Host-pathogen interactions in antibiotic therapy for listeriosis

• Project/Area Number: 18K07106
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49050:Bacteriology-related
• Research Institution: Kanazawa University
• Principal Investigator: Tsuchiya Kohsuke 金沢大学, がん進展制御研究所, 准教授 (50437216)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: パイロトーシス / インフラマソーム / ガスダーミンD / リステリア / inflammasome / pyroptosis / Listeria / AIM2 / 細菌感染治療 / 抗生物質 / GSDMD

Outline of Final Research Achievements

In macrophages infected, for example, by bacteria, the innate immune mechanism inflammasome is activated, which in turn induces the activation of the proteolytic enzyme caspase-1, leading to inflammatory programme cell death called pyrotosis. We found that the therapeutic effect of ampicillin administration during Listeria infection is promoted by an inflammasome and investigated the molecular mechanism of the improved therapeutic efficacy. We found that Listeria trapped within intracellular vacuoles become resistant to ampicillin treatment and prevent complete bacterial elimination, and that induction of pyrotosis is necessary to eliminate Listeria in the vacuoles. From this study, a co-ordinated action of antibiotic treatment and the immune system was revealed.

Academic Significance and Societal Importance of the Research Achievements

リステリアは汚染された食物を介して感染し、敗血症や髄膜炎といった重篤なリステリア症を引き起こす。リステリア症の治療には抗生物質が用いられるが依然として致死率が高い。リステリア症の第一選択薬はアンピシリンであるが、ゲンタマイシンなどとの併用が好ましいとされる。本研究は、インフラマソームを介したパイロトーシスの誘導がアンピシリンによる徹底した菌排除に必要であり、細胞内におけるアンピシリンとゲンタマイシンの併用効果の根底にあることを初めて明らかにした。さらに、小胞内に潜む細菌が抗生物質治療におけるリスク要因になり得ることを示した。これらの成果は適切な治療方針の決定に寄与するものである。

Research Products

• [Int'l Joint Research] 西南大学(中国)
• [Int'l Joint Research] 西南大学(中国)
• [Journal Article] Listeria toxin promotes phosphorylation of the inflammasome adaptor ASC through Lyn and Syk to exacerbate pathogen expansion (2022)
  • Author(s): Tanishita Yuko、Sekiya Hisateru、Inohara Naohiro、Tsuchiya Kohsuke、Mitsuyama Masao、Nunez Gabriel、Hara Hideki
  • Journal Title: Cell Reports Volume: 38 Issue: 8 Pages: 110414-110414
  • DOI: 10.1016/j.celrep.2022.110414
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gasdermin D mediates the maturation and release of IL-1α downstream of inflammasomes (2021)
  • Author(s): Tsuchiya K, Hosojima S, Hara H, Kushiyama H, Mahib M. R., Kinoshita T, Suda T
  • Journal Title: Cell Rep. Volume: 34 Issue: 12 Pages: 108887-108887
  • DOI: 10.1016/j.celrep.2021.108887
  • Peer Reviewed / Open Access
• [Journal Article] Mint3 depletion-mediated glycolytic and oxidative alterations promote pyroptosis and prevent the spread of Listeria monocytogenes infection in macrophages (2021)
  • Author(s): Uematsu Takayuki、Tsuchiya Kohsuke、Kobayashi Noritada、Seiki Motoharu、Inoue Jun-ichiro、Kaneko Shuichi、Sakamoto Takeharu
  • Journal Title: Cell Death and Disease Volume: 12 Issue: 4 Pages: 404-404
  • DOI: 10.1038/s41419-021-03691-y
  • Peer Reviewed / Open Access
• [Journal Article] Switching from Apoptosis to Pyroptosis: Gasdermin-Elicited Inflammation and Antitumor Immunity (2021)
  • Author(s): Tsuchiya Kohsuke
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 1 Pages: 426-426
  • DOI: 10.3390/ijms22010426
  • Peer Reviewed / Open Access
• [Journal Article] Gasdermin D‐independent release of interleukin‐1 β by living macrophages in response to mycoplasmal lipoproteins and lipopeptides (2020)
  • Author(s): Saeki Ayumi、Tsuchiya Kohsuke、Suda Takashi、Into Takeshi、Hasebe Akira、Suzuki Toshihiko、Shibata Ken‐ichiro
  • Journal Title: Immunology Volume: 161 Issue: 2 Pages: 114-122
  • DOI: 10.1111/imm.13230
  • NAID: 120007151366
  • Peer Reviewed / Open Access
• [Journal Article] Caspase-7 mediates caspase-1-induced apoptosis independently of Bid. (2020)
  • Author(s): Mahib M.R., Hosojima S., Kushiyama H., Kinoshita T., Shiroishi T., Suda T.*, Tsuchiya K.
  • Journal Title: Microbiology and Immunology Volume: 64 Issue: 2 Pages: 143-152
  • DOI: 10.1111/1348-0421.12756
  • Peer Reviewed / Open Access
• [Journal Article] Inflammasome-associated Cell Death: Pyroptosis, Apoptosis, and Physiological Implications. (2020)
  • Author(s): Tsuchiya K.
  • Journal Title: Microbiology and Immunology Volume: In press Issue: 4 Pages: 252-269
  • DOI: 10.1111/1348-0421.12771
  • Peer Reviewed
• [Journal Article] Caspase-1 initiates apoptosis in the absence of gasdermin D (2019)
  • Author(s): Tsuchiya K, Nakajima S, SHosojima S, Nguyen DT, Hattori T, Le TM, Hori O, Mahib MR, Yamaguchi Y, Miura M, Kinoshita T, Kushiyama H, Sakurai M, Shiroishi T, Suda T
  • Journal Title: Nature Communications Volume: In press Issue: 1 Pages: 2091-2091
  • DOI: 10.1038/s41467-019-09753-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ASC and NLRP3 maintain innate immune homeostasis in the airway through an inflammasome-independent mechanism. (2019)
  • Author(s): Fang R., Uchiyama R., Sakai S., Hara H., Tsutsui H., Suda T., Mitsuyama M., Kawamura I., Tsuchiya K.
  • Journal Title: Mucosal Immunology Volume: 12 Issue: 5 Pages: 1092-1103
  • DOI: 10.1038/s41385-019-0181-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Gasdermin D mediates the release and maturation of IL-1α during inflammasome formation. (2021)
  • Author(s): Kohsuke Tsuchiya, Takashi Suda.
  • Organizer: 第94回日本細菌学会総会
• [Presentation] Pyroptosis enhances antibiotic therapy of listeriosis. (2019)
  • Author(s): Tsuchiya K, Suda T.
  • Organizer: 第92回日本細菌学会総会
• [Presentation] Caspase-1 initiates apoptosis in the absence of gasdermin D. (2019)
  • Author(s): Tsuchiya K, Mahib MR, Suda T.
  • Organizer: The 17th International Congress of Immunology (IUIS2019)
  • Int'l Joint Research
• [Presentation] Gasdermin D (GSDMD) mediates IL-1α maturation during inflammasome formation. (2019)
  • Author(s): Tsuchiya K, Suda T.
  • Organizer: 第 48 回日本免疫学会学術集会
• [Presentation] Pyroptosis enhances killing of Listeria monocytogenes by ampicillin in vivo (2018)
  • Author(s): 土屋晃介（筆頭演者）ほか
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Caspase-1 initiates apoptosis in the absence of gasdermin D (2018)
  • Author(s): 土屋晃介（筆頭演者）ほか
  • Organizer: 第27回日本Cell Death学会学術集会