Cross-reactive antibodies to influenza virus hemagglutinins and their epitopes

• Project/Area Number: 24390110
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: Hokkaido University
• Principal Investigator: Takada Ayato 北海道大学, 人獣共通感染症リサーチセンター, 教授 (10292062)
• Co-Investigator(Renkei-kenkyūsha): ITO Kimihito 北海道大学, 人獣共通感染症リサーチセンター, 教授 (60396314) ; IGARASHI Manabu 北海道大学, 人獣共通感染症リサーチセンター, 准教授 (10374240)
• Research Collaborator: YOSHIDA Reiko ; MURAMATSU Mieko ; MIYAMOTO Hiroko ; Wilson Ian
• Project Period (FY): 2012-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2015: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2014: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2013: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
• Keywords: ウイルス / インフルエンザ / 亜型 / 抗体 / 中和 / 感染防御 / 感染症 / インフルエンザウイルス / ヘマグルチニン / 亜型間交差 / 感染性中和

Outline of Final Research Achievements

By focusing on a novel antiviral function (budding inhibition), we found potential roles of anti-hemagglutinin antibodies in cross-protective immunity against influenza A viruses with multiple HA subtypes. It was particularly noted that the comparison between IgG and IgA antibodies recognizing the same epitope on the HA molecule clearly demonstrated the greater potential of HA-specific IgA than IgG antibodies in antiviral activities. It was also attempted to modify antibody specificity by structure-based molecular simulation and production of recombinant antibodies.

Research Products

• [Int'l Joint Research] The Scripps Research Institute(米国)
• [Journal Article] Genetic predisposition to acquire a polybasic cleavage site for highly pathogenic avian influenza virus hemagglutinin (2017)
  • Author(s): Nao N, Yamagishi J, Miyamoto H, Igarashi M, Manzoor R, Ohnuma A, Tsuda Y, Furuyama W, Shigeno A, Kajihara M, Kishida N, Yoshida R, Takada A
  • Journal Title: MBio Volume: 8 Issue: 1 Pages: 1-15
  • DOI: 10.1128/mbio.02298-16
  • NAID: 120006337761
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Constitutive aryl hydrocarbon receptor signaling constrains type I interferon-mediated antiviral innate defense. (2016)
  • Author(s): Yamada T, Horimoto H, Kameyama T, Hayakawa S, Yamato H, Dazai M, Takada A, Kida H, Bott D, Zhou AC, Hutin D, Watts TH, Asaka M, Matthews, Takaoka A
  • Journal Title: Nat Immunol. Volume: 印刷中 Issue: 6 Pages: 687-694
  • DOI: 10.1038/ni.3422
  • NAID: 120005849912
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Characterization of the glycoproteins of bat-derived influenza viruses. (2016)
  • Author(s): Maruyama J, Nao N, Miyamoto H, Maeda K, Ogawa H, Yoshida R, Igarashi M, Takada A
  • Journal Title: Virology Volume: 488 Pages: 43-50
  • DOI: 10.1016/j.virol.2015.11.002
  • NAID: 120005906991
  • Peer Reviewed / Open Access
• [Journal Article] Genetic and antigenic characterization of H5 and H7 influenza viruses isolated from migratory water birds in Hokkaido, Japan and Mongolia from 2010 to 2014 (2015)
  • Author(s): Hiono T, Ohkawara A, Ogasawara K, Okamatsu M, Tamura T, Chu DH, Suzuki M, Kuribayashi S, Shichinohe S, Takada A, Ogawa H, Yoshida R, Miyamoto H, Nao N, Furuyama W, Maruyama J, Eguchi N, Ulziibat G, Enkhbold B, Shatar M, Jargalsaikhan T, Byambadorj S, Damdinjav B, Sakoda Y, Kida H.
  • Journal Title: Virus Genes Volume: 51 (1) Issue: 1 Pages: 57-68
  • DOI: 10.1007/s11262-015-1214-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A Single Amino Acid in the M1 Protein Responsible for the Different Pathogenic Potentials of H5N1 Highly Pathogenic Avian Influenza Virus Strains (2015)
  • Author(s): Nao N, Kajihara M, Manzoor R, Maruyama J, Yoshida R, Muramatsu M, Miyamoto H, Igarashi M, Eguchi N, Sato M, Kondoh T, Okamatsu M, Sakoda Y, Kida H, Takada A
  • Journal Title: PLoS One Volume: 10(9) Issue: 9 Pages: e0137989-e0137989
  • DOI: 10.1371/journal.pone.0137989
  • NAID: 120005672370
  • Peer Reviewed / Open Access
• [Journal Article] Effect of the PB2 and M genes on the replication of H6 influenza virus in chickens (2014)
  • Author(s): Ozaki H, Guan Y, Peiris M, Webster R, Takada A, Webby R
  • Journal Title: Influenza. Res. Treat. Volume: 該当しない Pages: 547839-547839
  • DOI: 10.1155/2014/547839
  • Peer Reviewed / Open Access
• [Journal Article] The zoonotic potential of avian influenza viruses isolated from wild waterfowl in Zambia (2014)
  • Author(s): Simulundu E, Nao N, Yabe J, Muto NA, Sithebe T, Sawa H, Manzoor R, Kajihara M, Muramatsu M, Ishii A, Ogawa H, Mweene AS, Takada A
  • Journal Title: Arch. Virol. Volume: 159 Issue: 6 Pages: 2633-2640
  • DOI: 10.1371/journal.ppat.1004192
  • NAID: 120005656330
  • Peer Reviewed / Open Access
• [Journal Article] Novel mutations in Marburg virus glycoprotein associated with viral evasion from antibody mediated immune pressure. (2013)
  • Author(s): Kajihara, M., et al.
  • Journal Title: Journal of general virology Volume: 94 Issue: 4 Pages: 876-883
  • DOI: 10.1099/vir.0.049114-0
  • Peer Reviewed
• [Journal Article] The genetic and antigenic diversity of avian influenza viruses isolated from domestic ducks, muscovy ducks, and chickens in northern and southern Vietnam, 2010-2012 (2013)
  • Author(s): Okamatsu M, Nishi T, Nomura N, Yamamoto N, Sakoda Y, Sakurai K, Chu HD, Thanh LP, Van Nguyen L, Van Hoang N, Tien TN, Yoshida R, Takada A, Kida H
  • Journal Title: Virus Genes Volume: 47 Issue: 2 Pages: 317-329
  • DOI: 10.1007/s11262-013-0954-7
  • Peer Reviewed
• [Journal Article] Heterosubtypic antiviral activity of hemagglutinin-specific antibodies induced by intranasal immunization with inactivated influenza viruses in mice. (2013)
  • Author(s): Muramatsu M. et al.
  • Journal Title: PLoS One Volume: 8 Issue: 8 Pages: e71534-e71534
  • DOI: 10.1371/journal.pone.0071534
  • Peer Reviewed
• [Journal Article] Comparison of Antiviral Activity between IgA and IgG Specific to Influenza Virus Hemagglutinin: Increased Potential of IgA for Heterosubtypic Immunity (2013)
  • Author(s): Muramatsu M, Yoshida R, Yokoyama A, Miyamoto H, Kajihara M, Maruyama J, Nao N, Manzoor R, Takada A
  • Journal Title: PLoS ONE Volume: 9 Issue: 1 Pages: e85582-e85582
  • DOI: 10.1371/journal.pone.0085582
  • NAID: 120005425353
  • Peer Reviewed
• [Journal Article] Heat Shock Protein 70 Modulates Influenza A Virus Polymerase Activity (2013)
  • Author(s): Manzoor R, Kuroda K, Yoshida R, Tsuda Y, Fujikura D, Miyamoto H, Kajihara M, Kida H, Takada A
  • Journal Title: J. Biol. Chem. Volume: 289 Issue: 11 Pages: 7599-7614
  • DOI: 10.1074/jbc.m113.507798
  • NAID: 120005460233
  • Peer Reviewed
• [Journal Article] Heterosubtypic antibody recognition of the influenza virus hemagglutinin receptor binding site enhanced bv avidity. (2012)
  • Author(s): Lee PS, Yoshida R, Ekiert DC, Sakai N, Suzuki Y, Takada A, Wilson IA.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 109 Issue: 42 Pages: 13467-13474
  • DOI: 10.1073/pnas.1212371109
  • Peer Reviewed
• [Journal Article] Inhibition of Marburg virus budding by nonneutralizing antibodies to the envelope glycoprotein. (2012)
  • Author(s): Kajihara M, Marzi A, Nakayama E, Noda T, Kuroda M, Manzoor R, Matsuno K, Feldmann
  • Journal Title: J Virol Volume: 86 Pages: 13467-13474
  • Peer Reviewed
• [Journal Article] Inhibitory effects of an M2-specific monoclonal antibody on different strains of influenza A virus. (2012)
  • Author(s): Muto NA, Yoshida R, Suzuki T, Kobayashi s, Ozaki H, Fujikura D, Manzoor R, Muramatsu M, Takada A, Kimura T, Sawa H.
  • Journal Title: Jpn J Vet Res Volume: 60 Pages: 71-83
  • Peer Reviewed
• [Presentation] Genetic Predisposition to Acquire a Polybasic Cleavage Site for Highly Pathogenic Avian Influenza Virus Hemagglutinin/インフルエンザウイルスヘマグルチニン開裂部位への塩基性アミノ酸挿入メカニズム解 (2016)
  • Author(s): Naganori Nao, Junya Yamagishi, Hiroko Miyamoto, Manabu Igarashi, Rashid Manzoor, Aiko Ohnuma, Yoshimi Tsuda, Wakako Furuyama, Masahiro Kajihara, Reiko Yoshida, Ayato Takada
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（札幌市、日本）
  • Year and Date: 2016-10-23
• [Presentation] Computational analysis of a conformational epitope of a broadly neutralizing antibody in influenza A virus hemagglutinin (2016)
  • Author(s): Manabu Igarashi，Masakazu Sekijima，Nobuaki Yasuo，Takashi Abe，Reiko Yoshida，Hiroaki Tokiwa，Teruaki Watabe，Takatsugu Hirokawa，Ayato Takada
  • Organizer: Options IX for the Control of Influenza
  • Place of Presentation: Sheraton Grand Chicago Hotel (Chicago, USA)
  • Year and Date: 2016-08-26
  • Int'l Joint Research
• [Presentation] A genetic basis for the acquisition of basic amino acid residues at the cleavage site of influenza virus hemagglutinin (2016)
  • Author(s): Naganori Nao, Junya Yamagishi, Hiroko Miyamoto, Aiko Ohnuma, Wakako Furuyama, Yoshimi Tsuda, Rashid Manzoor, Reiko Yoshida, Manabu Igarashi, Ayato Takada
  • Organizer: Options IX for the Control of Influenza
  • Place of Presentation: Sheraton Grand Chicago Hotel (Chicago, USA)
  • Year and Date: 2016-08-25
  • Int'l Joint Research
• [Presentation] 人獣共通感染症としてのインフルエンザ (2016)
  • Author(s): 高田礼人
  • Organizer: 第24回呼吸器疾患・感染症研究会
  • Place of Presentation: 泉ガーデンタワー（東京港区、日本）
  • Year and Date: 2016-08-20
  • Invited
• [Presentation] 人獣共通感染症研究最前線 －エボラ出血熱とインフルエンザ－ (2016)
  • Author(s): 高田礼人
  • Organizer: 第４５回野依フォーラム例会
  • Place of Presentation: 名古屋大学 野依記念物質科学研究館（名古屋市、日本）
  • Year and Date: 2016-04-15
  • Invited
• [Presentation] Characterization of the glycoproteins of bat-derived influenza viruses (2015)
  • Author(s): Junki Maruyama，Naganori Nao，Hiroko Miyamoto，Ken Maeda，Hirohito Ogawa，Reiko Yoshida，Manabu Igarashi，Ayato Takada
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡市、日本）
  • Year and Date: 2015-11-22
• [Presentation] Characterization of the hemagglutinin of bat-derived influenza viruses (2015)
  • Author(s): Junki Maruyama, Nao Naganori, Hiroko Miyamoto, Ken Maeda, Hirohito Ogawa, Reiko Yoshida, Ayato Takada
  • Organizer: Sixteenth International Conference on Negative Strand Viruses
  • Place of Presentation: Auditorium Department of Law (Siena, Italy)
  • Year and Date: 2015-06-15
  • Int'l Joint Research
• [Presentation] Comparison of Antiviral Activity Between IgA and IgG Specific to Influenza Virus Hemagglutinin: Increased Potential of IgA for Heterosubtypic Immunity (2015)
  • Author(s): Ayato Takada
  • Organizer: Acute Respiratory Infections (ARI) Panel Meeting, 17th International Conference on Emerging Infectious Diseases (EID) in the Pacific Rim Emerging Viral Diseases, United States-Japan
  • Place of Presentation: Academia Sinica (Taipei, Taiwan)
  • Year and Date: 2015-01-28
  • Invited
• [Presentation] H5N1 インフルエンザウイルスに対する中和抗体を用いた受動免疫の感染防御効果 (2014)
  • Author(s): 吉田玲子、伊藤靖、七戸新太郎、小笠原一誠、日尾野隆大、岡松正敏、迫田義博、喜田宏、Mai Quynh Le、河岡義裕、五十嵐学、鈴木定彦、高田礼人
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: パシフィコ横浜（横浜市、日本）
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] A 型インフルエンザウイルスヘマグルチニン特異的IgA 抗体の亜型間交差抗ウイルス活性 (2014)
  • Author(s): 村松美笑子、吉田玲子、横山文香、宮本洋子、梶原将大、丸山隼輝、直享則、Rashid Manzoor、高田礼人
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: パシフィコ横浜（横浜市、日本）
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] Comparison of antiviral activity between IgA and IgG: High potential of IgA antibodies specific to influenza virus hemagglutinin for heterosubtypic immunity (2014)
  • Author(s): Mieko Muramatsu, Reioko Yoshida, Ayaka Yokoyama, Hiroko Miyamoto, Masahiro Kajihara, Junki Maruyama, Naganori Nao, Rashid Manzoor, Ayato Takada
  • Organizer: The 13th Awaji International Forum on Infection and Immunity
  • Place of Presentation: 奈良県新公会堂（奈良市、日本）
  • Year and Date: 2014-09-24 – 2014-09-25
• [Presentation] Neutralizing monoclonal antibody therapy for H5N1 highly pathogenic avian influenza virus infection in animal models (2014)
  • Author(s): Reiko Yoshida, Yasushi Itoh, Shintaro Shichinohe, Kazumasa Ogasawara, Masatoshi Okamatsu, Yoshihiro Sakoda, Hiroshi Kida, Quynh Mai Le, Yoshihiro Kawaoka, Manabu Igarashi, Yasuhiko Suzuki, Ayato Takada
  • Organizer: The 13th Awaji International Forum on Infection and Immunity
  • Place of Presentation: 奈良県新公会堂（奈良市、日本）
  • Year and Date: 2014-09-24 – 2014-09-25
• [Presentation] Correlates of Hsp70 kinetics and influenza A virus polymerase activity (2014)
  • Author(s): Rashid Manzoor, Kazumichi Kuroda, Reiko Yoshida, Yoshimi Tsuda, Daisuke Fujikura, Hiroko Miyamoto, Masahiro Kajihara, Hiroshi Kida, Ayato Takada
  • Organizer: The 13th Awaji International Forum on Infection and Immunity
  • Place of Presentation: 奈良県新公会堂（奈良市、日本）
  • Year and Date: 2014-09-24 – 2014-09-25
• [Presentation] Comparison of antiviral activity between IgA and IgG (2014)
  • Author(s): Mieko Muramatsu, ReikoYoshida, Ayato Takada
  • Organizer: XVI International Congress of Virology
  • Place of Presentation: Montreal Convention Centre (Montreal, Canada)
  • Year and Date: 2014-07-28 – 2014-07-31
• [Presentation] Different pathogenicity of H5N1 highly pathogenic avian influenza viruses determined by a single amino acid in the M1 protein (2014)
  • Author(s): Naganori Nao, Masahiro Kajihara, Junki Maruyama, Takashi Kimura, Rashid Manzoor, Mieko Muramatsu, Reiko Yoshida, Masatoshi Okamatsu, Hiroshi Kida, Ayato Takada
  • Organizer: XVI International Congress of Virology
  • Place of Presentation: Montreal Convention Centre (Montreal, Canada)
  • Year and Date: 2014-07-28 – 2014-07-31
• [Presentation] 鳥インフルエンザの基礎 (2014)
  • Author(s): 高田礼人
  • Organizer: 第12回インフルエンザ夏季セミナー
  • Place of Presentation: 第一ホテル東京（東京都港区、日本）
  • Year and Date: 2014-07-20
  • Invited
• [Presentation] インフルエンザウイルスヘマグルチニン特異抗体の亜型間交差反応性 (2012)
  • Author(s): 村松美笑子、吉田玲子、宮本洋子、高田礼人
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: 大阪国際会議場、大阪
  • Year and Date: 2012-11-15
• [Presentation] 抗体によるマールブルグウイルスの出芽阻害 (2012)
  • Author(s): 梶原将大、Marzi Andrea、中山絵里、野田岳志、黒田誠、Manzoor Rashid、Feldmann Heinz、吉田玲子、河岡義裕、高田礼人
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: 大阪国際会議場、大阪
  • Year and Date: 2012-11-15
• [Presentation] 不活化インフルエンザウイルス接種によって誘導されるヘマグルチニン特異抗体の亜型間交 (2012)
  • Author(s): 村松美笑子、吉田玲子、宮本洋子、高田礼人
  • Organizer: 第154回日本獣医学会学術集会
  • Place of Presentation: 岩手大学、盛岡
  • Year and Date: 2012-09-14
• [Presentation] 抗体によるマールブルグウイルスの出芽阻害 (2012)
  • Author(s): 梶原将大、Andrea Marzi、中山絵里、野田岳志、黒田誠、Rashid Manzoor,松野啓太、Heinz Feldmann、吉田玲子、河岡義裕、高田礼人
  • Organizer: 第154回日本獣医学会学術集会
  • Place of Presentation: 岩手大学、盛岡
  • Year and Date: 2012-09-14
• [Presentation] Heterosubtypic binding activity of hemagglutinin-specific antibodies induced by inoculation of inactivated influenza virus in mice (2012)
  • Author(s): Mieko Muramatsu, Reiko Yoshida, Ayato Takada
  • Organizer: The 9th Japan-China International Conference of Virology
  • Place of Presentation: 北海道大学、札幌
  • Year and Date: 2012-06-12
• [Presentation] Modulatory effect of heat shock protein 70 (Hsp70) on influenza A virus polymerase activity
  • Author(s): Rashid Manzoor, Kazumichi Kuroda, Reiko Yoshida, Yoshimi Tsuda, Daisuke Fujikura, Hiroko Miyamoto, Masahiro Kajihara, Hiroshi Kida, Ayato Takada
  • Organizer: Fifteenth International Conference on Negative Strand Viruses
  • Place of Presentation: Palacio de Exposiciones y Congresos, Granada (Spain)
• [Presentation] Heterosubtypic antiviral activity of influenza virus
  • Author(s): Mieko Muramatsu, ReikoYoshida, Ayato Takada
  • Organizer: Fifteenth International Conference on Negative Strand Viruses
  • Place of Presentation: Palacio de Exposiciones y Congresos, Granada (Spain)
• [Presentation] Pathogenicity of H5N1 highly pathogenic avian influenza virus in wild ducks and herons
  • Author(s): Kosuke Soda, Tatsufumi Usui1, Yukiko Uno, Yasuko Nagai, Hiroichi Ozaki, Hiroshi Ito, Naoki Yamamoto, Tomokazu Tamura, Takahiro Hiono, Masatoshi Okamatsu, Yoshihiro Sakoda, Ayato Takada, Tsuyoshi Yamaguchi, Toshihiro Ito
  • Organizer: Fifteenth International Conference on Negative Strand Viruses
  • Place of Presentation: Palacio de Exposiciones y Congresos, Granada (Spain)
• [Presentation] A formula on the number of amino acid substitutions on the hemagglutinin molecules of H3N2 seasonal influenza viruses
  • Author(s): Kimihito Ito, Manabu Igarashi, Ayato Takada
  • Organizer: Fifteenth International Conference on Negative Strand Viruses
  • Place of Presentation: Palacio de Exposiciones y Congresos, Granada (Spain)
• [Presentation] 2010年に稚内で分離された2株の高病原性鳥インフルエンザウイルスの病原性比較
  • Author(s): 直亨則、梶原将大、丸山隼輝、木村享史、Manzoor Rashid、村松美笑子、岡松正敏、宮本洋子、吉田玲子、迫田義博、喜田宏、高田礼人
  • Organizer: 第61回日本ウイルス学会学術集会
  • Place of Presentation: 神戸国際会議場（神戸市）
• [Presentation] PB2 Protein of a Highly Pathogenic Avian Influenza Virus Strain A/chicken/Yamaguchi/7/2004 (H5N1) Determines Its Replication Potential in Pigs
  • Author(s): Rashid Manzoor, Yoshihiro Sakoda, Naoki Nomura, Yoshimi Tsuda, Hiroichi Ozaki, Masatoshi Okamatsu, Ayato Takada, Hiroshi Kida
  • Organizer: 第61回日本ウイルス学会学術集会
  • Place of Presentation: 神戸国際会議場（神戸市）
• [Presentation] 計算科学手法を用いたインフルエンザウイルスヘマグルチニンと亜型間交差反応性抗体との分子間相互作用の解析
  • Author(s): 五十嵐学、吉田玲子、関嶋政和、常盤広明、喜田宏、伊藤公人、高田礼人
  • Organizer: 第61回日本ウイルス学会学術集会
  • Place of Presentation: 神戸国際会議場（神戸市）
• [Presentation] Ecology of Avian Influenza Viruses: Topics from surveillance in Asia and Africa
  • Author(s): Ayato Takada
  • Organizer: 1st Kyoto International Symposium on Virus-Host Coevolution
  • Place of Presentation: Shiran-Kaikan（京都市）
  • Invited