Regulation of influenza protective antibody responses by microbiota

• Project/Area Number: 16K15296
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Takahashi Yoshimasa 国立感染症研究所, 免疫部, 部長 (60311403)
• Co-Investigator(Kenkyū-buntansha): 八村 敏志 東京大学, 大学院農学生命科学研究科(農学部), 准教授 (40238019)
• Co-Investigator(Renkei-kenkyūsha): Onodera Taishi 国立感染症研究所, 免疫部, 主任研究官 (90513143)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: インフルエンザ / 腸内細菌 / B細胞 / 抗体 / 免疫学

Outline of Final Research Achievements

In this study, we have investigated cross-reactivity of influenza hemagglutinin-binding monoclonal antibody panel to microbiota and identified several HA-binding monoclonal antibodies that are reactive to particular microbiota. Germline-reverted forms of antibodies possessed the cross-reactivity, indicating that the reactivity was already acquired in pre-immune status. Removal of microbiota using germ-free mice or antibiotics-treated mice elucidated the possible links between antigen-driven B cell development and microbiota. Thus, microbiota shapes the antibody repertoires to influenza viruses in both pre-immune and post-immune status.

Research Products

• [Journal Article] Role of germinal centers for the induction of broadly-reactive memory B cells. (2017)
  • Author(s): Takahashi Y, Kelsoe G
  • Journal Title: Current Opinion in Immunology Volume: 45 Pages: 119-125
  • DOI: 10.1016/j.coi.2017.03.002
  • Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Protective neutralizing influenza antibody response in the absence of T follicular helper cells (2016)
  • Author(s): Miyauchi K, Sugimoto-Ishige A, Harada Y, Adachi Y, Usami Y, Kaji T, Inoue K, Hasegawa H, Watanabe T, Hijikata A, Fukuyama S, Maemura T, Okada-Hatakeyama M, Ohara O, Kawaoka Y, Takahashi Y, Takemori T, Kubo M
  • Journal Title: Nature Immunology Volume: 17(12) Issue: 12 Pages: 1447-1458
  • DOI: 10.1038/ni.3563
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Regulated selection of germinal center cells into the memory B cell compartment. (2016)
  • Author(s): Shinnakasu, R., Inoue, T., Kometani, K., Moriyama, S., Adachi, Y., Nakayama, M., Takahashi, Y., Fukuyama, H., Okada, T.,Kurosaki,T.
  • Journal Title: Nat. Immunol. Volume: 17 Issue: 7 Pages: 861-9
  • DOI: 10.1038/ni.3460
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Influenza hemagglutinin epitopes emerging at viral replication sites promote the clonal selection and plasma cell development of broadly protective B cells. (2017)
  • Author(s): Adachi, Y., Nithichanon, A., Kuraoka, M., Kelsoe, G., Ato, M., Takahashi, Y.
  • Organizer: Keystone symposia
  • Int'l Joint Research
• [Presentation] Induction of broadly-protective B cell responses to mutating viruses. (2017)
  • Author(s): Takahashi, Y.
  • Organizer: 第46回日本免疫学会総会
  • Invited
• [Presentation] Regulation of antibody breadth to mutating viruses through distinct germinal center selection. (2017)
  • Author(s): Takahashi, Y., Adachi, Y., Onodera, T., Ato, M.
  • Organizer: The 16th Awaji International Forum on Infection and Immunity
  • Invited
• [Presentation] Broadly cross-reactive human memory B cells against norovirus express dual B cell antigen receptors. (2016)
  • Author(s): Onodera T, Ato M, Takahashi T
  • Organizer: 日本免疫学会
  • Place of Presentation: 沖縄
• [Presentation] Different accessibility of strain-specific versus cross-reactive BCRs to virus particles regulates site-specific germinal center selection. (2016)
  • Author(s): Adachi Y, Ato M, Takahashi Y
  • Organizer: 日本免疫学会
  • Place of Presentation: 沖縄
• [Presentation] Follicular helper NKT cells induce protective effect of a protein-based pneumococcal vaccine through stimulation of IgG production by B cells. (2016)
  • Author(s): Nakahara M, Takatsuka S, Ueno K, Onodera T, Takahashi Y, Kawakami K, Kubo M, Kinjo Y
  • Organizer: 日本免疫学会
  • Place of Presentation: 沖縄
• [Book] 次世代アジュバント開発のためのメカニズム解明と安全性評価 (2017)
  • Author(s): 高橋宜聖
  • Total Pages: 6
  • Publisher: シーエムシー出版
• [Patent(Industrial Property Rights)] MODIFIED H7 HEEMAGULUTTININ GLYCOPAROTEIN OF THE INFLUENZA A/SHANGHAI/2/2013 H7 SEQUENSE（インフルエンザ A/Shanghai/2/2013 H7ヘマグルチニン糖蛋白の修飾アミノ酸配列） (2016)
  • Inventor(s): Anne S De Groot 他3名
  • Industrial Property Rights Holder: Anne S De Groot 他3名
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-04-15
  • Overseas