、Yoshida Yasuhiro、Hoshino Yoshihiko、Suzuki Harukazu
    • Journal Title

      Frontiers in Immunology

      Volume: 15 Pages: 1374437-1374437

    • DOI

      10.3389/fimmu.2024.1374437

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Complete Chromosomal Genome Sequence of Mycobacterium sp. Strain IWGMT90018-18076.2022

    • Author(s)
      Fukano H, Yoshida M, Kazumi Y, Sakagami N, Ato M, Mitarai S, Hoshino Y
    • Journal Title

      Microbiol Resour Announc.

      Volume: 11 Issue: 6

    • DOI

      10.1128/mra.00078-22

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Therapeutic efficacy of rifalazil (KRM-1648) in a M. ulcerans-induced Buruli ulcer mouse model2022

    • Author(s)
      Fukano H, Nakanaga K, Goto M, Yoshida M, Ishii N, Hoshino Y.
    • Journal Title

      PLoS One

      Volume: 17 Issue: 10 Pages: e0274742-e0274742

    • DOI

      10.1371/journal.pone.0274742

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Complete Genome Sequence of Mycobacterium fortuitum subsp. fortuitum JCM 6387, a Type Strain of Human-Pathogenic Mycobacteria Showing Inducible Macrolide Resistance2022

    • Author(s)
      Yoshida M, Fukano H, Suzuki M, Hoshino Y
    • Journal Title

      Microbiology Resource Announcements

      Volume: 11 Issue: 4

    • DOI

      10.1128/mra.00060-22

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular Epidemiological Characteristics of Mycobacterium abscessus Complex Derived from Non-Cystic Fibrosis Patients in Japan and Taiwan2022

    • Author(s)
      Yoshida M, Chien JY, Morimoto K, Kinjo T, Aono A, Murase Y, Fujiwara K, Morishige Y, Nagano H, Jou R, Hasegawa N, Ato M, Hoshino Y, Hsueh PR, Mitarai S
    • Journal Title

      Microbiology Spectrum

      Volume: Ahead of Print Issue: 3

    • DOI

      10.1128/spectrum.00571-22

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A novel DNA chromatography method to discriminate Mycobacterium abscessus subspecies and macrolide susceptibility2021

    • Author(s)
      Yoshida Mitsunori、Sano Sotaro、Chien Jung-Yien、Fukano Hanako、Suzuki Masato、Asakura Takanori、Morimoto Kozo、Murase Yoshiro、Miyamoto Shigehiko、Kurashima Atsuyuki、Hasegawa Naoki、Hsueh Po-Ren、Mitarai Satoshi、Ato Manabu、Hoshino Yoshihiko
    • Journal Title

      EBioMedicine

      Volume: 64 Pages: 103187-103187

    • DOI

      10.1016/j.ebiom.2020.103187

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease2021

    • Author(s)
      Ho Namkoong, Yosuke Omae, Takanori Asakura, Makoto Ishii, Shoji Suzuki, Kozo Morimoto, Yosuke Kawai, Katsura Emoto, Andrew J. Oler, Eva P. Szymanski, Mitsunori Yoshida, et al.
    • Journal Title

      European Respiratory Journal

      Volume: 57 Issue: 2 Pages: 1902269-1902269

    • DOI

      10.1183/13993003.02269-2019

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Complete Genome Sequence of Mycobacterium heckeshornense JCM 15655T, Closely Related to a Pathogenic Nontuberculous Mycobacterial Species, Mycobacterium xenopi2021

    • Author(s)
      Yoshida Mitsunori、Fukano Hanako、Asakura Takanori、Suzuki Masato、Hoshino Yoshihiko
    • Journal Title

      Microbiology Resource Announcements

      Volume: 10 Issue: 10 Pages: 103187-103187

    • DOI

      10.1128/mra.00020-21

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Human pathogenic Mycobacterium kansasii (former subtype I) with zoonotic potential isolated from a diseased indoor pet cat, Japan2021

    • Author(s)
      Fukano Hanako、Terazono Tsukasa、Hirabayashi Aki、Yoshida Mitsunori、Suzuki Masato、Wada Shinpei、Ishii Norihisa、Hoshino Yoshihiko
    • Journal Title

      Emerging Microbes & Infections

      Volume: 10 Issue: 1 Pages: 220-222

    • DOI

      10.1080/22221751.2021.1878935

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Point mutation in the stop codon of MAV_RS14660 increases the growth rate of Mycobacterium avium subspecies hominissuis2021

    • Author(s)
      Kawakita Tomomi、Mukai Tetsu、Yoshida Mitsunori、Yamada Hiroyuki、Nakayama Masaaki、Miyamoto Yuji、Suzuki Masato、Nakata Noboru、Takii Takemasa、Ryo Akihide、Ohara Naoya、Ato Manabu
    • Journal Title

      Microbiology

      Volume: 167 Issue: 2 Pages: 1-14

    • DOI

      10.1099/mic.0.001007

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Patent(Industrial Property Rights)] 肺非結核性抗酸菌症の疾患感受性の判定方法2020

    • Inventor(s)
      星野仁彦、吉田光範、長谷川直樹、徳永勝士
    • Industrial Property Rights Holder
      星野仁彦、吉田光範、長谷川直樹、徳永勝士
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-123054
    • Filing Date
      2020
    • Related Report
      2020 Research-status Report
  • [Patent(Industrial Property Rights)] 抗酸菌のerm(41)遺伝子の一塩基変異を判別する方法、その方法に用いるプローブ及びプライマーセット2020

    • Inventor(s)
      星野仁彦、吉田光範、佐野創太郎、宮本重彦
    • Industrial Property Rights Holder
      星野仁彦、吉田光範、佐野創太郎、宮本重彦
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-066277
    • Filing Date
      2020
    • Related Report
      2020 Research-status Report
  • [Patent(Industrial Property Rights)] マイコバクテロイデス・アブセサスを検出するためのプライマーセット、キット及び方法2020

    • Inventor(s)
      星野仁彦、吉田光範、佐野創太郎、宮本重彦
    • Industrial Property Rights Holder
      星野仁彦、吉田光範、佐野創太郎、宮本重彦
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-066306
    • Filing Date
      2020
    • Related Report
      2020 Research-status Report
  • [Patent(Industrial Property Rights)] マイコバクテロイデス・アブセッサス・コンプレックスに属する抗酸菌のerm(41)遺伝子の一塩基変異を判別する方法、その方法に用いるプライマーセット及びプローブ2020

    • Inventor(s)
      星野仁彦、吉田光範、佐野創太郎、宮本重彦
    • Industrial Property Rights Holder
      星野仁彦、吉田光範、佐野創太郎、宮本重彦
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Research-status Report
    • Overseas

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Published: 2020-04-28   Modified: 2025-01-30  

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