Development of animal models for study on persistent infection with pancreatropic and cardiotropic picornaviruses

• Project/Area Number: 15K08511
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Nagata Noriyo 国立感染症研究所, 感染病理部, 室長 (30270648)
• Research Collaborator: Yamada S. ; Hagiwara K. ; Miyazaki M.
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ピコルナウイルス / 膵親和ウイルス / 筋親和ウイルス / 持続感染 / 動物モデル / 膵親和性ウイルス / 筋親和性ウイルス

Outline of Final Research Achievements

Coxsackievirus B infection causes acute/chronic diseases such as diabetes and myocarditis; however, the pathogenesis is unclear. Here, we developed an immunodeficient mouse model of persistent infection with recent CVB2 isolates. Immunodeficient mice received CVB2 isolates via the intravenous route and showed transient body weight loss, but survived more than three months. Infectious virus was detected in feces and sera. Histopathological examination revealed that pancreatitis and myocarditis were prolonged in these animals. This animal model will increase our understanding of the pathogenesis of persistent CVB infection.

Academic Significance and Societal Importance of the Research Achievements

コクサッキーウイルスB群は慢性あるいは急性の糖尿病や心筋炎を引き起こすことが知られているが、その病態病理は不明のままである。我々は、最近分離されたコクサッキーウイルスB2と免疫不全マウスを利用し、持続感染モデルを作出した。この動物モデルを応用することにより、これらのウイルスによって引き起こされる慢性疾患や持続感染症の発症メカニズムの理解や治療法を検討することが可能となる。

Research Products

• [Journal Article] Propagation of Rhinovirus C in Differentiated Immortalized Human Airway HBEC3-KT Epithelial Cells (2019)
  • Author(s): Nakauchi Mina、Nagata Noriyo、Takayama Ikuyo、Saito Shinji、Kubo Hideyuki、Kaida Atsushi、Oba Kunihiro、Odagiri Takato、Kageyama Tsutomu
  • Journal Title: Viruses Volume: 11 Issue: 3 Pages: 216-216
  • DOI: 10.3390/v11030216
  • Peer Reviewed / Open Access
• [Journal Article] VP1 Amino Acid Residue 145 of Enterovirus 71 Is a Key Residue for Its Receptor Attachment and Resistance to Neutralizing Antibody during Cynomolgus Monkey Infection (2018)
  • Author(s): Fujii Ken、Sudaka Yui、Takashino Ayako、Kobayashi Kyousuke、Kataoka Chikako、Suzuki Tadaki、Iwata-Yoshikawa Naoko、Kotani Osamu、Ami Yasushi、Shimizu Hiroyuki、Nagata Noriyo、Mizuta Katsumi、Matsuzaki Yoko、Koike Satoshi
  • Journal Title: Journal of Virology Volume: 92 Issue: 15 Pages: 1-17
  • DOI: 10.1128/jvi.00682-18
  • Peer Reviewed
• [Journal Article] Intracerebral inoculation of mouse-passaged Saffold virus type 3 affects cerebellar development in neonatal mice. (2016)
  • Author(s): Kotani O, Suzuki T, Yokoyama M, Iwata-Yoshikawa N, Nakajima N, Sato H, Hasegawa H, Taguchi F, Shimizu H, Nagata N.
  • Journal Title: J Virol Volume: pii: JVI. Issue: 21 Pages: 00864-16
  • DOI: 10.1128/jvi.00864-16
  • Peer Reviewed / Open Access
• [Journal Article] A Transgenic Mouse Model of Poliomyelitis (2016)
  • Author(s): Koike S, Nagata N.
  • Journal Title: Methods Mol Biol. Volume: 1387 Pages: 129-144
  • DOI: 10.1007/978-1-4939-3292-4_7
  • ISBN: 9781493932917, 9781493932924
• [Journal Article] Neuropathogenicity of Two Saffold Virus Type 3 Isolates in Mouse Models. (2016)
  • Author(s): Kotani O, Naeem A, Suzuki T, Iwata-Yoshikawa N, Sato Y, Nakajima N, Hosomi T, Tsukagoshi H, Kozawa K, Hasegawa H, Taguchi F, Shimizu H, Nagata N.
  • Journal Title: PLOS One Volume: 11 Issue: 2 Pages: 1-29
  • DOI: 10.1371/journal.pone.0148184
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Pathogenicity of recent Coxsackievirus B2 isolates in adult mice (2018)
  • Author(s): Nagata, N, Iwata-Yoshikawa, N, Doan YH, Shimizu H, Hasegawa H.
  • Organizer: EUROPIC 2018, 20th International conference on picornaviruses
  • Int'l Joint Research
• [Presentation] Development of a flaccid paralysis mouse model after infection with Enterovirus D68 (2018)
  • Author(s): Miyazaki, M, Saito, H, Shibata, C, Doan, YH, Arao, Y, Iwata-Yoshikawa, N, Hasegawa, H, Shimizu H, Nagata N.
  • Organizer: EUROPIC 2018, 20th International conference on picornaviruses
  • Int'l Joint Research
• [Presentation] Cis-allosteric regulation of the interaction surfaces of Enterovirus A71 capsid protein by the VP1 single amino acid residue at position 145 (2018)
  • Author(s): Kotani, O, Yokoyama, M, Fujii, K, Kobayashi, K, Nagata, N, Shimizu, H, Koike, S, Sato, H.
  • Organizer: EUROPIC 2018, 20th International conference on picornaviruses
  • Int'l Joint Research
• [Presentation] Murine models of persistent infection by coxsackievirus B2 isolates (2018)
  • Author(s): Nagata, N, Iwata-Yoshikawa, N, Doan YH, Shimizu H, Hasegawa H.
  • Organizer: 第66回 日本ウイルス学会学術集会
• [Presentation] 感染マウスモデルを用いたサフォードウイルスの脱髄病変形成メカニズムの解明 (2017)
  • Author(s): 萩原圭、小谷治、岩田奈織子、長谷川秀樹、清水博之、永田典代
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] エンテロウイルスD68型感染後の弛緩性麻痺発現マウスモデルの構築 (2017)
  • Author(s): 宮崎誠、斎藤博之、柴田ちひろ、YEN HAI DOAN、荒尾雄二郎、岩田奈織子、長谷川秀樹、清水博之、永田典代
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Pathogenicity of recent Coxsackievirus B2 isolates in adult mice inoculated via the mucosal route. (2016)
  • Author(s): Nagata N, Iwata-Yoshikawa N, Iizuka S, Agoh M, Shimizu H, Hasegawa H.
  • Organizer: 第64回日本ウイルス学会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-23
• [Presentation] Virulence of recent coxsackievirus B2 isolates in a neonatal mouse model. (2016)
  • Author(s): Nagata N, Ushioda W, Nakamura T, Agoh M, Iizuka S, Kotani O, Iwata-Yoshikawa N, Shimizu H, Hasegawa H.
  • Organizer: 19th International Picornavirus meeting
  • Place of Presentation: スイス
  • Year and Date: 2016-09-04
  • Int'l Joint Research
• [Presentation] Utility of a neonatal mouse model for studying coxsackievirus B2 (2015)
  • Author(s): Nagata N, Ushioda W, Nakamura T, Iizuka S, Kotani O, Iwata-Yoshikawa N, Simizu H, Hasegawa H.
  • 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
  • Year and Date: 2015-11-22
• [Presentation] The pathogenesis of a Saffold virus isolate from upper respiratory inflammation in a mouse model (2015)
  • Author(s): Yamada S, Kotani O, Iwata-Yoshikawa N, Hasegawa H, Shimizu H, Nagata N.
  • 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
  • Year and Date: 2015-11-22
• [Presentation] A molecular mechanism of adaptive evolution of Saffold virus type 3 in cerebellum of mouse (2015)
  • Author(s): Kotani O, Yokoyama M, Suzuki T, Iwata-Yosikawa N, Hasegawa H, Shimizu H, Sato H, Nagata N.
  • 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
  • Year and Date: 2015-11-22