インフルエンザウィルスの認識と応答

• Project Area: Molecular basis of host cell competency in virus infection
• Project/Area Number: 15H01267
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo University of Science
• Principal Investigator: 久保 允人 東京理科大学, 研究推進機構生命医科学研究所, 教授 (40277281)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000); Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: インフルエンザ / ウイルス / 1分子解析 / インフルエンザウイルス

Outline of Annual Research Achievements

インフルエンザウイルス感染症において肺炎は主要な死因の一つであるが、その発症機序については不明な部分が多い。インフルエンザウイルスは肺胞上皮細胞やマクロファージで増殖し、NK細胞、マクロファージ、好中球が主な自然免疫担当細胞と考えられてきた。ところが、この肺炎症はマスト細胞の存在に依存することが、ジフテリアトキシン投与によりマスト細胞を除去できるMas-TRECKマウスシステムを用いて証明された。マスト細胞は細胞内にヒスタミンなどを含む多くの顆粒を保有し、脱顆粒によりアレルギー症状を引き起こす肺にも数多く分布する自然免疫細胞である。RNAsequencingによりウイルス感染後の遺伝子プロファイルを解析したところ、Mas-TRECKマウス由来のマクロファージでは、RIG-IやMxなどを含む抗ウイルス性遺伝子の発現が減弱しており、これに伴い肺への炎症性細胞の浸潤や出血の低下が観察された。同様の発現解析を自然免疫細胞ごと経時的に解析したところ、膜結合型セリンプロテアーゼTMPRSS2の発現がマスト細胞特異的に上昇していた。この酵素はウイルスのヘムアグルチニン（HA）を壊裂しウイルス増殖を促すことが知られている。このことからマスト細胞が感染初期におけるウイルス増殖を規定する可能性を想定したところ、マスト細胞の有無とウイルス増殖には高い相関が認められた。しかしながらマスト細胞由来のTMPRSS2が直接ウイルスの増殖を規定する機構の存在は証明できなかった。一方、トリプターゼは、マスト細胞特異的なプロテアーゼとして知られている。この酵素はTMPRSS2同様、HAを壊裂可能であることが証明されたことから、マスト細胞によるウイルス増殖は、トリプターゼによって規定されうることが明らかになり、これまで知られていなかったマスト細胞の新たな機能が明らかにされた。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Innate and adaptive type 2 immunity in lung allergic inflammation (2017)
  • Author(s): Kubo, M
  • Journal Title: Immunolgical Review Volume: - Issue: 1 Pages: 162-172
  • DOI: 10.1111/imr.12557
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Basophil-derived interleukin-4 promotes epicutaneous antigen sensitization concomitant with the development of food allergy (2017)
  • Author(s): Hussain M, Borcard L, Walsh KP, Pena Rodriguez M, Mueller C, Kim BS, Kubo M, Artis D, Noti M
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: - Issue: 1 Pages: 223-234.e5
  • DOI: 10.1016/j.jaci.2017.02.035
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] E3 ubiquitin ligases SIAH1/2 regulates hypoxia-inducible factor 1(HIF1)-mediated TH17 cell differentiation (2017)
  • Author(s): Matsui-Hasumi A, Sato Y, Uto-Konomi A, Yamashita S, Uehori J, Yoshimura A, Yamashita M, Asahara H, Suzuki S, Kubo M
  • Journal Title: Int.Immunol Volume: - Issue: 3 Pages: 133-143
  • DOI: 10.1093/intimm/dxx014
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Differences in the importance of mast cells, basophils, IgE and IgG, versus CD4+ T cells and ILC2 cells, in primary and secondary immunity to Strongyloides venezuelensis (2017)
  • Author(s): Mukai K, Karasuyama H, Kabashima K, Kubo M, Galli SJ
  • Journal Title: Infect Immun Volume: - Issue: 5
  • DOI: 10.1128/iai.00053-17
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] IL4 from T Follicular Helper Cells Downregulates Antitumor Immunity (2017)
  • Author(s): Shirota H, Klinman DM, Ito SE, Ito H, Kubo M, Ishioka C
  • Journal Title: Cancer Immunology Research Volume: 5（1） Pages: 61-71
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Allergin-1 inhibits TLR2-mediated mast cell activation and suppresses dermatitis (2016)
  • Author(s): Tsurusaki S, Tahara-Hanaoka S, Shibagaki S, Miyake S, Imai M, Shibayama S, Kubo M, Shibuya A
  • Journal Title: International Immunology Volume: 28(12) Issue: 12 Pages: 605-609
  • DOI: 10.1093/intimm/dxw046
  • NAID: 120007135029
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mathematical modeling of atopic dermatitis reveals “double switch” mechanisms underlying 4 common disease phenotypes (2016)
  • Author(s): Domínguez-Hüttinger E, Christodoulides P, Miyauchi K, Irvine AD, Okada-Hatakeyama M, Kubo M, Tanaka RJ
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: - Issue: 6 Pages: 1861-1872.e7
  • DOI: 10.1016/j.jaci.2016.10.026
  • Peer Reviewed / Open Access / 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） Pages: 1447-1458
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis (2016)
  • Author(s): Yasuda T, Fukada T, Nishida K, Nakayama M, Matsuda M, Miura I, Dainichi T, Fukuda S, Kabashima K, Nakaoka S, Bin BH, Kubo M, Ohno H, Hasegawa T, Ohara O, Koseki H, Wakana S, Yoshida H
  • Journal Title: J. Clin. Invest Volume: 126(6) Issue: 6 Pages: 2064-76
  • DOI: 10.1172/jci82887
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Oncolytic reovirus synergizes with chemotherapeutic agents to promote cell death in canine mammary gland tumor (2016)
  • Author(s): Igase M, Hwang CC, Kambayashi S, Kubo M, Coffey M, Miyama TS, Baba K, Okuda M, Noguchi S, Mizuno T
  • Journal Title: Can J Vet Res Volume: 80(1) Pages: 21-31
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CRTAM determines the CD4+ cytotoxic T lymphocyte lineage. (2016)
  • Author(s): Takeuchi, A., Badr Mel, S., Miyauchi, K., Ishihara, C., Onishi, R., Guo, Z., Sasaki. Y., Ike, H., Takumi, A., Tsuji, NM., Murakami, Y., Katakai, T., Kubo, M. and Saito, T.
  • Journal Title: J. Exp. Med. Volume: 213 Issue: 1 Pages: 123-138
  • DOI: 10.1084/jem.20150519
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High affinity IgM(+) memory B cells are generated through a germinal center-dependent pathway (2015)
  • Author(s): Hara Y, Tashiro Y, Murakami A, Nishimura M, Shimizu T, Kubo M, Burrows PD, Azuma T
  • Journal Title: Mol Immunol Volume: 68(2 Pt C) Issue: 2 Pages: 617-27
  • DOI: 10.1016/j.molimm.2015.10.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] PU.1 Suppresses Th2 Cytokine Expression via Silencing of GATA3 Transcription in Dendritic Cells (2015)
  • Author(s): Yashiro T, Kubo M, Ogawa H, Okumura K, Nishiyama C
  • Journal Title: PLoS One Volume: 10(9) Issue: 9 Pages: e0137699-e0137699
  • DOI: 10.1371/journal.pone.0137699
  • Peer Reviewed / Open Access
• [Journal Article] TCF-1 and LEF-1 help launch the T(FH) program (2015)
  • Author(s): Kubo M
  • Journal Title: Nat Immunol Volume: 16(9) Issue: 9 Pages: 900-1
  • DOI: 10.1038/ni.3254
  • Peer Reviewed
• [Journal Article] An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers. (2015)
  • Author(s): Morita H, Arae K, Unno H, Miyauchi K, Toyama S, Nambu A, Oboki K, Ohno T, Motomura K, Matsuda A, Yamaguchi S, Narushima S, Kajiwara N, Iikura M, Suto H, McKenzie AN, Takahashi T, Karasuyama H, Okumura K, Azuma M, Moro K, Akdis CA, Galli SJ, Koyasu S, Kubo M, Sudo K, Saito H, Matsumoto K, Nakae S.
  • Journal Title: Immunity Volume: 43 Issue: 1 Pages: 175-86
  • DOI: 10.1016/j.immuni.2015.06.021
  • NAID: 40020962854
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Notch signaling enhances FceRI-mediated cytokine production by mast cells through direct and indirect mechanisms (2015)
  • Author(s): Nakano, N., Nishiyama, C., Yagita, H., Hara, M., Motomura, Y., Kubo, M., Okumura, K., and Ogawa, H
  • Journal Title: J. Immunol Volume: 194(9) Issue: 9 Pages: 4535-44
  • DOI: 10.4049/jimmunol.1301850
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Zinc-binding metallothioneins are key modulators of IL-4 production by basophils (2015)
  • Author(s): Ugajin T, Nishida K, Yamasaki S, Suzuki J, Mita M, Kubo M, Yokozeki H, Hirano T
  • Journal Title: Mol Immunol Volume: 66 Issue: 2 Pages: 180-188
  • DOI: 10.1016/j.molimm.2015.03.002
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors (2015)
  • Author(s): Wei Xu, Rita G. Domingues, Diogo Fonseca-Pereira, Manuela Ferreira, Hélder Ribeiro, Silvia Lopez-Lastra, Yasutaka Motomura, Lara Moreira-Santos, Franck Bihl4, Véronique Braud, Barbara Kee, Hugh Brady, Mark C.Coles, Christian Vosshenrich, Kubo, M., James P. Di Santo and Henrique Veiga-Fernandes
  • Journal Title: Cell Report Volume: 10(12) Issue: 12 Pages: 2043-54
  • DOI: 10.1016/j.celrep.2015.02.057
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Helios enhances regulatory T cell function in cooperation with Foxp3 (2015)
  • Author(s): Takatori H, Kawashima H, Matsuki A, Meguro K, Tanaka S, Iwamoto T, Sanayama Y, Nishikawa N, Tamachi T, Ikeda K, Suto A, Suzuki K, Kagami S, Hirose K, Kubo M, Hori S, Nakajima H
  • Journal Title: Arthritis Rheumatol Volume: 67 Issue: 6 Pages: 1491-502
  • DOI: 10.1002/art.39091
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 新たなアレルギー発症メカニズム (2015)
  • Author(s): 久保允人
  • Journal Title: ファルマシア Volume: 51（6） Pages: 526-531
  • NAID: 130007448190
• [Journal Article] 好塩基球による免疫応答制御 (2015)
  • Author(s): 久保允人
  • Journal Title: 感染・炎症・免疫 Volume: 45-2 Pages: 63-67
• [Presentation] Role of T follicular helper (Tfh) and Th1 cells in anti-viral immunity (2017)
  • Author(s): Kubo Msaato
  • Organizer: 7th International Workshop of Kyoto T Cell Conference
  • Place of Presentation: Shiran Kaikan, Kyoto University, Kyoto
  • Year and Date: 2017-03-13
  • Int'l Joint Research
• [Presentation] New therapeutic approach for atopic dermatitis (AD) using comprehensive analysis and system biology (2017)
  • Author(s): Kubo Masato
  • Organizer: 2017 INTERNATIONAL BIOMEDECAL INTERFACE SYMPOSIUM
  • Place of Presentation: Taipei Medical University, Taipei, Taiwan
  • Year and Date: 2017-03-04
  • Int'l Joint Research / Invited
• [Presentation] Essential role of E4BP4 in effector function of lung ILC2 (2016)
  • Author(s): SUZUKI Narumi, OMI Ai, MIYAUCHI Kosuke, KUBO Masato
  • Organizer: The 45th Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: Okinawa Convention Center, Laguna Garden Hotel(Okinawa)
  • Year and Date: 2016-12-05
  • Int'l Joint Research
• [Presentation] IFNg and IL-6-dependent production of influenza virus specific IgA (2016)
  • Author(s): MIYAUCHI Kosuke, TAKEMORI Toshitada, KUBO Masato
  • Organizer: The 45th Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: Okinawa Convention Center, Laguna Garden Hotel(Okinawa)
  • Year and Date: 2016-12-05
  • Int'l Joint Research
• [Presentation] Role of T follicular helper (TFH) in humoral immunity (2016)
  • Author(s): Kubo Masato
  • Organizer: The 13th International Workshop on Autoantibodies and Autoimmunity (IWAA2016)
  • Place of Presentation: The Westin Miyako Kyoto(Kyoto)
  • Year and Date: 2016-10-11
  • Int'l Joint Research / Invited
• [Presentation] サイトカインシグナルと皮膚恒常性 (2016)
  • Author(s): 久保允人
  • Organizer: NEXT Lecture Meeting in Chiba
  • Place of Presentation: 千葉大学(千葉県千葉市)
  • Invited
• [Presentation] インフルエンザウイルスに対するT細胞依存性抗体産生制御機構 (2016)
  • Author(s): 久保允人
  • Organizer: ウイルス研究の潮流
  • Place of Presentation: 京都大学(京都府)
  • Invited
• [Presentation] 免疫疾患における細胞内シグナル伝達・サイトカインの基礎から応用へ (2016)
  • Author(s): 久保允人
  • Organizer: Cytokine Network Seminar ～免疫シグナル伝達の解明・進展～
  • Place of Presentation: 大阪大学(大阪府)
  • Invited
• [Presentation] アレルギーにおける自然免疫と獲得免疫のクロストーク (2016)
  • Author(s): 久保允人
  • Organizer: 第65回日本アレルギー学会学術大会
  • Place of Presentation: 東京国際フォーラム (東京)
  • Invited
• [Presentation] Humoral Immunity against Influenza virus infection (2015)
  • Author(s): KUBO Masato
  • Organizer: The 44th Annual Meeting of the Japanese Society for Immunology (JSI)
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2015-11-18
  • Int'l Joint Research / Invited
• [Presentation] Most of the CD8＋TIL are tumor-reactive in spontaneously regressing or progressing murine gastric cancer (2015)
  • Author(s): NAGAOKA Koji, HOSOI Akihiro, MATSUSHITA Hirokazu, KUBO Masato, TAKEDA Kazuyoshi, KAKIMI Kazuhiro
  • Organizer: The 44th Annual Meeting of the Japanese Society for Immunology (JSI)
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2015-11-18
  • Int'l Joint Research
• [Presentation] Germinal centers and follicular helper T cells are dispensable for a protective antibody response to acute influenza A virus infection (2015)
  • Author(s): MIYAUCHI Kosuke, SUGIMOTO-ISHIGE Akiko, TAKAHASHI Yoshimasa, HASEGAWA Hideki, TAKEMORI Toshitada, KUBO Masato
  • Organizer: The 44th Annual Meeting of the Japanese Society for Immunology (JSI)
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2015-11-18
  • Int'l Joint Research
• [Presentation] Pathogenic effect of PM2.5 and nanoparticle in Lung inflammation (2015)
  • Author(s): THARMALINGAM Jayaraman, MIYAUCHI Kosuke, KUBO Masato
  • Organizer: The 44th Annual Meeting of the Japanese Society for Immunology (JSI)
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2015-11-18
  • Int'l Joint Research
• [Presentation] Innate and acquired immunity in influenza virus infection (2015)
  • Author(s): KUBO Masato
  • Organizer: 2015 Fall Conference of The Korean Association of the Immunologists
  • Place of Presentation: Sejong University Convention Center（ Soul, Korea）
  • Year and Date: 2015-11-12
  • Int'l Joint Research / Invited
• [Presentation] Innate and acquired immunity in influenza virus infection (2015)
  • Author(s): KUBO Masato
  • Organizer: International Symposium on Allergy and Inflammation 2015
  • Place of Presentation: 大洗パークホテル（茨城県東茨城郡）
  • Year and Date: 2015-10-29
  • Int'l Joint Research / Invited
• [Presentation] アレルギーにおける白血球・リンパ球の役割 (2015)
  • Author(s): 久保允人
  • Organizer: 鹿児島呼吸器セミナー
  • Place of Presentation: 鹿児島大学（鹿児島県鹿児島市）
  • Year and Date: 2015-09-15
  • Invited
• [Presentation] Host defense mechanisms against Influenza virus infection (2015)
  • Author(s): KUBO Masato
  • Organizer: International Symposium of Center for Animal Disease Model (CADMIS) 2015
  • Place of Presentation: 学士会館（東京都千代田区）
  • Year and Date: 2015-07-21
  • Int'l Joint Research / Invited
• [Presentation] 転写因子E4BP4と自然リンパ球によるアレルギー性気道炎症の制御 (2015)
  • Author(s): 久保允人
  • Organizer: 第80回日本インターフェロン・サイトカイン学会学術集会
  • Place of Presentation: 東京工業大学（東京都目黒区）
  • Year and Date: 2015-07-17
  • Invited
• [Presentation] 皮膚の恒常と炎症の制御 (2015)
  • Author(s): 久保允人
  • Organizer: 第22回四国四大学皮膚科研究会
  • Place of Presentation: ザ クラウンパレス新阪急高知（高知県高知市）
  • Year and Date: 2015-07-11
  • Invited
• [Presentation] インフルエンザ感染における気道炎症制御と抗体産生制御について (2015)
  • Author(s): 久保允人
  • Organizer: ヘルスバイオサイエンス研究部 免疫学セミナー
  • Place of Presentation: 徳島大学医学部（徳島県徳島市）
  • Year and Date: 2015-07-10
  • Invited
• [Presentation] マスト細胞・好塩基球欠損マウスシステムの構築とサイトカイン産生能 (2015)
  • Author(s): 久保允人
  • Organizer: 第64回日本アレルギー学会学術大会
  • Place of Presentation: グランドプリンスホテル新高輪（東京都港区）
  • Year and Date: 2015-05-28
  • Invited
• [Presentation] 転写因子E4BP4 と自然リンパ球によるアレルギー性気道炎症の制御 (2015)
  • Author(s): 久保允人
  • Organizer: 第64回日本アレルギー学会学術大会
  • Place of Presentation: グランドプリンスホテル新高輪（東京都港区）
  • Year and Date: 2015-05-26
  • Invited
• [Presentation] アレルギー性気道炎症における自然免疫細胞 (2015)
  • Author(s): 久保允人
  • Organizer: SCIENCE in Shinagawa
  • Place of Presentation: ガーデンシティ品川（東京都港区）
  • Year and Date: 2015-04-18
  • Invited