Changes in receptor specificity and pathogenesis associated with mutations of capsid amino acids of enterovirus 71 in host adaptation

• Project/Area Number: 25293111
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: SHIMIZU HIROYUKI 国立感染症研究所, その他部局等, その他 (90270644)
• Co-Investigator(Renkei-kenkyūsha): NISHIMURA YORIHIRO 国立感染症研究所, ウイルス第二部第二室, 主任研究官 (00392316) ; KATAOKA CHIKAKO 北海道大学, 人獣共通感染症リサーチセンター, 特任助教 (10646623)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥11,960,000 (Direct Cost: ¥9,200,000、Indirect Cost: ¥2,760,000); Fiscal Year 2015: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2014: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2013: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: エンテロウイルス / エンテロウイルス71 / 受容体 / PSGL-1 / 手足口病 / レセプター / 動物モデル / 病原性 / 感染モデル / 分子進化 / カニクイザル

Outline of Final Research Achievements

In this research project, we investigated the involvement of the capsid amino acid mutation of enterovirus 71 (EV 71) in the viral phenotype and pathogenicity. Specific capsid amino acid residues including VP1-145 around the 5-fold vertex of the EV71 capsid were responsible for various viral phenotypes such as PSGL-1-binding specificity and neutralization antigenicity. In a cynomolgus monkey model, we demonstrated potent in vivo selection of EV71 variants with VP1-145E in host adaptation and the resultant VP1-145E variants were mainly associated with the development of viremia and neuropathogenesis presumably in a PSGL-1 independent manner. Therefore, the results suggest the in vivo involvement of amino acid polymorphisms at VP1-145 in cell-specific viral replication, in vivo fitness, and pathogenesis in EV71-infected individuals.

Research Products

• [Int'l Joint Research] The Children's Hospital of Philadelphia/University of Pennsylvania/Pennsylvania State University(米国)
• [Int'l Joint Research] Chinese CDC(中国)
• [Journal Article] Development and introduction of inactivated poliovirus vaccines derived from Sabin strains in Japan (2016)
  • Author(s): Shimizu H
  • Journal Title: Vaccine Volume: 34 Issue: 16 Pages: 1975-1985
  • DOI: 10.1016/j.vaccine.2014.11.015
  • Peer Reviewed / Acknowledgement Compliant
• [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
• [Journal Article] Human rhinovirus infections in hospitalized children: clinical, epidemiological and virological features. (2016)
  • Author(s): Tran DN, Trinh QD, Pham NT, Pham TM, Ha MT, Nguyen TQ, Okitsu S, Shimizu H, Hayakawa S, Mizuguchi M, Ushijima H.
  • Journal Title: Epidemiol Infect. Volume: 144 Issue: 2 Pages: 346-54
  • DOI: 10.1017/s0950268815000953
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cosavirus (family Picornaviridae) in pigs in Thailand and Japan (2016)
  • Author(s): Okitsu S, Khamrin P, Hanaoka N, Thongprachum A, Takanashi S, Fujimoto T, Mizuguchi M, Shimizu H, Hayakawa S, Maneekarn N, Ushijima H
  • Journal Title: Arch Virol Volume: 161 Issue: 1 Pages: 159-163
  • DOI: 10.1007/s00705-015-2637-2
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The suramin derivative NF449 interacts with the 5-fold vertex of the enterovirus A71 capsid to prevent virus attachment to PSGL-1 and heparan sulfate (2015)
  • Author(s): Nishimura Y, McLaughlin NP, Pan J, Goldstein S, Hafenstein S, Shimizu H, Winkler JD, Bergelson JM
  • Journal Title: PLoS Pathogens Volume: 11 Issue: 10 Pages: e1005184-e1005184
  • DOI: 10.1371/journal.ppat.1005184
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The Role of VP1 Amino Acid Residue 145 of Enterovirus 71 in Viral Fitness and Pathogenesis in a Cynomolgus Monkey Model. (2015)
  • Author(s): Kataoka C, Suzuki T, Kotani O, Iwata-Yoshikawa N, Nagata N, Ami Y, Wakita T, Nishimura Y, Shimizu H.
  • Journal Title: PLoS Pathog. Volume: 11(7) Issue: 7 Pages: e1005033-e1005033
  • DOI: 10.1371/journal.ppat.1005033
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An Insight into Recombination with Enterovirus Species C and Nucleotide G-480 Reversion from the Viewpoint of Neurovirulence of Vaccine-Derived Polioviruses (2015)
  • Author(s): Zhang Y, Yan D, Zhu S, Nishimura Y, Ye X, Wang D, Jorba J, Zhu H, An H, Shimizu H, Kew O, Xu W
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 17291-17291
  • DOI: 10.1038/srep17291
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of an efficient entire-capsid-coding-region amplification method for direct detection of poliovirus from stool extracts (2015)
  • Author(s): Arita M, Kilpatrick DR, Nakamura T, Burns CC, Bukbuk D, Oderinde SB, Oberste MS, Kew OM, Pallansch MA, Shimizu H
  • Journal Title: J Clin Microbiol Volume: 53 Issue: 1 Pages: 73-78
  • DOI: 10.1128/jcm.02384-14
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Establishment of a panel of in-house polyclonal antibodies for the diagnosis of enterovirus infections (2014)
  • Author(s): Kotani O, Iwata-Yoshikawa N, Suzuki T, Sato Y, Nakajima N, Koike S, Iwasaki T, Sata T, Yamashita T, Minagawa H, Taguchi F, Hasegawa H, Shimizu H, Nagata N
  • Journal Title: Neuropathology Volume: 35 Issue: 2 Pages: 107-121
  • DOI: 10.1111/neup.12171
  • Peer Reviewed
• [Journal Article] Surveillance of hand, foot, and mouth disease for a vaccine (2014)
  • Author(s): Shimizu H, Nakashima K
  • Journal Title: Lancet Infect Dis Volume: 14 Issue: 4 Pages: 262-3
  • DOI: 10.1016/s1473-3099(13)70330-x
  • Peer Reviewed
• [Journal Article] Genetic diversity of circulating Saffold viruses in Pakistan and Afghanistan (2014)
  • Author(s): Naeem A, Hosomi T, Nishimura Y, Alam MM, Oka T, Zaidi SS, Shimizu H
  • Journal Title: J Gen Virol Volume: 95 Issue: 9 Pages: 1945-1957
  • DOI: 10.1099/vir.0.066498-0
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A Case of Atypical Hand-Foot-and-Mouth Disease Caused by Coxsackievirus A6: Differential Diagnosis from Varicella in a Pediatric Intensive Care Unit (2013)
  • Author(s): Yasui Y, Makino T, Hanaoka N, Shimizu H, Kanou K, Kobayashi M, Konagaya M, Fujimoto T
  • Journal Title: Jpn J Infect Dis Volume: 66 Pages: 564-566
  • NAID: 130003390346
  • Peer Reviewed
• [Journal Article] A Strain-Specific Epitope of Enterovirus 71 Identified by Cryo-Electron Microscopy of the Complex with Fab from Neutralizing Antibody (2013)
  • Author(s): Lee H, Cifuente JO, Ashley RE, Conway JF, Makhov AM, Tano Y, Shimizu H, Nishimura Y, Hafenstein S
  • Journal Title: J Virol Volume: 87 Issue: 21 Pages: 11363-11370
  • DOI: 10.1128/jvi.01926-13
  • Peer Reviewed
• [Journal Article] Enterovirus 71 Binding to PSGL-1 on Leukocytes : VP1-145 Acts as a Molecular Switch to Control Receptor Interaction (2013)
  • Author(s): Nishimura Y, Lee H, Hafenstein S, Kataoka C, Wakita T, Bergelson JM, Shimizu H
  • Journal Title: PLoS Pathog Volume: 9 Issue: 7 Pages: e1003511-e1003511
  • DOI: 10.1371/journal.ppat.1003511
  • Peer Reviewed
• [Journal Article] Clinical manifestations of coxsackievirus a6 infection associated with a major outbreak of hand, foot, and mouth disease in Japan (2013)
  • Author(s): Kobayashi M, Makino T, Hanaoka N, Shimizu H, Enomoto M, Okabe N, Kanou K, Konagaya M, Oishi K, Fujimoto T
  • Journal Title: Jpn J Infect Dis Volume: 66 Pages: 260-261
  • NAID: 130003381685
  • Peer Reviewed
• [Journal Article] Multiple Independent Emergences of Type 2 Vaccine-Derived Polioviruses during a Large Outbreak in northern Nigeria (2013)
  • Author(s): Burns CC et al.
  • Journal Title: J Virol Volume: 87 Issue: 9 Pages: 4907-4922
  • DOI: 10.1128/jvi.02954-12
  • Peer Reviewed
• [Presentation] Current Outbreaks of Acute Flaccid Paralysis in Laos and Japan (2016)
  • Author(s): Shimizu H
  • Organizer: NIID International Seminar on Infectious Diseases
  • Place of Presentation: 東京
  • Year and Date: 2016-01-26
  • 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
  • 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
  • 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
  • Year and Date: 2015-11-22
• [Presentation] 2011年と2012年の北部ベトナムにおける手足口病の流行状況 (2015)
  • Author(s): 片岡周子、Tran Thi Nguyen Hoa、中村朋史、Nguyen Thi Hien Thanh、清水博之
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2015-11-22
• [Presentation] Development of direct detection method of polioviruses from environmental samples (2015)
  • Author(s): Nakamura T, Arita M, Shimizu H
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2015-11-22
• [Presentation] NF449 interacts with the 5-fold vertex of the enterovirus 71 capsid to prevent virus attachment to PSGL-1 and heparan sulfate (2015)
  • Author(s): Nishimura Y, McLaughlin N, Pan J, Goldstein S, Hafenstein S, Shimizu H, Winkler JD, Bergelson JM
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2015-11-22
• [Presentation] 不活化ポリオワクチン導入によるポリオの予防接種状況および抗体保有状況の推移について（2012～2014年度感染症流行予測調査より） (2015)
  • Author(s): 佐藤 弘、多屋馨子、大石和徳、清水博之
  • Organizer: 第47回日本小児感染症学会学術集会
  • Place of Presentation: 福島
  • Year and Date: 2015-10-31
• [Presentation] The suramin derivative NF449 interacts with the 5-fold vertex of the enterovirus 71 capsid to prevent virus attachment to PSGL-1 and heparan sulfate (2015)
  • Author(s): Nishimura Y, McLaughlin N, Pan J, Goldstein S, Hafenstein S, Shimizu H, Winkler JD, Bergelson JM
  • Organizer: 10th Asia-Pacific Congress of Medical Virology 2015
  • Place of Presentation: 台北
  • Year and Date: 2015-10-15
  • Int'l Joint Research
• [Presentation] ポリオウイルス病原体管理に関するWHO行動計画(GAP III)と今後の課題 (2015)
  • Author(s): 清水博之
  • Organizer: 第15回日本バイオセーフティ学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-09-15
• [Presentation] Immunogenicity of Booster Doses of the Inactivated Polio Vaccine among Japanese adult travelers (2015)
  • Author(s): Fukushima S, Nakano T, Shimizu H, Hamada A
  • Organizer: The 14th Conference of International society of Travel Medicine
  • Place of Presentation: ケベック
  • Year and Date: 2015-05-24
  • Int'l Joint Research
• [Presentation] エンテロウイルス71のカニクイザルにおける病原性の解析 (2014)
  • Author(s): 8)片岡周子、西村順裕、鈴木忠樹、小谷治、岩田奈織子、永田典代、網康至、清水博之
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] ウイルス受容体特異性を応用したポリオウイルス直接検出法の開発 (2014)
  • Author(s): 中村 朋史、有田 峰太郎、清水 博之
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] Molecular basis of virus-host interaction and pathogenesis of enterovirus 71 infection (2014)
  • Author(s): Shimizu H
  • Organizer: Monto Ho Memorial Lectures on Enterovirus 71, 2014 International Symposium on Infectious Disease and Signal Transduction
  • Place of Presentation: Tainan, Taiwan
  • Year and Date: 2014-11-02
  • Invited
• [Presentation] 世界ポリオ根絶計画とポリオワクチンのこれから (2014)
  • Author(s): 清水博之
  • Organizer: 第46回日本小児感染症学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-19
  • Invited
• [Presentation] The molecular basis of the interaction between EV71 and PSGL-1 from structural and functional standpoints (2014)
  • Author(s): Shimizu H
  • Organizer: TLL Seminar, Temasek Life Science Laboratory
  • Place of Presentation: Singapore
  • Year and Date: 2014-09-25
  • Invited
• [Presentation] Structural and functional basis of the interaction between enterovirus 71 and a cellular receptor, PSGL-1 (2014)
  • Author(s): Shimizu H
  • Organizer: Protein Island Matsuyama International Symposium
  • Place of Presentation: Matsuyama,Ehime
  • Year and Date: 2014-09-17
  • Invited
• [Presentation] VP1-145 of enterovirus 71 is one of the determinants for pathogenicity in a cynomolgus monkey model (2014)
  • Author(s): Kataoka C, Nishimura Y, Suzuki T, Kotani O, Iwata N, Nagata A, Ami Y, Shimizu H
  • Organizer: Europic 2014
  • Place of Presentation: Belgium
• [Presentation] エンテロウイルス71と受容体PSGL-1との結合：VP1-145は受容体特異性を制御する分子スイッチである (2013)
  • Author(s): 西村順裕、Hyunwook Lee、Susan Hafenstein、片岡周子、脇田隆字、Jeffrey M. Bergelson、清水博之
  • Organizer: 第61回日本ウイルス学会学術集会
  • Place of Presentation: 神戸市
• [Presentation] エンテロウイルス71のカニクイザルにおける病原性の解析 (2013)
  • Author(s): 片岡周子 西村順裕 鈴木忠樹 小谷治 岩田奈織子 永田典代 網康至 清水博之
  • Organizer: 第61回日本ウイルス学会学術集会
  • Place of Presentation: 神戸市
• [Presentation] and, Foot, and Mouth Disease and infectious agent surveillance in Japan (2013)
  • Author(s): Shimizu H
  • Organizer: International Workshop on Hand, Foot and Mouth Disease
  • Place of Presentation: Hanoi
  • Invited
• [Presentation] olecular Epidemiology and Virulence (viral) factors of EV71 (2013)
  • Author(s): Shimizu H
  • Organizer: International Workshop on Hand, Foot and Mouth Disease
  • Place of Presentation: Hanoi
  • Invited
• [Presentation] アジアにおける手足口病とエンテロウイルス感染症流行の現状
  • Author(s): 清水博之
  • Organizer: 第87回日本感染症学会学術講演会・第61回日本化学療法学会総会合同学会
  • Place of Presentation: 横浜市
  • Invited
• [Book] 感染症予防必携 (第３版) 「急性灰白髄炎」の項を担当 (2015)
  • Author(s): 清水博之
  • Total Pages: 634
  • Publisher: 日本公衆衛生協会
• [Book] まるわかりワクチン Q&A Q25およびQ26を担当 (2015)
  • Author(s): 清水博之
  • Total Pages: 407
  • Publisher: 日本医事新報社
• [Book] 臨床医のための呼吸器・消化管ウイルス感染症 消化器ウイルス篇 エンテロウイルス-ポリオウイルスおよび非ポリオエンテロウイルス」の項を分担執筆 (2014)
  • Author(s): 清水博之
  • Total Pages: 135
  • Publisher: 診断と治療社
• [Remarks] EV71のVP1蛋白質の145番目のアミノ酸はウイルスの適応性と病原性に関わる
  • URL: http://www.nih.go.jp/niid/ja/basic-science/460-virology/6085-virology-2015-5.html
• [Remarks] NF449はEV-A71キャプシドの５回転軸に相互作用しPSGL-1とヘパラン硫酸への結合を阻害する
  • URL: http://www.nih.go.jp/niid/ja/basic-science/460-virology/5990-virology-2015-3.html
• [Remarks] 便抽出液からポリオウイルスを直接検出するための、カプシドコーディング全領域の高効率増幅法の開発
  • URL: http://www.nih.go.jp/niid/ja/basic-science/460-virology/5277-vir-2014-02.html