Preclinical trial of bacteriophage therapy against severe Pseudomonas aeruginosa pnneumoina

• Project/Area Number: 18K19590
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: 佐和 貞治 京都府立医科大学, 医学(系)研究科(研究院), 教授 (10206013)
• Co-Investigator(Kenkyū-buntansha): 木下 真央 京都府立医科大学, 医学(系)研究科(研究院), 助教 (20816384) ; 藤木 純平 酪農学園大学, 獣医学群, 講師 (30805114) ; 清水 優 京都府立医科大学, 医学(系)研究科(研究院), 助教 (40800131) ; 岩野 英知 酪農学園大学, 獣医学群, 教授 (60382488)
• Project Period (FY): 2018-06-29 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: バクテリオファージ療法 / 緑膿菌 / 重症肺炎 / 薬剤耐性 / グラム陰性菌 / 緑膿菌性肺炎 / 三型分泌毒素 / 急性肺傷害 / 多剤耐性菌 / 抗菌療法 / ファージ療法 / 肺炎 / III型分泌システム / 動物モデル / 耐性菌 / 敗血症 / バクテリオファージ / 薬剤耐性菌 / 抗菌薬

Outline of Annual Research Achievements

重症細菌性肺炎に対するバクテリオファージ療法について、重症緑膿菌性肺炎動物モデルを用いてその実用性を検討した。社会背景として、地球規模での抗菌剤の汎用により多剤耐性菌が世界中で蔓延し、超多剤耐性や全抗菌剤耐性菌などのスーパーバクテリアの出現も懸念され、人類の将来にとって多剤耐性菌による細菌感染症が大きな懸念となっている。本研究では、マウス重症緑膿菌性肺炎モデル等を用いて、バクテリオファージ療法の治療療効果や副作用について調べ、抗菌剤に代わる新たな重症細菌性肺炎の治療法としての実用化に向けた基礎的データを集積した。緑膿菌の主要な病原毒性は、そのⅢ型分泌システムによる細胞障害に起因する。Ⅲ型分泌システムでは、細菌は特殊殊な分泌装置を通じて、直接、標的細胞の細胞質内にタンパク毒素を注入する。緑膿菌の場合、ExoS, ExoT, ExoU, ExoYと4種類の分泌毒素が同定されている。中でもExoUは、その酵素機能が同定されたホスホリパーゼA2作用をもつ強力な細胞毒であり、緑膿菌性肺炎における主要な肺上皮傷害因子である。この毒素の細胞内転移は急速な細胞壊死を誘導し、組織障害をもたらす。細菌による肺傷害がファージにより抑制できるかどうかは、ファージの殺菌作用のみならず、殺菌に関わる時間的因子や、ファージの細菌への付着など複雑な要因が影響するため、緑膿菌・培養肺上皮細胞のin vitro共培養系でファージ療法の細胞保護作用を評価することで、より効果的にin vivoので治療効果を発揮を期待できるファージ選定を行えるようにした。選定したバクテリオファージについて、マウスの緑膿菌性肺炎モデルを用いて、ファージ療法及び抗III型分泌毒性阻害抗体である抗PcrV抗体療法の療法との併用療法を試みて、結果、従来の抗菌療法に頼らない新しい治療法としてのポテンシャルを実証できた。

Research Products

• [Journal Article] Immunological response to subcutaneous and intranasal administration of SARS-CoV-2 spike protein in mice. (2024)
  • Author(s): Kinoshita M, Muranishi K, Kawaguchi K, Sudo K, Inoue K, Ishikura H, Sawa T
  • Journal Title: Vaccines Volume: 12 Issue: 4 Pages: 343-343
  • DOI: 10.3390/vaccines12040343
  • Peer Reviewed / Open Access
• [Journal Article] Prediction of acute lung injury assessed by chest computed tomography, oxygen saturation/fraction of inspired oxygen ratio, and serum lactate dehydrogenase in patients with COVID-19 (2024)
  • Author(s): Matsubara Shin、Sudo Kazuki、Kushimoto Kohsuke、Yoshii Ryogo、Inoue Keita、Kinoshita Mao、Kooguchi Kunihiko、Shikata Satoru、Inaba Tohru、Sawa Teiji
  • Journal Title: Journal of Infection and Chemotherapy Volume: 30 Issue: 5 Pages: 406-416
  • DOI: 10.1016/j.jiac.2023.11.013
  • Peer Reviewed
• [Journal Article] 悪心・嘔吐の細胞レベルでの起源. (2024)
  • Author(s): 佐和貞治.
  • Journal Title: 麻酔 Volume: 73 Pages: 5-10
• [Journal Article] Antibody Response Following the Intranasal Administration of SARS-CoV-2 Spike Protein-CpG Oligonucleotide Vaccine (2023)
  • Author(s): Muranishi Kentaro、Kinoshita Mao、Inoue Keita、Ohara Junya、Mihara Toshihito、Sudo Kazuki、Ishii Ken J.、Sawa Teiji、Ishikura Hiroyasu
  • Journal Title: Vaccines Volume: 12 Issue: 1 Pages: 5-5
  • DOI: 10.3390/vaccines12010005
  • Peer Reviewed / Open Access
• [Journal Article] Choice of respiratory therapy for COVID-19 patients with acute hypoxemic respiratory failure: a retrospective case series study (2023)
  • Author(s): Sudo Kazuki、Sawa Teiji、Kushimoto Kohsuke、Yoshii Ryogo、Yuasa Kento、Inoue Keita、Kinoshita Mao、Yamasaki Masaki、Kooguchi Kunihiko
  • Journal Title: PeerJ Volume: 11 Pages: e15174-e15174
  • DOI: 10.7717/peerj.15174
  • Peer Reviewed / Open Access
• [Journal Article] Effect of a Novel Trivalent Vaccine Formulation against Acute Lung Injury Caused by Pseudomonas aeruginosa (2023)
  • Author(s): Inoue Keita、Kinoshita Mao、Muranishi Kentaro、Ohara Junya、Sudo Kazuki、Kawaguchi Ken、Shimizu Masaru、Naito Yoshifumi、Moriyama Kiyoshi、Sawa Teiji
  • Journal Title: Vaccines Volume: 11 Issue: 6 Pages: 1088-1088
  • DOI: 10.3390/vaccines11061088
  • Peer Reviewed / Open Access
• [Journal Article] 生体防御としての悪心・嘔吐とその進化学的意義. 嘔気が関わる線虫からの知見：ミトコンドリアストレスと統合的ストレス応答. (2023)
  • Author(s): 佐和貞治
  • Journal Title: Anet Volume: 27 Pages: 3-9
• [Journal Article] 緑膿菌ワクチンの可能性. (2023)
  • Author(s): 佐和貞治，川口顕，須藤和樹，小原潤也，井上敬太，木下真央，内藤慶史.
  • Journal Title: 呼吸器内科 Volume: 43 Pages: 440-446
• [Journal Article] Adverse reactions to the first and second doses of Pfizer-BioNTech COVID-19 vaccine among healthcare workers. (2022)
  • Author(s): Maruyama A, Sawa T, Teramukai S, Katoh N.
  • Journal Title: J Infect Chemothe Volume: Mar 25 Issue: 7 Pages: 934-942
  • DOI: 10.1016/j.jiac.2022.03.015
  • Peer Reviewed / Open Access
• [Journal Article] Difficult Airway Management in Neonates and Infants: Knowledge of Devices and a Device-Oriented Strategy (2021)
  • Author(s): Sawa Teiji、Kainuma Atsushi、Akiyama Koichi、Kinoshita Mao、Shibasaki Masayuki
  • Journal Title: Frontiers in Pediatrics Volume: 9 Pages: 654291-654291
  • DOI: 10.3389/fped.2021.654291
  • Peer Reviewed / Open Access
• [Journal Article] Power spectrum and spectrogram of EEG analysis during general anesthesia: Python-based computer programming analysis. (2021)
  • Author(s): Sawa T, Yamada T, Obata Y
  • Journal Title: J Clin Monit Comput Volume: Oct 29 Issue: 3 Pages: 1-1
  • DOI: 10.1007/s10877-021-00771-4
  • Peer Reviewed / Open Access
• [Journal Article] Epidemiological survey of serum titers from adults against various Gram-negative bacterial V-antigens. (2020)
  • Author(s): Kinoshita M, Shimizu M, Akiyama K, Kato H, Moriyama K, Sawa T.
  • Journal Title: PLoS One Volume: 15 Issue: 3 Pages: 15-15
  • DOI: 10.1371/journal.pone.0220924
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular diversity of extended-spectrum β-lactamases and carbapenemases, and antimicrobial resistance. (2020)
  • Author(s): Sawa T, Kooguchi K, Moriyama K.
  • Journal Title: J Intensive Care Volume: 28 Issue: 1 Pages: 13-13
  • DOI: 10.1186/s40560-020-0429-6
  • Peer Reviewed / Open Access
• [Journal Article] Molecular epidemiology of clinically high-risk Pseudomonas aeruginosa strains: Practical overview. (2020)
  • Author(s): Sawa T, Momiyama K, Mihara
  • Journal Title: Microbiol Immunol Volume: - Issue: 5 Pages: 1-1
  • DOI: 10.1111/1348-0421.12776
  • Peer Reviewed / Open Access
• [Journal Article] Secondary in-hospital epidemiological investigation after an outbreak of Pseudomonas aeruginosa ST357 (2020)
  • Author(s): Mihara T, Kimura T, Momiyama K, Kainuma A, Akiyama K, Ohara J, Inoue K, Kinoshita M, Shimizu M, Moriyama K, Fujita N, Sawa T.
  • Journal Title: J Infect Chemother Volume: 26 Issue: 3 Pages: 257-265
  • DOI: 10.1016/j.jiac.2019.09.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immunoglobulin for Treating Bacterial Infections: One More Mechanism of Action. Development of Therapeutic Antibodies against Toxins and Pathogens. (2019)
  • Author(s): Sawa T, Kinoshita M, Inoue K, Ohara J, Moriyama K.
  • Journal Title: Antibodies Volume: 8 Issue: 4 Pages: 52-52
  • DOI: 10.3390/antib8040052
  • Peer Reviewed / Open Access
• [Journal Article] The protective effects of nasal PcrV-CpG oligonucleotide vaccination against Pseudomonas aeruginosa pneumonia. (2018)
  • Author(s): Naito Y, Hamaoka S, Kinoshita M, Kainuma A, Shimizu M, Katoh H, Moriyama K, Ishii KJ, Sawa T.
  • Journal Title: Microbiol Immunol Volume: 62 Pages: 774-785
  • NAID: 40021778113
  • Peer Reviewed
• [Journal Article] An outbreak of fluoroquinolone-resistant Pseudomonas aeruginosa ST357 harboring the exoU gene. (2018)
  • Author(s): Kainuma A, Momiyama K, Kimura T, Akiyama K, Inoue K, Naito Y, Kinoshita M, Shimizu M, Kato H, Shime N, Fujita N, Sawa T.
  • Journal Title: J Infect Chemother. Volume: in press Issue: 8 Pages: 615-622
  • DOI: 10.1016/j.jiac.2018.03.008
  • Peer Reviewed / Open Access
• [Journal Article] 多剤耐性緑膿菌に対する免疫療法. (2018)
  • Author(s): 内藤慶史、佐和貞治.
  • Journal Title: 医学のあゆみ Volume: 264 Pages: 444-449
• [Presentation] Development of EEG mode decompositor:Hilbert spectrum analysis of electroencephalography durng geenral anesthesia by modified empirical wavelet transform (wavelet mode decomposition). (2023)
  • Author(s): Sawa T, Sudo K, Obata Y, Akiyama K
  • Organizer: Annual Meeting of International Anesthesia Society
  • Int'l Joint Research
• [Presentation] Statistical causal inferences involving respiratory management in COVID-19 severe respiratory failure: a retrospective-single center cohort study. (2023)
  • Author(s): Sudo K, Sawa T, Kushimoto K, Yoshii R, Yuasa K, Inoue K, Kinoshita M, Yamasaki M, Kooguchi K.
  • Organizer: Annual Meeting of International Anesthesia Society
  • Int'l Joint Research
• [Presentation] Clinical research for decision making in the initiation of mechanical ventilation therapy using ROX index and chest CT images in COVID-19 patients; Single-center retrospective cohort study. (2022)
  • Author(s): Sudo K, Kinoshita M, Kento K, Inoue K, Ohara J, Muranishi K, Sawa T.
  • Organizer: The 22nd KSCCM-JSICM Joint Congress.
  • Int'l Joint Research
• [Presentation] ランスレーショナル・リサーチ 細菌感染と急性肺傷害 (2022)
  • Author(s): 佐和貞治
  • Organizer: 第42回日本臨床麻酔学会大会
  • Int'l Joint Research / Invited
• [Presentation] COVID-19重症呼吸不全の呼吸療法選択に関与する因子についての因果推論ベイジアンネットワーク解析 (2022)
  • Author(s): 須藤和樹, 湯浅健人, 串本洸輔, 吉井龍吾, 井上敬太, 山崎正記, 木下真央, 小尾口邦彦,佐和貞治.
  • Organizer: ４大学連携研究フォーラム
• [Presentation] COVID-19重症患者での人工呼吸管理/高流量経鼻酸素療法選択の統計学的因果推論ネットワーク解析. (2022)
  • Author(s): 須藤和樹, 湯浅健人, 吉井龍吾, 井上敬太, 山崎正記, 小尾口邦彦, 佐和貞治
  • Organizer: 第40回日本麻酔・集中治療テクノロジー学会
  • Int'l Joint Research
• [Presentation] バクテリオファージと PcrV 抗体の治療効果の検討 (2022)
  • Author(s): 小原潤也、藤木純平 、木下真央 、井上敬太 、須藤和樹、湯浅健人、岩野英知、佐和貞治
  • Organizer: 第56回緑膿菌感染症研究会
• [Presentation] シンポジウム. 緑膿菌に学び， 緑膿菌を操る . タイプ III 毒素分泌機構 (2020)
  • Author(s): 佐和貞治
  • Organizer: 第94回日本感染症学会学術講演会, 2020年8月東京.
  • Invited
• [Presentation] Frequency analysis-linked Poincare plot-integrated score (f-PIS) of the electroencephalogram during general anesthesia. (2018)
  • Author(s): Sawa T, Hayashi K, Kainuma A, Inoue K, Kinoshita M.
  • Organizer: IARS 2018. Annual Meeting and International Science Symposium. International Anesthesia Research Society.
  • Invited
• [Presentation] Arterial pulse waveform analysis. (2018)
  • Author(s): Sawa T. Experience exchange session.
  • Organizer: Experience exchange session. Edwards Life Science Limited,
  • Int'l Joint Research / Invited
• [Presentation] 緑膿菌毒素に対する免疫グロブリン新知見. (2018)
  • Author(s): 佐和貞治.
  • Organizer: 鹿児島県薬剤師会講演会.
  • Invited
• [Book] TLR9リガンド添加緑膿菌V抗原ワクチンによる粘膜免疫誘導の検討. 第52回緑膿菌感染症研究会公演記録 (2018)
  • Author(s): 内藤慶史、濱岡早枝子、井上敬太、甲斐沼篤、石井健、佐和貞治.
  • Total Pages: 3
  • Publisher: 日本緑膿菌感染症研究会
• [Book] 診断と治療社 (2018)
  • Author(s): 木下真央、佐和貞治.
  • Total Pages: 6
  • Publisher: 麻酔科研修ノート 改訂第3版. 感染症.
  • ISBN: 9784787824011
• [Book] Construction of a recombinant single-chain antibody fragment against bacterial type III secretion. Antibody Engineering, (2018)
  • Author(s): Sawa T, Kainuma A, Moriyama K, Naito Y.
  • Total Pages: 15
  • Publisher: InTech
• [Remarks] 京都府立医科大学麻酔科学教室 佐和貞治
  • URL: http://www.f.kpu-m.ac.jp/k/anesth/index.php?TeijiSawa