Strategy of Salmonella persistent infection based on suppression of bone-marrow derived immune cells induced by secreted proteins

• Project/Area Number: 18K07102
• 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: Chiba University
• Principal Investigator: Takaya Akiko 千葉大学, 大学院薬学研究院, 准教授 (80334217)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: サルモネラ / 持続感染 / 免疫抑制 / 骨髄系細胞 / 病原因子 / 分泌タンパク質 / Lonプロテアーゼ / 凝集タンパク質 / ミエロイド細胞 / 腹腔特異的マクロファージ / 分泌蛋白質 / 骨髄形質細胞 / IgG / ワクチン / 骨髄記憶免疫細胞

Outline of Final Research Achievements

In this study, we found the novel mechanism that Salmonella has an ability to suppress humoral immunity via secretion of the virulence factor, SiiE Our result suggested that SiiE inhibits the interaction between the integrin β1 on plasma cells and laminin β1 on stromal cells in bone marrow. Furthermore, our study was also suggested that accumulation of immature myeloid cells provide a balance of immunosuppressive and protective functions in the host response to the persistent infection with Salmonella. Taking these findings together, it is suggested that Salmonella could maintain persistent infection by suppressing the host immune response in various strategies.

Academic Significance and Societal Importance of the Research Achievements

病原細菌の持続感染では宿主に特異的な記憶免疫が形成されることから、弱毒化ワクチンなどに応用される。今回の成果は、ある種の弱毒化ワクチンなどでは宿主の持つ長期記憶等の免疫応答を低下させる可能性を示唆している。従って、弱毒化ワクチンなどの利用において他の抗体変化を調べることで安全性や効果について検討することの重要性を示唆している。一方、骨髄の長命形質細胞を特異的に阻害する戦略により免疫疾患の治療などへの応用に発展する可能性も考えられる。

Research Products

• [Int'l Joint Research] Rheuma-Forschungszentrum Berlin (DRFZ)(ドイツ)
• [Int'l Joint Research] Deutsches Rheuma-Forschungszentrum(ドイツ)
• [Journal Article] Exploration of <i>Salmonella</i> effector mutant strains on MTR4 and RRP6 degradation (2020)
  • Author(s): Sun Xiaoning、Kawata Kentaro、Miki Atsuko、Wada Youichiro、Nagahama Masami、Takaya Akiko、Akimitsu Nobuyoshi
  • Journal Title: BioScience Trends Volume: 14 Issue: 4 Pages: 255-262
  • DOI: 10.5582/bst.2020.03085
  • NAID: 130007906511
  • ISSN: 1881-7815, 1881-7823
  • Year and Date: 2020-08-31
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Staphylococcus Agr virulence is critical for epidermal colonization and associates with atopic dermatitis development (2020)
  • Author(s): Nakamura Y, Takahashi H, Takaya A, Inoue Y, Katayama Y, Kusuya Y, Shoji T, Takada S, Nakagawa S, Oguma R, Saito N, Ozawa N, Nakano T, Yamaide F, Dissanayake E, Suzuki S, Villaruz A, Varadarajan S, Matsumoto M, Kobayashi T, Kono M, Sato Y, Akiyama M, Otto M, Matsue H, Nunez G, Shimojo N.
  • Journal Title: Sci Transl Med. Volume: 8 Issue: 551 Pages: 4068-4068
  • DOI: 10.1126/scitranslmed.aay4068
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Humoral Immunity vs. Salmonella (2020)
  • Author(s): Takaya Akiko、Yamamoto Tomoko、Tokoyoda Koji
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 3155-3155
  • DOI: 10.3389/fimmu.2019.03155
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Salmonella SiiE prevents an efficient humoral immune memory by interfering with IgG+ plasma cell persistence in the bone marrow (2019)
  • Author(s): Manne Christian、Takaya Akiko、Yamasaki Yuzuru、Mursell Mathias、Hojyo Shintaro、Wu Tsung-Yen、Sarkander Jana、McGrath Mairi A.、Cornelis Rebecca、Hahne Stefanie、Cheng Qingyu、Kawamoto Tadafumi、Hiepe Falk、Kaufmann Stefan H. E.、Yamamoto Tomoko、Radbruch Andreas、Tokoyoda Koji
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 116 Issue: 15 Pages: 7425-7430
  • DOI: 10.1073/pnas.1818242116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chaperone-mediated secretion switching from early to middle substrates in the type III secretion system encoded by Salmonella pathogenicity island 2 (2019)
  • Author(s): Takaya Akiko、Takeda Hikari、Tashiro Shogo、Kawashima Hiroto、Yamamoto Tomoko
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 10 Pages: 3783-3793
  • DOI: 10.1074/jbc.ra118.005072
  • Peer Reviewed / Open Access
• [Journal Article] Diminished nuclear RNA decay upon Salmonella infection upregulates antibacterial noncoding RNAs (2018)
  • Author(s): Imamura Katsutoshi、Takaya Akiko、Ishida Yo‐ichi、Fukuoka Yayoi、Taya Toshiki、Nakaki Ryo、Kakeda Miho、Imamachi Naoto、Sato Aiko、Yamada Toshimichi、Onoguchi‐Mizutani Rena、Akizuki Gen、Tanu Tanzina、Tao Kazuyuki、Miyao Sotaro、Suzuki Yutaka、Nagahama Masami、Yamamoto Tomoko、Jensen Torben Heick、Akimitsu Nobuyoshi
  • Journal Title: The EMBO Journal Volume: 37 Issue: 13
  • DOI: 10.15252/embj.201797723
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ATP依存型Lonプロテアーゼによるパーシスタンス制御機構 (2021)
  • Author(s): 前川尚輝、板寺健悟、石原潤一、梶谷颯希、田中大器、関口哲志、庄子習一、石橋正己、高橋弘喜、高屋明子
  • Organizer: 第94回 日本細菌学会総会
• [Presentation] Large peritoneal macrophage delivers Salmonella from the peritoneal cavity to the greater omentum (2020)
  • Author(s): 高屋 明子，田代 翔吾，横井 達成，後藤 義幸，高橋 志達， 岡 健太郎，川島 博人，山本 友子
  • Organizer: 第93回日本細菌学会総会
• [Presentation] サルモネラ全身感染発症における DnaK シャペロンシステムによ る細胞分裂制御 (2020)
  • Author(s): 横井 達成，川島 博人，山本 友子，高屋 明子
  • Organizer: 第93回日本細菌学会総会
• [Presentation] Dissemination of Salmonella by Large Peritoneal Macrophages (2020)
  • Author(s): Akiko Takaya, Shogo Tashiro, Tatsunari Yokoi, Yoshiyuki Goto, Motomichi Takahashi, Kentaro Oka, Hiroto Kawashima, Tomoko Yamamoto
  • Organizer: 感染症研究グローバルネットワークフォーラム 2019
  • Int'l Joint Research
• [Presentation] Analysis of chaperones in the assembly of the type III secretion apparatus encoded by Salmonella Pathogenicity Island-2 (2020)
  • Author(s): Shogo Tashiro, Hikari Takeda, Hiroto Kawashima, Tomoko Yamamoto, Akiko Takaya
  • Organizer: 感染症研究グローバルネットワークフォーラム 2019
  • Int'l Joint Research
• [Presentation] DnaK chaperon system controls Salmonella pathogenesis via regulation of cell division (2020)
  • Author(s): Tatsunari Yokoi, Hiroto Kawashima, Tomoko Yamamoto, Akiko Takaya
  • Organizer: 感染症研究グローバルネットワークフォーラム 2019
  • Int'l Joint Research
• [Presentation] Salmonella Pathogenicity Island 4-encoded SiiE reduces IgGsecreting plasma cell in the bone marrow (2019)
  • Author(s): 高屋 明子，常世田 好司，山本 友子
  • Organizer: 第92回日本細菌学会総会
• [Presentation] サルモネラSiiEによる骨髄IgGプラズマ細胞制御 (2018)
  • Author(s): 高屋明子、常世田好司、山本友子
  • Organizer: 第１０１回日本細菌学会関東支部総会
• [Remarks] 千葉大学大学院薬学研究院免疫微生物学研究室
  • URL: http://www.p.chiba-u.jp/lab/bisei/index.html