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Mechanism of refractoriness via cell-to-cell communication between Aspergillus and non-tuberculous Mycobacterium

Research Project

Project/Area Number 20K08840
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54030:Infectious disease medicine-related
Research InstitutionNagasaki University

Principal Investigator

Izumikawa Koichi  長崎大学, 医歯薬学総合研究科(医学系), 教授 (20404212)

Co-Investigator(Kenkyū-buntansha) 田代 将人  長崎大学, 医歯薬学総合研究科(医学系), 講師 (20713457)
田中 健之  長崎大学, 病院(医学系), 講師 (30432967)
高園 貴弘  長崎大学, 医歯薬学総合研究科(医学系), 准教授 (30716569)
角田 俊之  福岡大学, 医学部, 准教授 (70444817)
串間 尚子  福岡大学, 医学部, 准教授 (90642497)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Keywordsアスペルギルス / 非結核性抗酸菌 / 相互作用 / 細胞間コミュニケーション
Outline of Research at the Start

我が国では呼吸器疾患の患者が多く、アスペルギルス、非結核性抗酸菌などが、単独、あるいは同時に感染することがあり、共感染した場合は単独感染時よりもさらに難治化する。共感染時の病態に各々の微生物が病原性やヒト免疫に及ぼす相互的な影響や作用は十分に解明されていない。本研究は、非結核性抗酸菌とアスペルギルスのquorum-sensingを主体とした細胞間コミュニケーションに着目し、真菌のautoinducerなどが、非結核性抗酸菌の増殖・バイオフィルム形成能、免疫担当細胞、などに与える影響、マウスにおける病原性への影響を検討する。これらの共感染時の病態解明により、抗微生物薬に依存しない新治療戦略の構築が可能となる。

Outline of Final Research Achievements

We focused on cell-to-cell communication between non-tuberculous Mycobacterium and Aspergillus and investigated the pathogenesis and mutual pathogenic effects using in vitro, lung microenvironment and mouse models. 1) We demonstrated that culture supernatants of non-tuberculous Mycobacterium enhanced the biofilm forming ability of Aspergillus. 2) We demonstrated that Aspergillus spores promoted apoptosis of alveolar epithelial cells and fibroblast proliferation in a three-dimensional human airway microenvironment model. 3) In a mouse model of chronic pulmonary aspergillosis, macrophages responded to Aspergillus mycetoma with foam cell formation.
These results provide insight into the pathogenesis of pulmonary aspergillosis and demonstrate that the existence of non-tuberculous Mycobacterium can be an aggravating factor of chronic pulmonary aspergillosis.

Academic Significance and Societal Importance of the Research Achievements

我が国では陳旧性肺結核、気管支拡張症、COPDなどの呼吸器疾患の患者が多く、これらの疾患に糸状真菌であるアスペルギルス、細菌である非結核性抗酸菌や緑膿菌などが、単独、あるいは同時に感染することがあり、共感染した場合は単独感染時よりもさらに難治化する。今回の研究の結果より、肺アスペルギルス症の病態解明、ならびに、肺局所における非結核性抗酸菌の存在が肺アスペルギルス症の増悪因子になりうることが証明された。今後の治療の開発に寄与すると思われる。

Report

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

    (31 results)

All 2023 2022 2021 2020

All Journal Article (16 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 14 results,  Open Access: 8 results) Presentation (13 results) (of which Int'l Joint Research: 1 results,  Invited: 5 results) Book (2 results)

  • [Journal Article] Pulmonary phaeohyphomycosis due to Exophiala dermatitidis in a patient with pulmonary non-tuberculous mycobacterial infection2023

    • Author(s)
      Setoguchi Daichi、Iwanaga Naoki、Ito Yuya、Ashizawa Nobuyuki、Hirayama Tatsuro、Takeda Kazuaki、Ide Shotaro、Takemoto Shinnosuke、Tashiro Masato、Hosogaya Naoki、Takazono Takahiro、Sakamoto Noriho、Obase Yasushi、Izumikawa Koichi、Yanagihara Katsunori、Mukae Hiroshi
    • Journal Title

      Journal of Infection and Chemotherapy

      Volume: 29 Issue: 6 Pages: 615-619

    • DOI

      10.1016/j.jiac.2023.03.010

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] アゾール耐性アスペルギルス2023

    • Author(s)
      田代将人、泉川公一
    • Journal Title

      臨床と微生物

      Volume: 50 Pages: 81-83

    • Related Report
      2022 Annual Research Report
  • [Journal Article] アスペルギルス症の検査2023

    • Author(s)
      田代将人、泉川公一
    • Journal Title

      SRL宝函

      Volume: 43 Pages: 46-48

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Efficacy and safety of isavuconazole against deep-seated mycoses: A phase 3, randomized, open-label study in Japan2023

    • Author(s)
      Kohno Shigeru、Izumikawa Koichi、et al.
    • Journal Title

      Journal of Infection and Chemotherapy

      Volume: 29 Issue: 2 Pages: 163

    • DOI

      10.1016/j.jiac.2022.10.010

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 研究プロトコール 肺MAC症および慢性肺アスペルギルス症に対するFDG-PETを用いた疾患活動性評価の探索的研究2022

    • Author(s)
      細萱 直希, 高園 貴弘, 井手口 怜子, 芦澤 信之, 平山 達朗, 武田 和明, 岩永 直樹, 井手 昇太郎, 田代 将人, 山本 和子, 工藤 崇, 泉川 公一, 柳原 克紀, 迎 寛
    • Journal Title

      長崎医学会雑誌

      Volume: 97 Pages: 237-246

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Association between fluid infusions and the recovery from acute kidney injury in patients administered liposomal amphotericin B: a nationwide observational study2022

    • Author(s)
      Tashiro Masato、Obata Yoko、Takazono Takahiro、Ota Yuki、Wakamura Tomotaro、Shiozawa Yui、Tsuyuki Ai、Miyazaki Taiga、Nishino Tomoya、Izumikawa Koichi
    • Journal Title

      Renal Failure

      Volume: 44 Issue: 1 Pages: 282-292

    • DOI

      10.1080/0886022x.2022.2036618

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A comparison of liposomal amphotericin B alone and in combination with flucytosine in the treatment of non-HIV Cryptococcal meningitis: A nationwide observational study.2022

    • Author(s)
      Takazono T, Hidaka Y, Morimoto S, Tashiro M, Ashizawa N, Hirayama T, Takeda K, Iwanaga N, Hosogaya N, Yamamoto K, Fushimi K, Yanagihara K, Mukae H, Izumikawa K.
    • Journal Title

      Mycoses

      Volume: 65 Issue: 9 Pages: 897-902

    • DOI

      10.1111/myc.13493

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Treatment outcome definitions in chronic pulmonary aspergillosis: a CPAnet consensus statement2022

    • Author(s)
      Van Braeckel Eva、Page Iain、Izumikawa Koichi、et al.
    • Journal Title

      European Respiratory Journal

      Volume: 59 Issue: 6 Pages: 2102950-2102950

    • DOI

      10.1183/13993003.02950-2021

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Serum cytokines usefulness for understanding the pathology in allergic bronchopulmonary aspergillosis and chronic pulmonary aspergillosis.2022

    • Author(s)
      Ito Y, Takazono T, Obase Y, Fukahori S, Ashizawa N, Hirayama T, Tashiro M, Yamamoto K, Imamura Y, Hosogaya N, Fukushima C, Morinaga Y, Yanagihara K, Izumikawa K, Mukae H.
    • Journal Title

      Journal of Fungi

      Volume: 8 Issue: 5 Pages: 436-436

    • DOI

      10.3390/jof8050436

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] COVID-19 associated pulmonary aspergillosis: a nationwide survey by the Japanese Respiratory Society2021

    • Author(s)
      Takazono Takahiro、Mukae Hiroshi、Izumikawa Koichi、Hasegawa Naoki、Yokoyama Akihito
    • Journal Title

      ERJ Open Research

      Volume: 7 Issue: 4 Pages: 1-4

    • DOI

      10.1183/23120541.00402-2021

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Effects of Aspergillus fumigatus Conidia on Apoptosis and Proliferation in an In Vitro Model of the Lung Microenvironment2021

    • Author(s)
      Kushima Hisako、Tsunoda Toshiyuki、Matsumoto Taichi、Kinoshita Yoshiaki、Izumikawa Koichi、Shirasawa Senji、Fujita Masaki、Ishii Hiroshi
    • Journal Title

      Microorganisms

      Volume: 9 Issue: 7 Pages: 1435-1435

    • DOI

      10.3390/microorganisms9071435

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical and experimental phenotype of azole-resistant Aspergillus fumigatus with a HapE splice site mutation: a case report2021

    • Author(s)
      Ito Yuya、Takazono Takahiro、Koga Satoru、Nakano Yuichiro、Ashizawa Nobuyuki、Hirayama Tatsuro、Tashiro Masato、Saijo Tomomi、Yamamoto Kazuko、Imamura Yoshifumi、Miyazaki Taiga、Yanagihara Katsunori、Izumikawa Koichi、Mukae Hiroshi
    • Journal Title

      BMC Infectious Diseases

      Volume: 21 Issue: 1 Pages: 573-573

    • DOI

      10.1186/s12879-021-06279-1

    • NAID

      120007168844

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Transition of triazole-resistant Aspergillus fumigatus isolates in a Japanese tertiary hospital and subsequent genetic analysis2021

    • Author(s)
      Takazono Takahiro、Ito Yuya、Tashiro Masato、Nakano Yuichiro、Hirayama Tatsuro、Hosogaya Naoki、Saijo Tomomi、Yamamoto Kazuko、Imamura Yoshifumi、Miyazaki Taiga、Yanagihara Katsunori、Kohno Shigeru、Mukae Hiroshi、Izumikawa Koichi
    • Journal Title

      Journal of Infection and Chemotherapy

      Volume: 27 Issue: 3 Pages: 537-539

    • DOI

      10.1016/j.jiac.2020.11.027

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Detection of invasive pulmonary aspergillosis in mice using lung perfusion single-photon emission computed tomography with [99mTc]MAA2020

    • Author(s)
      Yoshida Masataka、Tashiro Masato、Nishi Kodai、Mishima Maki、Kawano Kei、Takazono Takahiro、Saijo Tomomi、Yamamoto Kazuko、Imamura Yoshifumi、Miyazaki Taiga、Kudo Takashi、Yanagihara Katsunori、Mukae Hiroshi、Izumikawa Koichi
    • Journal Title

      Medical Mycology

      Volume: - Issue: 7 Pages: 965-972

    • DOI

      10.1093/mmy/myz131

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Galectin-3 enhances neutrophil motility and extravasation into the airways during Aspergillus fumigatus infection2020

    • Author(s)
      Snarr Brendan D.、St-Pierre Guillaume、Takazono Takahiro、Sugrue Michele、Baden Lindsey R.、Izumikawa Koichi、Mukae Hiroshi、Wingard John R.、King Irah L.、Divangahi Maziar、Satoh Masahiko S.、Yipp Bryan G.、Sato Sachiko、Sheppard Donald C.
    • Journal Title

      PLOS Pathogens

      Volume: 16 Issue: 8 Pages: 1008741-008741

    • DOI

      10.1371/journal.ppat.1008741

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Characteristics of azole-resistant Aspergillus fumigatus attached to agricultural products imported to Japan2020

    • Author(s)
      Nakano Yuichiro、Tashiro Masato、Urano Ryo、Kikuchi Minori、Ito Naoki、Moriya Eriko、Shirahige Tomoyuki、Mishima Maki、Takazono Takahiro、Miyazaki Taiga、Izumikawa Koichi
    • Journal Title

      Journal of Infection and Chemotherapy

      Volume: 26 Issue: 10 Pages: 1021-1025

    • DOI

      10.1016/j.jiac.2020.05.008

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 深在性真菌症の基礎研究-臨床への架け橋- アスペルギルス感染症に対する免疫療法2022

    • Author(s)
      古賀 哲, 高園 貴弘, 伊藤 裕也, 中田 奈々, 芦澤 信之, 武田 和明, 井手 昇太郎, 田代 将人, 泉川 公一, 柳原 克紀, 迎 寛
    • Organizer
      第66回日本医真菌学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 基礎研究からみる深在性真菌症 アスペルギローマの病態と新たな治療戦略の可能性 モデルマウス研究から見えてきたこと2022

    • Author(s)
      濱島 良介, 田代 将人, 高園 貴弘, 泉川 公一
    • Organizer
      第66回日本医真菌学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] アレルギー性気管支肺アスペルギルス症を背景に慢性肺アスペルギルス症を発症した患者のサイトカイン変化2022

    • Author(s)
      塚本 祐生, 伊藤 裕也, 高園 貴弘, 田代 将人, 山本 和子, 福島 千鶴, 尾長谷 靖, 泉川 公一, 迎 寛
    • Organizer
      第66回日本医真菌学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] アスペルギローママウスモデルにおけるA.fumigatusの二次代謝産物の病原性解析2022

    • Author(s)
      濱島 良介, 田代 将人, 中野 裕一郎, 老木 紗予子, 高園 貴弘, 萩原 大祐, 泉川 公一
    • Organizer
      第66回日本医真菌学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 新規マウスモデルを用いたアスペルギローマへのLiposomal amphotericin Bの移行性の検討2022

    • Author(s)
      濱島 良介, 田代 将人, 高園 貴弘, 松元 加奈, 森田 邦彦, 泉川 公一, 中野 裕一郎
    • Organizer
      第70回日本化学療法学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 明日の実地臨床から使える神経感染症の 検査法とその解釈 真菌による中枢神経系感染症2022

    • Author(s)
      泉川公一
    • Organizer
      第26回日本神経感染症学会総会・学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 呼吸器真菌症の発展と課題2022

    • Author(s)
      泉川公一
    • Organizer
      第66回日本医真菌学会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Emerging antifungal resistant fungi Pathophysiology, Diagnosis, and Management of Chronic Pulmonary Aspergillosis2022

    • Author(s)
      泉川公一
    • Organizer
      ISHAM 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] COVID-19の新知見と合併する感染症 ~深在性真菌症を中心に~2022

    • Author(s)
      泉川公一
    • Organizer
      第44回日本造血・免疫細胞療法学会総会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 慢性肺アスペルギルス症のよりよい理解のための臨床研究 ~病態、診断、マネジメント~2021

    • Author(s)
      泉川公一
    • Organizer
      第65回日本医真菌学会総会・学術集会/真菌症フォーラム2021
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Expertが斬る「泉川公一がアスペルギルスを斬る」2021

    • Author(s)
      泉川公一
    • Organizer
      第36回日本環境感染学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 肉芽腫を形成する呼吸器感染症の臨床2020

    • Author(s)
      泉川公一
    • Organizer
      第64回日本医真菌学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] エビデンス創出につながる臨床研究、深在性真菌感染症領域における臨床研究の実践と課題2020

    • Author(s)
      泉川公一
    • Organizer
      第94回日本感染症学会
    • Related Report
      2020 Research-status Report
  • [Book] 感染症最新の治療2022-20242021

    • Author(s)
      田代将人、泉川公一
    • Total Pages
      5
    • Publisher
      南江堂
    • Related Report
      2021 Research-status Report
  • [Book] 呼吸器内科2021

    • Author(s)
      田代将人、泉川公一
    • Total Pages
      5
    • Publisher
      科学評論社
    • Related Report
      2021 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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