Study of tuberculosis and development of vaccine in latent infected cynomolgus monkeys.

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17H04079
• Research Institution: National Institutes of Biomedical Innovation, Health and Nutrition
• Principal Investigator: 保富 康宏 国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 霊長類医科学研究センター, センター長 (90281724)
• Co-Investigator(Kenkyū-buntansha): 辻村 祐佑 国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 霊長類医科学研究センター, 研究員 (30512404) ; 山本 拓也 国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 免疫老化プロジェクト, プロジェクトリーダー (60752368)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 結核 / ワクチン / カニクイザル

Outline of Annual Research Achievements

結核は世界中で蔓延し、800万人以上の新規患者、100万人以上の死亡者が現在でも出ている。我が国でも毎年多くの発症者が確認されており、先進国中では中等度発症国となっている。結核菌は宿主の体内環境に適応し長期に潜伏感染する細胞内寄生細菌であり、宿主の免疫力によって休眠状態になっている。世界保健機関 (WHO) の報告では人類の30%が結核菌に感染していると述べられており、そのうちの5~10%が感染後2年以内に活動性結核を発症するが大半は非発症のままである)。また一生のうち潜伏性結核感染が活動性結核に進展する（治癒後再発を含む）のは10%と言われている。しかしながら発症を防御するような予防ワクチンや治療薬、発症に至る詳細な解析や診断マーカーは存在しない。カニクイザルは唯一最良のヒト結核モデルと考えられており、ヒトで認められる病変が観察され、ヒトと同様の潜伏性感染/再活性化が再現されることから、詳細な病態解析も行われている。報告から低量の結核菌感染にてカニクイザルの45%が潜伏性感染になり、ヒトでの報告同様に抗TNF抗体投与で再活性化を促せる。本研究において解明されるべき点は1) 新規粘膜免疫誘導型ワクチンによる潜伏状態からの肺結核発症抑制効果と誘導される免疫反応の検討、2) 潜伏感染から発症に至るメカニズムの解析や診断マーカーの探索である。この目的を遂行するために、カニクイザルの非感染/潜伏感染/活性化のそれぞれのモデルを樹立し、コロニーを作製・維持を行った。また、結核菌の感染予防ならびに再活動化の抑制もできる新規粘膜免疫誘導型ワクチンを開発し、検討したところ、既存のBCGワクチン以上に肺での結核菌の予防効果を示した。さらに潜伏感染カニクイザルにおいては極めて効果的な免疫反応が呼吸器に誘導されていることは確認された。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Echocardiographic evaluation of cardiac function in cynomolgus monkeys over a wide age range. (2020)
  • Author(s): Nakayama S, Koie H, Pai C, Ito-Fujishiro Y, Kanayama K, Sankai T, Yasutomi Y, Ageyama N.
  • Journal Title: Exp Anim Volume: - Pages: -
  • DOI: 10.1538/expanim.19-0128
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Development of an effective alternative model for in vivo hypnozoite-induced relapse infection: A Japanese macaque (Macaca fuscata) model experimentally infected with Plasmodium cynomolgi.. (2020)
  • Author(s): .Kawai S, Annoura T, Araki T, Shiogama Y, Soma S, Takano JI, Sato MO, Kaneko O, Yasutomi Y, Chigusa Y
  • Journal Title: Parasitol Int Volume: - Pages: -
  • DOI: 10.1016/j.parint.2020.102096
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Leucine-rich alpha 2 glycoprotein is a new marker for active disease of tuberculosis (2020)
  • Author(s): .Fujimoto M, Matsumoto T, Serada S, Tsujimura Y, Hashimoto S, Yasutomi Y, Naka T.
  • Journal Title: Sci Rep Volume: 10 Pages: -
  • DOI: 10.1038/s41598-020-60450-3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intranasal vaccination with HBs and HBc protein combined with carboxyl vinyl polymer induces strong neutralizing antibody, anti-HBs IgA, and IFNG response. (2019)
  • Author(s): Sanada T, Yamamoto N, Kayesh MEH, Tsukiyama-Kohara K, Hasegawa H, Miyazaki T, Takano JI, Shiogama Y, Yasutomi Y, Goh Y, Yoshida O, Hiasa Y, Kohara M。
  • Journal Title: Biochem Biophys Res Commun. Volume: 520 Pages: 86-92
  • DOI: 10.1016/j.bbrc.2019.09.072
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Construction of complete Tupaia belangeri transcriptome database by whole-genome and comprehensive RNA sequencing (2019)
  • Author(s): Sanada T, Tsukiyama-Kohara K, Shin-I T, Yamamoto N, Kayesh MEH, Yamane D, Takano JI, Shiogama Y, Yasutomi Y, Ikeo K, Gojobori T, Mizokami M, Kohara M.
  • Journal Title: Sci Rep Volume: 26 Pages: 12372
  • DOI: 10.1038/s41598-019-48867-x.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Three-dimensional electron microscopy analysis reveals endopolygeny-like nuclear architecture segregation in Plasmodium oocyst development. (2019)
  • Author(s): Araki T, Kawai S, Kakuta S, Kobayashi H, Umeki Y, Saito-Nakano Y, Sasaki T, Nagamune K, Yasutomi Y, Nozaki T, Franke-Fayard B, Khan SM, Hisaeda H, Annoura T.
  • Journal Title: Parasitol Int Volume: - Pages: -
  • DOI: 10.1016/j.parint.2019.102034.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Establishment of a new formula for QT interval correction using a large colony of cynomolgus monkeys. (2019)
  • Author(s): Nakayama S, Koie H, Kato-Tateishi M, Pai C, Ito-Fujishiro Y, Kanayama K, Sankai T, Yasutomi Y, Ageyama N
  • Journal Title: Exp Anim Volume: - Pages: -
  • DOI: 10.1538/expanim.19-0009.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Immunization with components of the viral fusion apparatus elicits antibodies that neutralize Epstein-Barr virus in B cells and epithelial cells. (2019)
  • Author(s): Bu W, Joyce MG, Nguyen H, Banh DV, Aguilar F, Tariq Z, Yap ML, Tsujimura Y, Gillespie RA, Tsybovsky Y, Andrews SF, Narpala SR, McDermott AB, Rossmann MG, Yasutomi Y, Nabel GJ, Kanekiyo M, Cohen JI,
  • Journal Title: Immunity Volume: 50 Pages: 1305-1316
  • DOI: 10.1016/j.immuni.2019.03.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Avian H5N1 influenza virus infection causes severe pneumonia in the Northern tree shrew (Tupaia belangeri).Virology. (2019)
  • Author(s): Sanada T, Yasui F, Honda T, Kayesh MEH, Takano JI, Shiogama Y, Yasutomi Y, Tsukiyama-Kohara K, Kohara M.
  • Journal Title: Virology Volume: 529 Pages: 101-110
  • DOI: 10.1016/j.virol.2019.01.015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A unique nanoparticulate TLR9 agonist enables a HA split vaccine to confer FcγR-mediated protection against heterologous lethal influenza virus infection. (2019)
  • Author(s): Yamamoto T, Masuta Y, Momota M, Kanekiyo M, Kanuma T, Takahama S, Moriishi E, Yasutomi Y, Saito T, Graham BS, Takahashi Y, Ishii KJ
  • Journal Title: Int Immunol. Volume: 31 Pages: 81-90
  • DOI: 10.1093/intimm/dxy069
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Elevated Membrane Cholesterol Disrupts Lysosomal Degradation to Induce β-Amyloid Accumulation: The Potential Mechanism Underlying Augmentation of β-Amyloid Pathology by Type 2 Diabetes Mellitus. (2019)
  • Author(s): Takeuchi S, Ueda N, Suzuki K, Shimozawa N, Yasutomi Y, Kimura N.
  • Journal Title: Am J Pathol. Volume: 1892 Pages: 391-404.
  • DOI: 10.1016/j.ajpath.2018.10.011.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] SOCS1 antagonist-expressing recombinant BCG enhances anti-tuberculosis protection in a mouse model, (2019)
  • Author(s): Mizuno S, Soma S, Inada H, Kanuma T, Matsuo K, Yasutomi Y.
  • Journal Title: J. Immunol Volume: 203 Pages: 188-197
  • DOI: 10.4049/jimmunol.1800694
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Successful Inflammation Imaging of Non-Human Primate Hearts Using an Antibody Specific for Tenascin-C. (2019)
  • Author(s): Ageyama,N.,Kurosawa,H., Fujimoto,O., Uehara,T., Hiroe,M., Arano,Y., Yoshida,T., Yasutomi,Y., Imanaka-Yoshida,K.
  • Journal Title: Int Heart J Volume: 60 Pages: 151-158
  • DOI: 10.1536/ihj.17-734
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Partial Deletion of Glycoprotein B5R Enhances Vaccinia Virus Neutralization Escape while Preserving Oncolytic Function. (2019)
  • Author(s): Nakatake M., Kurosaki H., Kuwano N., Horita K., Ito M., Kono H., Okamura T., Hasegawa K., Yasutomi Y., Nakamura T.
  • Journal Title: Mol Ther Oncolytics Volume: 14 Pages: 159-171
  • DOI: 10.1016/j.omto.2019.05.003
  • Peer Reviewed / Int'l Joint Research
• [Presentation] SOCS1 antagonist-expressing recombinant BCG enhances anti-tuberculosis protection in a mouse model. (2019)
  • Author(s): Yasuhiro Yasutomi
  • Organizer: 103rd Immunology 2019, American Association of Immunology,
  • Int'l Joint Research
• [Presentation] Essential role of primate in vaccine development in Japan. (2019)
  • Author(s): Yasuhiro Yasutomi
  • Organizer: 13th Vaccine congress
  • Int'l Joint Research / Invited
• [Presentation] Hepatitis E virus vaccine. (2019)
  • Author(s): Yasuhiro Yasutomi
  • Organizer: 7th National Virology Conference Mongolia
  • Int'l Joint Research / Invited
• [Book] Mucosal Vaccine (2019)
  • Author(s): Tsujimura Y, Yasutomi Y.
  • Total Pages: 450
  • Publisher: ELSEVIER