Search for host factors in severe influenza virus infection using a nonhuman primate model

• Project/Area Number: 15H04720
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Itoh Yasushi 滋賀医科大学, 医学部, 准教授 (90324566)
• Co-Investigator(Kenkyū-buntansha): 椎名 隆 東海大学, 医学部, 教授 (00317744) ; 仲山 美沙子 滋賀医科大学, 医学部, 助教 (00510306) ; 小笠原 一誠 滋賀医科大学, 医学部, 教授 (20169163) ; 七戸 新太郎 帯広畜産大学, 畜産学部, 特任助教 (80737148) ; 石垣 宏仁 滋賀医科大学, 医学部, 助教 (90432301)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2017: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2016: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2015: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
• Keywords: インフルエンザウイルス / 霊長類モデル / サイトカインストーム / ゲノム / 遺伝子多型 / 高病原性鳥インフルエンザ / 次世代シーケンサー / 病理学 / 免疫学 / ウイルス / 感染症

Outline of Final Research Achievements

To determine genetic backgrounds that affect symptoms in influenza virus infection, we compared genomic sequences of cynomolgus macaques that showed severe clinical signs with those of macaques that showed mild clinical signs under an immunosuppressive condition. Using the next generation sequencing, we found a genetic polymorphism in a gene that codes a kind of chemokine with an amino acid substitution. The chemokine with the amino acid substitution showed a tendency to induce weak immune responses in cells. Therefore, it is suggested that this change is related to severe influenza virus infection in immunocompromised hosts.

Academic Significance and Societal Importance of the Research Achievements

インフルエンザウイルスに感染した時に、重症化しやすい遺伝子をもつサルを明らかにした。その結果に基づき、人の遺伝子が解析可能となると、重症になりやすい人があらかじめわかり、治療薬／予防薬開発のための標的分子が明らかになる。また、ワクチン開発と製造には時間がかかるため、パンデミック早期にはワクチン供給量に制限があり、接種の優先順位の決定が必要になる。その際に重症化遺伝子多型解析をハイリスクグループへのワクチンの優先接種に役立てることができる。

Research Products

• [Journal Article] Inactivated whole virus particle vaccine with potent immunogenicity and limited IL-6 production is ideal for influenza (2019)
  • Author(s): Sekiya T, Mifsud EJ, Ohno M, Nomura N, Sasada M, Fujikura D, Daito T, Shingai M, Ohara Y, Nishimura T, Endo M, Mitsumata R, Ikeda T, Hatanaka H, Kitayama H, Motokawa K, Sobue T, Suzuki S, Itoh Y, Brown LE, Ogasawara K, Kino Y, Kida H
  • Journal Title: Vaccine Volume: 37 Issue: 15 Pages: 2158-2166
  • DOI: 10.1016/j.vaccine.2019.02.057
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] カニクイザルモデルを用いた免疫抑制状態における鳥インフルエンザウイルスの病原性の解明 (2017)
  • Author(s): 伊藤靖、小笠原一誠
  • Journal Title: 臨床免疫・アレルギー科 Volume: 68 Pages: 31-37
• [Journal Article] Potential Risk of Repeated Nasal Vaccination that Induces Allergic Reaction with Mucosal IgE and Airway Eosinophilic Infiltration in Cynomolgus Macaques infected with H5N1 Highly Pathogenic Avian Influenza Virus. (2017)
  • Author(s): Nakayama M, Itoh Y, Shichinohe S, Nakabayashi R, Ishigaki H, Sakoda Y, Le QM, Kawaoka Y, Kida H, Ogasawara K
  • Journal Title: Vaccine Volume: 35 Issue: 7 Pages: 1008-1017
  • DOI: 10.1016/j.vaccine.2017.01.008
  • Peer Reviewed
• [Journal Article] Comparison of pathogenicities of H7 avian influenza viruses via intranasal and conjunctival inoculation in cynomolgus macaques (2016)
  • Author(s): Shichnohe S, Itoh Y, Nakayama M, Ozaki H, Soda K, Ishigaki H, Okamatsu M, Sakoda Y, Kida H, Ogasawara K
  • Journal Title: Virology Volume: 493 Pages: 31-38
  • DOI: 10.1016/j.virol.2016.03.007
  • Peer Reviewed
• [Journal Article] Vaccination against H9N2 avian influenza virus reduces bronchus-associated lymphoid tissue formation in cynomolgus macaques after intranasal virus challenge infection (2016)
  • Author(s): Nakayama M, Ozaki H, Itoh Y, Soda K, Ishigaki H, Okamatsu M, Sakoda Y, Park C-H, Tsuchiya H, Kida H, Ogasawara K
  • Journal Title: Pathology International Volume: 66 Issue: 12 Pages: 678-686
  • DOI: 10.1111/pin.12472
  • Peer Reviewed
• [Journal Article] Sensitization with vaccinia virus harboring hemagglutinin recovers the immune potential against highly pathogenic H5N1 influenza virus in non-human primates (2016)
  • Author(s): Fumihiko Yasui, Yasushi Itoh, Ai Ikejiri, Masahiro Kitabatake, Nobuo Sakaguchi, Keisuke Munekata, Shintaro Shichinohe, Yukiko Hayashi, Hirohito Ishigaki, Misako Nakayama, Yoshihiro Sakoda, Hiroshi Kida, Kazumasa Ogasawara, *Michinori Kohara
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 37915-37915
  • DOI: 10.1038/srep37915
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Translational research on influenza virus infection using a nonhuman primate model (2016)
  • Author(s): Itoh Y
  • Journal Title: Pathology International Volume: 66 Issue: 3 Pages: 132-141
  • DOI: 10.1111/pin.12385
  • Peer Reviewed
• [Journal Article] Discovery of novel MHC-class I alleles and haplotypes in Filipino cynomolgus macaques (Macaca fascicularis) by pyrosequencing and Sanger sequencing (2015)
  • Author(s): Shiina T, Yamada Y, Aarnink A, Suzuki S, Masuya A, Ito S, Ido D, Yamanaka H, Iwatani C, Tsuchiya H, Ishigaki H, Itoh Y, Ogasawara K, Kulski JK, Blancher A
  • Journal Title: Immunogenetics Volume: 67 Issue: 10 Pages: 563-578
  • DOI: 10.1007/s00251-015-0867-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Emergence of H7N9 Influenza A Virus Resistant to Neuraminidase Inhibitors in Nonhuman Primates (2015)
  • Author(s): Itoh Y, Shichinohe S, Nakayama M, Igarashi M, Ishii A, Ishigaki H, Ishida H, Kitagawa N, Sasamura T, Shiohara M, Doi M, Tsuchiya H, Nakamura S, Okamatsu M, Sakoda Y, Kida H, Ogasawara K
  • Journal Title: Antimicrob Agents Chemother Volume: 59(8) Issue: 8 Pages: 4962-4973
  • DOI: 10.1128/aac.00793-15
  • Peer Reviewed / Open Access
• [Presentation] Investigation of effects of the vaccine and antiviral drugs for influenza virus in cynomolgus macaques (2018)
  • Author(s): Yasushi Itoh
  • Organizer: The 3rd J-GRID International Symposium
  • Int'l Joint Research
• [Presentation] 霊長類を用いた疾患モデルにおける炎症反応の解析 (2018)
  • Author(s): 伊藤靖、石垣宏仁、仲山美沙子、小笠原一誠
  • Organizer: 第107回日本病理学会総会
  • Invited
• [Presentation] サルモデルを用いた季節性インフルエンザに対する不活化全粒子ワクチンの有効性評価 (2018)
  • Author(s): 伊藤靖、鈴木沙織、石垣宏仁、仲山美沙子、新開大史、大東卓史、野村直樹、喜田宏、小笠原一誠
  • Organizer: 第22回日本ワクチン学会学術集会
• [Presentation] Viral pneumonia caused by H5N1 highly pathogenic avian influenza virus in immunosuppressed macaques (2017)
  • Author(s): Yasushi Itoh, Misako Nakayama, Hirohito Ishigaki, Kazumasa Ogasawara
  • Organizer: 第106回日本病理学会総会
• [Presentation] カニクイザルを用いたインフルエンザワクチンによる免疫記憶に及ぼす免疫抑制剤の影響の解析 (2016)
  • Author(s): 伊藤 靖
  • Organizer: 第105回日本病理学会
• [Presentation] Pathogenicity of highly pathogenic avian influenza virus in a macaque model under an immunosuppressed condition. (2016)
  • Author(s): Yasushi Itoh
  • Organizer: 第４５回日本免疫学会学術集会
• [Presentation] Immunological memory restores antibody responses against H7N9 influenza virus after immunosuppression with cyclophosphamide and cyclosporine A in vaccinated macaques (2015)
  • Author(s): Yasushi Itoh
  • Organizer: 第４４回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2015-11-18
• [Presentation] カニクイザルを用いたＨ７Ｎ９亜型インフルエンザウイルスに対するウイルスライブラリー由来全粒子不活化ワクチンの有効性評価 (2015)
  • Author(s): 伊藤靖
  • Organizer: 第１９回日本ワクチン学会学術集会
  • Place of Presentation: 名鉄犬山ホテル
  • Year and Date: 2015-11-14
• [Remarks] 滋賀医科大学病理学講座疾患制御病理学部門
  • URL: http://www.shiga-med.ac.jp/~hqpatho2/
• [Remarks] 本研究室より発表した論文の紹介
  • URL: http://www.shiga-med.ac.jp/~hqpatho2/journal_club.html