Novel interaction between virus and host innate immune system

• Project/Area Number: 15K08517
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Kumamoto University
• Principal Investigator: OSHIUMI HIROYUKI 熊本大学, 大学院生命科学研究部(医), 教授 (50379103)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 自然免疫 / ウイルス / インターフェロン / シグナル / 細胞外小胞 / エクソソーム / サイトカイン / Ｃ型肝炎 / Ｂ型肝炎

Outline of Final Research Achievements

Viral infection is a serious threat to our life and society. The innate immune system is a first line of deference against viral infection and is also required for the activation of adaptive immune response. We have been studying about the molecular mechanisms underlying the innate immune response during viral infection. We revealed that: 1) DDX60 played a crucial role in RIG-I-dependent and -independent antiviral activities in vivo; 2) Epidermal growth factor receptor (EGFR) mediated phosphorylation of DDX60, thereby attenuating DDX60 antiviral function; 3) The Zyxin protein stabilized the interaction between RIG-I and its adaptor MAVS and promoted RIG-I-mediated type I interferon production; 4) Extracellular vesicles were required for the innate immune response to hepatitis B virus. These findings elucidated novel molecular mechanisms of the innate immune responses against viral infection.

Research Products

• [Int'l Joint Research] Universiti Kuala Lumpur(マレーシア)
• [Journal Article] Regulation of RIG-I Activation by K63-Linked Polyubiquitination (2018)
  • Author(s): Okamoto Masaaki、Kouwaki Takahisa、Fukushima Yoshimi、Oshiumi Hiroyuki
  • Journal Title: Frontiers in Immunology Volume: 8 Pages: 1942-1942
  • DOI: 10.3389/fimmu.2017.01942
  • Peer Reviewed / Open Access
• [Journal Article] TICAM-1 is dispensable in STING-mediated innate immune responses in myeloid immune cells (2018)
  • Author(s): Takashima Ken、Oshiumi Hiroyuki、Matsumoto Misako、Seya Tsukasa
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 499 Issue: 4 Pages: 985-991
  • DOI: 10.1016/j.bbrc.2018.04.035
  • Peer Reviewed
• [Journal Article] Activation of TLR3 and its adaptor TICAM-1 increases miR-21 levels in extracellular vesicles released from human cells (2018)
  • Author(s): Fukushima Yoshimi、Okamoto Masaaki、Ishikawa Kana、Kouwaki Takahisa、Tsukamoto Hirotake、Oshiumi Hiroyuki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: In Press Issue: 3 Pages: 744-750
  • DOI: 10.1016/j.bbrc.2018.04.146
  • Peer Reviewed / Open Access
• [Journal Article] Development of mouse models for analysis of human virus infections (2017)
  • Author(s): Takaki Hiromi、Oshiumi Hiroyuki、Shingai Masashi、Matsumoto Misako、Seya Tsukasa
  • Journal Title: Microbiology and Immunology Volume: 61 Issue: 3-4 Pages: 107-113
  • DOI: 10.1111/1348-0421.12477
  • NAID: 40021175296
  • Peer Reviewed
• [Journal Article] Recognition of Viral RNA by Pattern Recognition Receptors in the Induction of Innate Immunity and Excessive Inflammation During Respiratory Viral Infections (2017)
  • Author(s): Okamoto Masaaki、Tsukamoto Hirotake、Kouwaki Takahisa、Seya Tsukasa、Oshiumi Hiroyuki
  • Journal Title: Viral Immunology Volume: 30 Issue: 6 Pages: 408-420
  • DOI: 10.1089/vim.2016.0178
  • Peer Reviewed
• [Journal Article] Toll-like receptor 3 in nasal CD103+ dendritic cells is involved in immunoglobulin A production (2017)
  • Author(s): Takaki H、Kure S、Oshiumi H、Sakoda Y、Suzuki T、Ainai A、Hasegawa H、Matsumoto M、Seya T
  • Journal Title: Mucosal Immunology Volume: 11 Issue: 1 Pages: 82-96
  • DOI: 10.1038/mi.2017.48
  • Peer Reviewed
• [Journal Article] Functional interfaces between TICAM-2/TRAM and TICAM-1/TRIF in TLR4 signaling (2017)
  • Author(s): Funami Kenji、Matsumoto Misako、Oshiumi Hiroyuki、Inagaki Fuyuhiko、Seya Tsukasa
  • Journal Title: Biochemical Society Transactions Volume: 45 Issue: 4 Pages: 929-935
  • DOI: 10.1042/bst20160259
  • Peer Reviewed
• [Journal Article] Zyxin stabilizes RIG-I and MAVS interactions and promotes type I interferon response. (2017)
  • Author(s): Kouwaki T, Okamoto M, Tsukamoto H, Fukushima Y, Matsumoto M, Seya T, Oshiumi H.
  • Journal Title: Scientific Reports. Volume: ー Issue: 1 Pages: 11905-11905
  • DOI: 10.1038/s41598-017-12224-7
  • Peer Reviewed / Open Access
• [Journal Article] Aureobasidium pullulans-cultured fluid induces IL-18 production, leading to Th1-polarization during influenza A virus infection (2017)
  • Author(s): Fujikura Daisuke、Muramatsu Daisuke、Toyomane Kochi、Chiba Satoko、Daito Takuji、Iwai Atsushi、Kouwaki Takahisa、Okamoto Masaaki、Higashi Hideaki、Kida Hiroshi、Oshiumi Hiroyuki
  • Journal Title: The Journal of Biochemistry Volume: 163 Issue: 1 Pages: 31-38
  • DOI: 10.1093/jb/mvx062
  • NAID: 40021457359
  • Peer Reviewed
• [Journal Article] DNAJB1/HSP40 Suppresses Melanoma Differentiation-Associated Gene 5-Mitochondrial Antiviral Signaling Protein Function in Conjunction with HSP70 (2017)
  • Author(s): Takashima Ken、Oshiumi Hiroyuki、Matsumoto Misako、Seya Tsukasa
  • Journal Title: Journal of Innate Immunity Volume: 10 Issue: 1 Pages: 44-55
  • DOI: 10.1159/000480740
  • Peer Reviewed
• [Journal Article] Immune-suppressive effects of interleukin-6 on T-cell-mediated anti-tumor immunity (2017)
  • Author(s): Tsukamoto Hirotake、Fujieda Koji、Senju Satoru、Ikeda Tokunori、Oshiumi Hiroyuki、Nishimura Yasuharu
  • Journal Title: Cancer Science Volume: 109 Issue: 3 Pages: 523-530
  • DOI: 10.1111/cas.13433
  • Peer Reviewed / Open Access
• [Journal Article] cGAMP Promotes Germinal Center Formation and Production of IgA in Nasal-Associated Lymphoid Tissue (2017)
  • Author(s): Takaki Hiromi、Takashima Ken、Oshiumi Hiroyuki、Ainai Akira、Suzuki Tadaki、Hasegawa Hideki、Matsumoto Misako、Seya Tsukasa
  • Journal Title: Medical Sciences Volume: 5 Issue: 4 Pages: 35-35
  • DOI: 10.3390/medsci5040035
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular vesicles deliver host and virus RNA and regulate innate immune response. (2017)
  • Author(s): Kouwaki T., Okamoto M., Tsukamoto H., Fukushima Y. and Oshiumi H.
  • Journal Title: International Journal of Molecular Sciences Volume: 18 Issue: 3 Pages: 666-666
  • DOI: 10.3390/ijms18030666
  • Peer Reviewed / Open Access
• [Journal Article] HTLV-1 Tax induces formation of the active macromolecular IKK complex by generating Lys63- and Met1-linked hybrid polyubiquitin chains. (2017)
  • Author(s): Shibata Y, Tokunaga F, Goto E, Komatsu G, Gohda J, Saeki Y, Tanaka K, Takahashi H, Sawasaki T, Inoue S, Oshiumi H, Seya T, Nakano H, Tanaka Y, Iwai K, and Inoue J.
  • Journal Title: PLoS Pathog. Volume: 13 Issue: 12 Pages: e1006162-e1006162
  • DOI: 10.1371/journal.ppat.1006162
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Interferon-stimulated gene of 20 kDa protein (ISG20) degrades RNA of Hepatitis B virus to impede the replication of HBV in vitro and in vivo. (2016)
  • Author(s): Leong CR, Funami K, Oshiumi H, Mengao D, Takaki H, Matsumoto M, Aly HH, Watashi K, Chayama K, Seya T.
  • Journal Title: Oncotarget. Volume: 7 Issue: 42 Pages: 68179-68193
  • DOI: 10.18632/oncotarget.11907
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] STING in tumor and host cells cooperatively work for NK cell-mediated tumor growth retardation (2016)
  • Author(s): Takashima K, Takeda Y, Oshiumi H, Shime H, Okabe M, Ikawa M, Matsumoto M, Seya T.
  • Journal Title: Biochem Biophys Res Commun Volume: 478 Issue: 4 Pages: 1764-1771
  • DOI: 10.1016/j.bbrc.2016.09.021
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Extracellular Vesicles Including Exosomes Regulate Innate Immune Responses to Hepatitis B Virus Infection. (2016)
  • Author(s): Takahisa Kouwaki, Yoshimi Fukushima, Takuji Daito, Takahiro Sanada, Naoki Yamamoto, Edin J. Mifsud, Chean Ring Leong, Kyoko Tsukiyama-Kohara, Michinori Kohara, Misako Matsumoto, Tsukasa Seya and *Hiroyuki Oshiumi
  • Journal Title: Frontiers in Immunology. Volume: 7 Pages: 335-335
  • DOI: 10.3389/fimmu.2016.00335
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The dataset of proteins specifically interacted with activated TICAM-1 (2016)
  • Author(s): Funami K, Matsumoto M, Oshiumi H, Obuse C, Seya T.
  • Journal Title: Data Brief Volume: 8 Pages: 697-699
  • DOI: 10.1016/j.dib.2016.06.030
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Accessory Factors of Cytoplasmic Viral RNA Sensors Required for Antiviral Innate Immune Response (2016)
  • Author(s): Oshiumi H, Kouwaki T, Seya T
  • Journal Title: Frontiers in Immunology Volume: 7 Pages: 200-200
  • DOI: 10.3389/fimmu.2016.00200
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Biphasic function of TLR3 adjuvant on tumor and spleen dendritic cells promotes tumor T cell infiltration and regression in a vaccine therapy. (2016)
  • Author(s): Azuma M, Takeda Y, Nakajima H, Sugiyama H, Ebihara T, Oshiumi H, Matsumoto M, Seya T
  • Journal Title: OncoImmunology Volume: 8 Issue: 8 Pages: e1188244-e1188244
  • DOI: 10.1080/2162402x.2016.1188244
  • Peer Reviewed
• [Journal Article] Double-stranded RNA analog and type I interferon regulate expression of Trem paired receptors in murine myeloid cells. (2016)
  • Author(s): Kasamatsu, J., Deng, M., Matsumoto, M., Azuma, M., Funami, K., Shime, H., Kasahara, M., Oshiumi, H. and Seya, T.
  • Journal Title: BMC Immunol. Volume: 17 Issue: 1 Pages: 9-9
  • DOI: 10.1186/s12865-016-0147-y
  • NAID: 120005766743
  • Peer Reviewed / Open Access
• [Journal Article] RIOK3-mediated phosphorylation of MDA5 interferes with its assembly and attenuates the innate immune response (2015)
  • Author(s): Ken Takashima, Hiroyuki Oshiumi, Hiromi Takaki, Misako Matsumoto, Tsukasa Seya
  • Journal Title: Cell Reports Volume: 11 Issue: 2 Pages: 192-200
  • DOI: 10.1016/j.celrep.2015.03.027
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] DDX60 Is Involved in RIG-I-Dependent and Independent Antiviral Responses, and Its Function Is Attenuated by Virus-Induced EGFR Activation (2015)
  • Author(s): Hiroyuki Oshiumi, Moeko Miyashita, Masaaki Okamoto, Yuka Morioka, Masaru Okabe, Misako Matsumoto, Tsukasa Seya
  • Journal Title: Cell Reports Volume: 11 Issue: 8 Pages: 1193-1207
  • DOI: 10.1016/j.celrep.2015.04.047
  • NAID: 120005625293
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] PolyI:C-induced, TLR3/RIP3-Dependent Necroptosis Backs Up Immune Effector-Mediated Tumor Elimination In Vivo (2015)
  • Author(s): Ryo Takemura, Hiromi Takaki, Seiji Okada, Hiroaki Shime, Takashi Akazawa, Hiroyuki Oshiumi, Misako Matsumoto, Takanori Teshima, and Tsukasa Seya
  • Journal Title: Cancer Immunology Research Volume: 3 Issue: 8 Pages: 902-914
  • DOI: 10.1158/2326-6066.cir-14-0219
  • NAID: 120005820710
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Evolution of the DEAD box helicase family in chicken: chickens have no DHX9 ortholog (2015)
  • Author(s): Haruko Sato, Hiroyuki Oshiumi, Hiromi Takaki, Hirokazu Hikono, and Tsukasa Seya
  • Journal Title: Microbiology and Immunology Volume: 59 Issue: 10 Pages: 633-640
  • DOI: 10.1111/1348-0421.12322
  • NAID: 120005906889
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of a Regulatory Acidic Motif as the Determinant of Membrane Localization of TICAM-2 (2015)
  • Author(s): Kenji Funami, Misako Matsumoto, Yoshiaki Enokizono, Noriko Ishii, Megumi Tatematsu, Hiroyuki Oshiumi, Fuyuhiko Inagaki and Tsukasa Seya
  • Journal Title: The Journal of Immunology Volume: 195 Issue: 9 Pages: 4456-4465
  • DOI: 10.4049/jimmunol.1402628
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Interferon (IFN) and Cellular Immune Response Evoked in RNA-Pattern Sensing During Infection with Hepatitis C Virus (HCV) (2015)
  • Author(s): Masato Nakai , Hiroyuki Oshiumi , Kenji Funami, Masaaki Okamoto, Misako Matsumoto, Tsukasa Seya, and Naoya Sakamoto
  • Journal Title: Sensors Volume: 15 Issue: 10 Pages: 27160-27173
  • DOI: 10.3390/s151027160
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Links between recognition and degradation of cytoplasmic viral RNA in innate immune response (2015)
  • Author(s): Hiroyuki Oshiumi, Edin J Mifsud, and Takuji Daito
  • Journal Title: Reviews in Medical Virology Volume: 26 Issue: 2 Pages: 90-101
  • DOI: 10.1002/rmv.1865
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] インフルエンザ全粒子ワクチンに対する自然免疫応答での 細胞外小胞の役割 (2017)
  • Author(s): 押海裕之
  • Organizer: 日本生体防御学会学術集会
  • Invited
• [Presentation] 細胞外小胞による細胞間情報伝達における補体の役割 (2017)
  • Author(s): 押海裕之、岡本将明、福島好
  • Organizer: 日本補体学会学術集会
• [Presentation] B型肝炎ウイルスに対する自然免疫応答におけるエクソソームの役割 (2016)
  • Author(s): 押海裕之
  • Organizer: 第８１回日本インターフェロンサイトカイン学会学術集会
  • Place of Presentation: 長崎大学（長崎）
  • Invited
• [Presentation] Extracellular Vesicles Including Exosomes Regulates Innate Immune Responses to Hepatitis B Virus Infection (2016)
  • Author(s): Hiroyuki Oshiumi, Takahisa Kouwaki, Yoshimi Fukushima, Masaaki Okamoto
  • Organizer: 第１５回あわじしま感染症・免疫フォーラム
  • Place of Presentation: 淡路夢舞台国際会議場（兵庫）
  • Int'l Joint Research
• [Presentation] DDX60, a cytoplasmic RNA helicase, enhances RIG-I-dependent and –independent antiviral innate immune response (2015)
  • Author(s): Hiroyuki Oshiumi
  • Organizer: 日本免疫学会
  • Place of Presentation: 札幌コンベンションセンター（札幌市）
  • Year and Date: 2015-11-18
• [Patent(Industrial Property Rights)] ワクチン接種後副反応を予測する検査方法 (2017)
  • Inventor(s): 押海裕之
  • Industrial Property Rights Holder: 熊本大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-177767
  • Filing Date: 2017