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Multidimensional therapeutic strategy against severe infection/sepsis, focusing on respiratory activity of bacteria and activation of host phagocytic cells

Research Project

Project/Area Number 21H03038
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 55060:Emergency medicine-related
Research InstitutionNational Defense Medical College

Principal Investigator

Kinoshita Manabu  防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 免疫・微生物学, 教授 (70531391)

Co-Investigator(Kenkyū-buntansha) 中島 弘幸  防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 免疫・微生物学, 准教授 (10574064)
鈴木 博章  筑波大学, 数理物質系, 教授 (20282337)
小野 岳史  防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 国際感染症学, 助教 (20535182)
小野 聡  東京医科大学, 医学部, 兼任教授 (30531355)
中島 正裕  防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 免疫・微生物学, 助教 (70738103)
熊谷 裕生  防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 内科学, 教授 (50170048)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2023: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2022: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2021: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Keywords重症感染症 / 細菌活性測定チップ / 薬剤感受性迅速診断 / MPLAプレコンディショニング / 合成CRP / MPLAプレコンディショニン / compromised host / MLPAプレコンディショニング
Outline of Research at the Start

重症感染症に対する病態重症化を時間軸とした多角的な治療戦略を探索する。まず、①好中球と共培養した大腸菌の呼吸活性を細菌呼吸活性測定チップで測定して、好中球の抗菌活性を迅速診断し宿主の感染リスクを評価する。次に、②感染ハイリスク例にサルモネラ由来lipid A (MPLA)などを極微量反復接種し(MPLAプレコンディショニング)、貪食細胞機能の増強と感染予防効果をみる。③感染起炎菌を抗生剤と共培養して菌の呼吸活性をチップで測定し、薬剤感受性を20分で迅速診断する。④感染後に貪食能増強効果がある合成CRPを投与し、貪食細胞機能の増強と感染予後に与える影響を検討する。

Outline of Final Research Achievements

Our oxygen sensor that can measure respiratory activity of bacteria could precisely evaluate the host compromised condition by measuring antibacterial activity of host neutrophils using this sensor. Trained innate immunity by LPS/MPLA preconditioning could augment bactericidal activity of host phagocytes, resulting in resistance to infection in compromised hosts. When infections occur in patients, effectivity of antibiotics should be rapidly evaluated by monitoring the change in respiratory activities of antibiotic-loaded bacteria using this sensor. Synthetic CRP peptides could effectively augment bactericidal activity of phagocytes even after infection occurs, resulting in reducing infection mortality. The current multi-layered therapeutic strategy may contribute to improvement of poor septic mortalities.

Academic Significance and Societal Importance of the Research Achievements

我々が開発した細菌呼吸活性測定チップは2022年5月に特許登録された(第7066087号)。抗生剤による菌の呼吸活性減弱をみることで30分以内に菌の薬剤感受性が迅速診断でき、従来の感染症へのエンピリックな治療が激変する可能性がある。また、好中球の抗菌活性はヒトのストレスの程度を反映するが、ヒト好中球を大腸菌と共培養し呼吸活性の減弱をみることで抗菌活性が評価でき、ストレスの程度を測ることが可能となった。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (27 results)

All 2024 2023 2022 2021

All Journal Article (23 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 23 results,  Open Access: 18 results) Presentation (4 results) (of which Int'l Joint Research: 4 results)

  • [Journal Article] Bipolar Clark-type oxygen electrode arrays for imaging and multiplexed measurements of the respiratory activity of cells2024

    • Author(s)
      Y. Shirato, A. -J. Hsueh, N. A. Ab Mutalib, Y. Deng, R. Suematsu, A. Kato, B. M. Kearney, M. Kinoshita, and H. Suzuki
    • Journal Title

      ACS Omega

      Volume: 9 Issue: 9 Pages: 10825-10833

    • DOI

      10.1021/acsomega.3c09802

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] <scp>l</scp>-Carnitine pretreatment ameliorates heat stress-induced acute kidney injury by restoring mitochondrial function of tubular cells2024

    • Author(s)
      Goto Hiroyasu、Nakashima Hiroyuki、Mori Kazuma、Tanoue Keiko、Ito Seigo、Kearney Bradley M.、Kato Azusa、Nakashima Masahiro、Imakiire Toshihiko、Kumagai Hiroo、Kinoshita Manabu、Oshima Naoki
    • Journal Title

      American Journal of Physiology-Renal Physiology

      Volume: 326 Issue: 3 Pages: F338-F351

    • DOI

      10.1152/ajprenal.00196.2023

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] arlytreatmentwithFibrinogeng-chainpeptide-coated,ADP-encapsulatedLiposomes(H12-(ADP)-liposomes)amelioratespost-partumhemorrhagewithcoagulopathycausedbyamnioticfluidembolisminrabbits2023

    • Author(s)
      KokiKaneko,MD;KohsukeHagisawa,MD,PhD;ManabuKinoshita,MD,PhD;YukaOhtsuka,MD;RukaSasa,MD;MorihiroHotta,MS;DaizohSaitoh,MD,PhD;KimiyaSato,MD,PhD;ShinjiTakeoka,PhD;KatsuoTerui,
    • Journal Title

      American Journal Obstetrics Gynecology Global Reports

      Volume: November Issue: 4 Pages: 1-11

    • DOI

      10.1016/j.xagr.2023.100280

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel phenotypical and functional sub‐classification of liver macrophages highlights changes in population dynamics in experimental mouse models2023

    • Author(s)
      Nakashima Hiroyuki、Kearney Bradley M.、Kato Azusa、Miyazaki Hiromi、Ito Seigo、Nakashima Masahiro、Kinoshita Manabu
    • Journal Title

      Cytometry Part A

      Volume: 103 Issue: 11 Pages: 902-914

    • DOI

      10.1002/cyto.a.24783

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Heatstroke-induced acute kidney injury and the innate immune system2023

    • Author(s)
      Goto Hiroyasu、Kinoshita Manabu、Oshima Naoki
    • Journal Title

      Frontiers in Medicine

      Volume: 10 Pages: 1250457-1250457

    • DOI

      10.3389/fmed.2023.1250457

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] In?vitro study on the effect of fibrinogen γ-chain peptide-coated ADP-encapsulated liposomes on postcardiopulmonary bypass coagulopathy using patient blood2023

    • Author(s)
      Ishida Osamu、Hagisawa Kohsuke、Yamanaka Nozomu、Nakashima Hiroyuki、Kearney Bradley M.、Tsutsumi Koji、Takeoka Shinji、Kinoshita Manabu
    • Journal Title

      Journal of Thrombosis and Haemostasis

      Volume: 23 Issue: 7 Pages: 1934-1942

    • DOI

      10.1016/j.jtha.2023.03.018

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Early treatment with C-reactive protein-derived peptide reduces septic acute kidney injury in mice via controlled activation of kidney macrophages2023

    • Author(s)
      Ito Seigo、Goto Hiroyasu、Tanoue Keiko、Koiwai Kazuki、Ishikiriyama Takuya、Kearney Bradley M、Mori Kazuma、Nakashima Masahiro、Nakashima Hiroyuki、Kumagai Hiroo、Seki Shuhji、Kinoshita Manabu、Oshima Naoki
    • Journal Title

      Journal of Leukocyte Biology

      Volume: 113 Issue: 4 Pages: 400-413

    • DOI

      10.1093/jleuko/qiad015

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Antitumor Immunity Exerted by Natural Killer and Natural Killer T Cells in the Liver2023

    • Author(s)
      Nakashima Hiroyuki、Kinoshita Manabu
    • Journal Title

      Journal of Clinical Medicine

      Volume: 12 Issue: 3 Pages: 866-866

    • DOI

      10.3390/jcm12030866

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pioglitazone Modifies Kupffer Cell Function and Protects against Escherichia coli-Induced Bacteremia in Burned Mice2022

    • Author(s)
      Miyazaki Hiromi、Kinoshita Manabu、Nakashima Hiroyuki、Nakamura Shingo、Saitoh Daizoh
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 21 Pages: 12746-12746

    • DOI

      10.3390/ijms232112746

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Heat acclimation ameliorated heat stress-induced acute kidney injury and prevented changes in kidney macrophages and fibrosis2022

    • Author(s)
      Goto Hiroyasu、Nakashima Masahiro、Nakashima Hiroyuki、Noguchi Midori、Imakiire Toshihiko、Oshima Naoki、Kinoshita Manabu、Kumagai Hiroo
    • Journal Title

      American Journal of Physiology-Renal Physiology

      Volume: 323 Issue: 3 Pages: F243-F254

    • DOI

      10.1152/ajprenal.00065.2022

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mouse Liver B Cells Phagocytose <i>Streptococcus pneumoniae</i> and Initiate Immune Responses against Their Antigens2022

    • Author(s)
      Nakashima Masahiro、Kinoshita Manabu、Nakashima Hiroyuki、Kato Azusa、Mori Kazuma、Koiwai Kazuki、Shinomiya Nariyoshi、Seki Shuhji
    • Journal Title

      The Journal of Immunology

      Volume: 209 Issue: 1 Pages: 26-37

    • DOI

      10.4049/jimmunol.2100520

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Early biomarkers for kidney injury in heat-related illness patients: a prospective observational study at Japanese Self-Defense Force Fuji Hospital2022

    • Author(s)
      Goto Hiroyasu、Shoda Shinichi、Nakashima Hiroyuki、Noguchi Midori、Imakiire Toshihiko、Ohshima Naoki、Kinoshita Manabu、Tomimatsu Soichi、Kumagai Hiroo
    • Journal Title

      Nephrology Dialysis Transplantation

      Volume: 38 Issue: 3 Pages: 644-654

    • DOI

      10.1093/ndt/gfac166

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of L-Carnitine Treatment on Kidney Mitochondria and Macrophages in Mice with Diabetic Nephropathy2022

    • Author(s)
      Ito Seigo、Nakashima Masahiro、Ishikiriyama Takuya、Nakashima Hiroyuki、Yamagata Akira、Imakiire Toshihiko、Kinoshita Manabu、Seki Shuhji、Kumagai Hiroo、Oshima Naoki
    • Journal Title

      Kidney and Blood Pressure Research

      Volume: 47 Issue: 4 Pages: 277-290

    • DOI

      10.1159/000522013

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Nitric oxide facilitates the targeting Kupffer cells of a nano-antioxidant for the treatment of NASH.2022

    • Author(s)
      Sonoda K, Wakayama T, Kinoshita M, Shuto T, Kai H, Tanaka M, Sasaki Y, Iwakiri Y, Otagiri M
    • Journal Title

      J Control Release

      Volume: 341 Pages: 457-474

    • DOI

      10.1016/j.jconrel.2021.11.039

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The Efficacy of Posttreatment with Synthetic C-Reactive Protein in Murine Bacterial Peritonitis via Activation of FcγRI-Expressing Kupffer Cells2021

    • Author(s)
      Kinoshita Manabu、Ito Seigo、Ishikiriyama Takuya、Sekiguchi Kumiko、Yamaguchi Ryota、Tsuruhara Ryoichi、Matsuda Akihisa、Koiwa Kazuki、Nakashima Masahiro、Nakashima Hiroyuki、Miyashita Masao、Seki Shuhji
    • Journal Title

      Journal of Innate Immunity

      Volume: Online ahead Issue: 5 Pages: 1-13

    • DOI

      10.1159/000515333

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Microdevice with integrated Clark-type oxygen electrode for measurement of respiratory activity of cells2021

    • Author(s)
      Hsueh AJ, Park S, Satoh T, Shimizu T, Koiwai K, Nakashima M, Morimoto Y, Kinoshita M, Suzuki H
    • Journal Title

      Analytical Chemistry

      Volume: 93 Issue: 13 Pages: 5577-5585

    • DOI

      10.1021/acs.analchem.1c00227

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Generalized Shwartzman reaction as an experimental endotoxin shock model -role of intermediate T cell receptor-expressing innate T lymphocytes in its pathogenesis-2021

    • Author(s)
      Kinoshita M, Nakashima M, Seki S, Nakashima H
    • Journal Title

      Fungal Genomics & Biology

      Volume: 11 Pages: 1-5

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The role of Kupffer cells in systemic anti-microbial defense2021

    • Author(s)
      Nakashima H, Nakashima M, Kinoshita M, Seki S
    • Journal Title

      IntechOpen, Antimicrobial Immune Response

      Volume: 1 Pages: 1-13

    • DOI

      10.5772/intechopen.97256

    • ISBN
      9781839687822, 9781839687839
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A comparison of thyroidal protection by iodine and perchlorate against radioiodine exposure in Caucasians and Japanese2021

    • Author(s)
      Rump A.、Eder S.、Hermann C.、Lamkowski A.、Kinoshita M.、Yamamoto T.、Abend M.、Shinomiya N.、Port M.
    • Journal Title

      Archives of Toxicology

      Volume: 95 Issue: 7 Pages: 2335-2350

    • DOI

      10.1007/s00204-021-03065-5

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Enhanced cellular engraftment of adipose-derived mesenchymal stem cell spheroids by using nanosheets as scaffolds2021

    • Author(s)
      Nagano Hisato、Suematsu Yoshitaka、Takuma Megumi、Aoki Shimpo、Satoh Ayano、Takayama Eiji、Kinoshita Manabu、Morimoto Yuji、Takeoka Shinji、Fujie Toshinori、Kiyosawa Tomoharu
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 1-12

    • DOI

      10.1038/s41598-021-93642-6

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Contrasting functional responses of resident Kupffer cells and recruited liver macrophages to irradiation and liver X receptor stimulation2021

    • Author(s)
      Ishikiriyama Takuya、Nakashima Hiroyuki、Endo-Umeda Kaori、Nakashima Masahiro、Ito Seigo、Kinoshita Manabu、Ikarashi Masami、Makishima Makoto、Seki Shuhji
    • Journal Title

      PLOS ONE

      Volume: 16 Issue: 7 Pages: e0254886-e0254886

    • DOI

      10.1371/journal.pone.0254886

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lipopolysaccharide Preconditioning Augments Phagocytosis of Malaria-Parasitized Red Blood Cells by Bone Marrow-Derived Macrophages in the Liver, Thereby Increasing the Murine Survival after Plasmodium yoelii Infection2021

    • Author(s)
      Ono Takeshi、Yamaguchi Yoko、Nakashima Hiroyuki、Nakashima Masahiro、Ishikiriyama Takuya、Seki Shuhji、Kinoshita Manabu
    • Journal Title

      Infection and Immunity

      Volume: 89 Issue: 11

    • DOI

      10.1128/iai.00249-21

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effects of a CCR2 antagonist on macrophages and Toll-like receptor 9 expression in a mouse model of diabetic nephropathy2021

    • Author(s)
      Ito Seigo、Nakashima Hiroyuki、Ishikiriyama Takuya、Nakashima Masahiro、Yamagata Akira、Imakiire Toshihiko、Kinoshita Manabu、Seki Shuhji、Kumagai Hiroo、Oshima Naoki
    • Journal Title

      American Journal of Physiology-Renal Physiology

      Volume: 321 Issue: 6 Pages: F757-F770

    • DOI

      10.1152/ajprenal.00191.2021

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Early biomarkers for kidney injury in heat-related illness patients: A prospective observational study at Japanese Self-Defense Force Fuji Hospital2023

    • Author(s)
      Goto H, Shoda S, Nakashima H, Noguchi M, Imakiire T, Oshima N, Kinoshita M, Tomimatsu S, Kumagai H
    • Organizer
      Military Health System Research Symposium
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] H12-(ADP)-Liposomes Effectively Promote Hemostasis and Improve Survival Rates in Experimental Animal Model of Non-compressible Torso Hemorrhage with Thrombocytopenia.2023

    • Author(s)
      Hagisawa K, Kinoshita M, Ishida O, Kearney BM, Takeoka S
    • Organizer
      Military Health System Research Symposium
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Resuscitative efficacy of hemoglobin vesicles for severe postpartum hemorrhage in pregnant rabbits2023

    • Author(s)
      Kinoshita M, Hagisawa K, Ishibashi H, Sakai H, Terui K
    • Organizer
      The 45th Annunal Congress on Shock
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Radioprotective Effect of Vitamin C in Human Fibroblast Cells.2023

    • Author(s)
      Take J, Moriya K, Eder S, Steinestel K, Hermann C, Lamkowski A, Rump A, Abend M, Yamamoto T, Port M, Shinomiya N, Kinoshita M, Imai K
    • Organizer
      ConRad2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research

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Published: 2021-04-28   Modified: 2025-01-30  

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