Evaluation methods for viral gene NS1 regulating cytokine storm induced with influenza virus

• Project/Area Number: 24659268
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Laboratory medicine
• Research Institution: Teikyo University
• Principal Investigator: Suzuki Kazuo 帝京大学, 医療共通教育研究センター, 教授 (20192130)
• Co-Investigator(Kenkyū-buntansha): KATO Yusuke 徳島大学, 疾患酵素学研究センター, 准教授 (70596816)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2013: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: インフルエンザ / A/H5N1 / 高病原性 / 分子構造 / ARDS / 肺上皮細胞 / タイトジャンクション / インフルエンザウイルス / サイトカインストーム / NS1 / モデリング / ｻｲﾄｶｲﾝｽﾄｰﾑ / ﾓﾃﾞﾘﾝｸﾞ / ＡＲＤＳ / ＮＳ１

Outline of Final Research Achievements

Avian influenza H5N1 has shown high mortality rate in human with 60%. Non-structural protein 1 (NS1) is a virulence factor of H5N1. Mutation at the 42nd residue within the RNA-binding domain (RBD) of NS1 dramatically changes the degree of pathogenicity of H5N1 in mice. We here studied the impact of this mutation on the function of RBD, and found that RBD with S42 binds double-stranded RNA (dsRNA), whereas that with P42 does not. Analysis of structural models of the RBD proteins with S42 and P42 suggested remarkable difference in the structure of the dsRNA-binding interface, whereas structural analysis did not indicate difference between those RBD proteins. Our results suggest that the single amino acid replacement induces a minor, but global structural change leading to the loss of function of NS1 thereby the change in the degree of pathogenicity In addition, PL site of NS1 may associate with down-regulation of tight junction molecules on epithelial cells in lung.

Research Products

• [Journal Article] Mechanism of a Mutation in Non-Structural Protein 1 Inducing High Pathogenicity of Avian Influenza Virus H5N1. (2016)
  • Author(s): Yusuke S. Kato YS, Fukuia K, Suzuki K.
  • Journal Title: Protein & Peptide Letters Volume: in press
  • NAID: 120006028620
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Simulated pathogenesis of severe acute respiratory distress syndrome and leukopenia induced with influenza A/H5N1virus infection and its treatment with immunoglobulins. (2016)
  • Author(s): Yasuda H, Kawachi S, Suzuki K.
  • Journal Title: J Math Monographs Volume: 9 Pages: 89-104
  • NAID: 120005744551
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The voltage-gated proton channel Hv1/VSOP inhibits neutrophil granule release (2016)
  • Author(s): Okochi Y, Aratani Y, Adissu HA, Miyawaki N, Sasaki M, Suzuki K, Okamura Y.
  • Journal Title: J Leukoc Biol. Volume: 99 Issue: 1 Pages: 7-19
  • DOI: 10.1189/jlb.3hi0814-393r
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The voltage-gated proton channel Hv1/VSOP inhibits neutrophil granule release. (2016)
  • Author(s): Okochi1 Y, Aratani Y, Adissu HA, Miyawaki N, Sasaki M, Suzuki K, Okamura Y.
  • Journal Title: J Leuko Biol. 2016; Jan;99(1):7-19. Volume: 99 Pages: 7-19
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 2013/2014シーズンのインフルエンザ小児症例に対するノイラミニダーゼ阻害薬の臨床効果の比較 (2015)
  • Author(s): 菱木はるか、石和田稔彦、内藤幸子、長澤耕男、染谷知宏、井上紳江、原木真名、黒崎知道、亀岡洋祐、鈴木和男
  • Journal Title: JpJAntibiotic Volume: 68 Pages: 337-343
  • Open Access / Acknowledgement Compliant
• [Journal Article] The voltage-gated proton channel Hv1/VSOP inhibits neutrophil granule release. (2015)
  • Author(s): Okochi1 Y, Aratani Y, Adissu HA, Miyawaki N, Sasaki M, Suzuki K, Okamura Y.
  • Journal Title: J Leuko Biol. Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Immunomodulation with eicosapentaenoic acid supports the treatment of autoimmune small-vessel vasculitis. (2014)
  • Author(s): Hirahashi J, Kawahata K, Arita M, Iwamoto R, Hishikawa K, Honda M, Hamasaki Y, Tanaka M, Okubo K, Kurosawa M, Takase O, Nakakuki M, Saiga K, Suzuki K, Kawachi S, Tojo A, Seki G, Marumo T, Hayashi M, Fujita T.
  • Journal Title: Sci. Rep Volume: 4 Issue: 1 Pages: 6406-6406
  • DOI: 10.1038/srep06406
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Susceptibility QTLs for pathogenic leukocytosis in SCG/Kj mice, a spontaneously occurring crescentic glomerulonephritis and vasculitis model. (2014)
  • Author(s): Hamano Y, Abe M, Matsuoka S, Zhang D, Kondo Y, Kagami Y, Ishigami A, Maruyama N, Tsuruta Y, Yumura W, Suzuki K
  • Journal Title: Clin Exp Immunol. Volume: 2014 Mar 24. Issue: 1 Pages: 353-365
  • DOI: 10.1111/cei.12333
  • Peer Reviewed / Open Access
• [Journal Article] Effect of invariant natural killer T cells with IL-5 and activated IL-6 receptor in ventilator-associated lung injury in mice. (2014)
  • Author(s): Shiga Y, Sugamata R, Iwamura C, Nagao T, Zao J, Kawakami K, Kawachi S, Nakayama T, Suzuki K.
  • Journal Title: Exp Lung Res. Volume: 40 Issue: 1 Pages: 1-11
  • DOI: 10.3109/01902148.2013.854518
  • Peer Reviewed
• [Journal Article] A novel autoantibody against moesin in the serum of patients with MPO-ANCA-associated vasculitis (2014)
  • Author(s): Suzuki K, Nagao T, Itabashi M, Hamano Y, Sugamata R, Yamazaki Y, Yumura W, Tsukita S, Wang PC, Nakayama T, Suzuki K
  • Journal Title: Nephrol Dial Transplant Volume: 29 Issue: 6 Pages: 1168-1177
  • DOI: 10.1093/ndt/gft469
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mutations in HADHB, which encodes the β-subunit of mitochondrial trifunctional protein, cause infantile onset hypoparathyroidism and peripheral polyneuropathy. (2014)
  • Author(s): Naiki M, Ochi N, Kato YS , Purevsuren J, Yamada K, Kimura R, Fukushi D, Hara S, Yamada Y, Kumagai T, Yamaguchi S, Wakamatsu N
  • Journal Title: Am J Med Genet A Volume: in press Issue: 5 Pages: 1180-1187
  • DOI: 10.1002/ajmg.a.36434
  • Peer Reviewed
• [Journal Article] Leucomycin A3 (LM-A3), a 16-membered macrolide antibiotic, inhibits Influenza A virus infection and disease progression. (2013)
  • Author(s): Sugamata R, Sugawara A, Nagao T, Suzuki K, Hirose T, Yamamoto K, Oshima M, Kobayashi K, Sunazuka T, Akagawa KS, Omura S, Nakayama T, Suzuki K.
  • Journal Title: J. Antibiotics Volume: 67 Pages: 213-22
  • Peer Reviewed
• [Journal Article] Remarks on the Asia Pacific Meeting of Vasculitis and ANCA Workshop 2012. (2013)
  • Author(s): Suzuki K.
  • Journal Title: Clin Exp Nephrol Volume: 17 Issue: 5 Pages: 599-602
  • DOI: 10.1007/s10157-013-0805-9
  • Peer Reviewed
• [Journal Article] Proposal of anti-moesin as a novel biomarker for ANCA-associated vasculitis. (2013)
  • Author(s): Suzuki K, Suzuki K, Nagao T, Nakayama T.
  • Journal Title: Clin Exp Nephrol. Volume: 17 Issue: 5 Pages: 638-641
  • DOI: 10.1007/s10157-013-0861-1
  • Peer Reviewed
• [Journal Article] Correlation of Interleukin-6 and monocyte chemotactic protein-1 levels with the crescent formation and myeloperoxidase-specific anti-neutrophil cytoplasmic antibody titer in SCG/Kj mice by treatment with anti-interleukin-6 receptor antibody or Mizoribine. (2013)
  • Author(s): Nagao T, Kusunoki R, Iwamura C, Kobayashi S, Yumura W, Kameoka Y, Nakayama T, Suzuki K.
  • Journal Title: Microbiol Immunol. Volume: 57 Issue: 9 Pages: 640-650
  • DOI: 10.1111/1348-0421.12080
  • Peer Reviewed
• [Journal Article] Myeloperoxidase deficiency induces MIP-2 production via ERK activation in zymosan-stimulated mouse neutrophils. (2013)
  • Author(s): Tateno, N., Matsumoto, N., Motowaki, T., Suzuki, K., and Aratani, Y.
  • Journal Title: Free Radic. Res. Volume: 47 Issue: 5 Pages: 376-385
  • DOI: 10.3109/10715762.2013.778990
  • Peer Reviewed
• [Journal Article] Coordination structures of Mg^<2+> and Ca^<2+> in three types of tobacco calmodulins in solution: Fourier-transform infrared spectroscopic studies of side-chain coo- groups (2013)
  • Author(s): N. Suzuki, L. F. Imai, Y. Kato, K. Nagata, Y. Ohashi, K. Kuchitsu, M. Tanokura, A. Sakamoto, M. Nara, M. Nakano, and N. Yonezawa
  • Journal Title: Biopolymers Volume: 99 Issue: 7 Pages: 472-483
  • DOI: 10.1002/bip.22203
  • Peer Reviewed
• [Journal Article] Structure of the Ca(2+)-saturated C-terminal domain of scallop troponin C in complex with a troponin I fragment (2013)
  • Author(s): Kato YS, Yumoto F, Tanaka H, Miyakawa T, Miyauchi Y, Takeshita D, Sawano Y, Ojima T, Ohtsuki I, Tanokura M
  • Journal Title: Biol Chem Volume: 394 Issue: 1 Pages: 55-68
  • DOI: 10.1515/hsz-2012-0152
  • Peer Reviewed
• [Journal Article] Characterization of the mutant β-subunit of β-hexosaminidase for dimer formation responsible for the adult form of Sandhoff disease with the motor neuron disease phenotype. (2013)
  • Author(s): Yamada K
  • Journal Title: J Biochem Volume: 153 Issue: 1 Pages: 111-119
  • DOI: 10.1093/jb/mvs131
  • Peer Reviewed
• [Journal Article] Pathological study of archival lung tissues from five fatal cases of avian H5N1 influenza in Vietnam (2012)
  • Author(s): N. Nakajima, N. Van Tin, Y. Sato, HN Thach, H. Katano, PH Diep, T. Kumasaka, NT Thuy, H. Hasegawa, LT San, S. Kawachi, NT Liem, K. Suzuki, T. Sata
  • Journal Title: Mod. Pathol. Volume: 26 Issue: 3 Pages: 357-369
  • DOI: 10.1038/modpathol.2012.193
  • Peer Reviewed
• [Journal Article] Clinical features of patients with anti-neutrophil cytoplasmic autoantibodies targeting native myeloperoxidase antigen (2012)
  • Author(s): Yamanishi Y, Ito-Ihara T, Nagao T, Uno K, Kobayashi S, Muso E et. al
  • Journal Title: Mod Rheumatol. Volume: 21 Issue: 5 Pages: 1-9
  • DOI: 10.1007/s10165-012-0781-z
  • NAID: 10031201155
  • Peer Reviewed
• [Journal Article] Deficiency of claudin-18 causes paracellular H+ leakage, up-regulation of interleukin-1β, and atrophic gastritis in mice. (2012)
  • Author(s): Hayashi, D., Tamura, A., Tanaka, H., Yamazaki, Y., Watanabe S. Suzuki, K., Suzuki, K. Sentani, K., Yasui, W., Rakugi, H., Isaka, Y., and Tsukita, S.
  • Journal Title: Gastroenterology Volume: 142 Issue: 2 Pages: 292-304
  • DOI: 10.1053/j.gastro.2011.10.040
  • Peer Reviewed
• [Journal Article] Contribution of neutrophil-derived myeloperoxidase in the early phase of fulminant acute respiratory distress syndrome induced by influenza virus infection (2012)
  • Author(s): Sugamata R et al.
  • Journal Title: Microbiology and Immunology Volume: 56 Issue: 3 Pages: 171-182
  • DOI: 10.1111/j.1348-0421.2011.00424.x
  • Peer Reviewed
• [Journal Article] Apoptotic signaling in endothelial cells with neutrophil activation. (2012)
  • Author(s): Koshio O, Nagao T, Mabuchi A, Ono Y, Suzuki K.
  • Journal Title: Mol Cell Biochem DOI 10.1007/s11010-011-1179-5 Volume: 363 Issue: 1-2 Pages: 269-280
  • DOI: 10.1007/s11010-011-1179-5
  • Peer Reviewed
• [Journal Article] Novel antiviral characters of nanosized copper(I) iodide particles showing inactivation activity against 2009 pandeminc H1N1 influenza virus. (2012)
  • Author(s): Fujimori Y, Sato T, Hayata T, Nagao T, Nakayama M, Nakayama T, Sugamata R, Suzuki K.
  • Journal Title: Appl Environ Microbiol Volume: 78(4) Issue: 4 Pages: 951-955
  • DOI: 10.1128/aem.06284-11
  • Peer Reviewed
• [Presentation] インフルエンザの薬剤耐性を見る (2015)
  • Author(s): 加藤有介、菱木はるか、亀岡洋祐、伊東玲子、鈴木章一、小川知子、石和田稔彦、鈴木和男
  • Organizer: 第24回バイオイメージング学会
  • Place of Presentation: 東京理科大学
  • Year and Date: 2015-09-27
  • Invited
• [Presentation] Contribution of MPO sever e ARDS inducted with influenza virus and autoimmune disease MPO-AMCA-related vasculitis. (2015)
  • Author(s): Kazuo Suzuki
  • Organizer: 9th International Human Peroxidase Meeting.
  • Place of Presentation: Colone, Germany
  • Year and Date: 2015-09-14
  • Int'l Joint Research / Invited
• [Presentation] Project JST/AMED e-ASIA JRP (2015)
  • Author(s): 鈴木和男
  • Organizer: 第8回ADC研Symposium
  • Place of Presentation: 東京
  • Year and Date: 2015-03-14
  • Invited
• [Presentation] エボラ出血熱 In the NIAID-NIH, USA (2015)
  • Author(s): 鈴木和男
  • Organizer: 第7回ADC研 Symposium
  • Place of Presentation: 東京
  • Year and Date: 2015-01-17
  • Invited
• [Presentation] 国際共同研究によるインフルエンザおよび血管炎の臨床疫学の成果と今後の展開 (2014)
  • Author(s): 鈴木和男
  • Organizer: シンポジウム「感染症/生態系監視ネットワークの構築」
  • Place of Presentation: 日本大学(藤沢市)
  • Year and Date: 2014-12-12 – 2014-12-13
  • Invited
• [Presentation] トリインフルエンザ劇症化におけるNS1分子機構 (2014)
  • Author(s): 加藤有介
  • Organizer: 第20回MPO研究会
  • Place of Presentation: 熱海市
  • Year and Date: 2014-11-07 – 2014-11-08
• [Presentation] 天然痘とバイオテロ：バイオテロ対策のシミュレーション (2014)
  • Author(s): 鈴木和男
  • Organizer: 第5回ADC研 Symposium
  • Place of Presentation: 東京
  • Year and Date: 2014-08-01
  • Invited
• [Presentation] インフルエンザによる重症ARDS症例の検討－ベトナムハノイ国立小児病院PICUにおけるStudy 2005-2013より (2014)
  • Author(s): 河内正治1, 2, 3 Shoji Kawachi 中島典子3 Noriko Nakajima、鈴木和男3, 5 Kazuo Suzuki、Nguyen Trung Thuy4, Tran Minh Dien4, Le Thanh Hai4
  • Organizer: 第4回ADC研-Symposium
  • Place of Presentation: 東京
  • Year and Date: 2014-07-05
  • Invited
• [Presentation] 東南アジアのパンデミックインフルエンザおよび危機管理の現状と対策 (2014)
  • Author(s): 鈴木和男
  • Organizer: １３回日本旅行医学会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-19 – 2014-04-22
  • Invited
• [Presentation] 抗好中球細胞質抗体関連血管炎に関わる新規自己抗体Anti-Moesin (2012)
  • Author(s): 鈴木和男
  • Organizer: 第40回臨床免疫学会総会
  • Place of Presentation: 東京
• [Presentation] インフルエンザ（H5N1）の死因となる劇症型ARDSの病態解析とモデル動物・治療法の開発：海外症例に学ぶ―高病原性インフルエンザH5N1のパンデミックの脅威とハノイとの共同研究― (2012)
  • Author(s): 鈴木和男
  • Organizer: 第９回肺研究フォーラム２１
  • Place of Presentation: 神戸
• [Presentation] Pulmonary Infectious Diseases induced associated with Influenza and TB in Asia Countries
  • Author(s): Kazuo Suzuki.
  • Organizer: International Symposium in e-ASIA.
  • Place of Presentation: Tokyo
• [Presentation] Trends in quality of healthcare and Asian infectious diseases
  • Author(s): Kazuo Suzuki.
  • Organizer: International Symposium I.
  • Place of Presentation: Tokyo
• [Presentation] バイオサイエンス研究のために研究費をいかに獲得するか?
  • Author(s): 鈴木和男
  • Organizer: 第87回日本細菌学会
  • Place of Presentation: Tokyo
  • Invited
• [Presentation] T-, L-プラスチンEF-handのCa2+感受性の違い
  • Author(s): 宮川 拓也、四宮 博人、湯本 史明、加藤 有介、田之倉 優
  • Organizer: 第22回日本バイオイメージング学会学術集会
  • Place of Presentation: Tokyo
• [Presentation] 「難治性疾患の治療法と新薬開発の最前線」難病対策の動向と難治性血管炎の治療戦略
  • Author(s): 鈴木和男
  • Organizer: 産学連携セミナー
  • Place of Presentation: 東京
  • Invited
• [Presentation] 呼吸器系ウイルス検出パネルの評価と感染症におけるサイトカインパネルの有用性
  • Author(s): 鈴木和男
  • Organizer: PLANET xMPA 2012
  • Place of Presentation: 東京
  • Invited
• [Book] 「血管炎－基礎と臨床のクロストーク」序文 (2013)
  • Author(s): 鈴木和男
  • Total Pages: 19
  • Publisher: 日本臨床社
• [Book] 「血管炎－基礎と臨床のクロストーク」血管炎の新しいバイオマーカー：抗moesin抗体 (2013)
  • Author(s): 鈴木和男、鈴木浩也
  • Total Pages: 19
  • Publisher: 日本臨床社