Analysis of anti-viral innate immunity and therapeutic strategies for upper respiratory disease.

• Project/Area Number: 26293370
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: Sapporo Medical University
• Principal Investigator: Himi Tetsuo 札幌医科大学, 医学部, 教授 (90181114)
• Co-Investigator(Kenkyū-buntansha): 横田 伸一 札幌医科大学, 医学部, 教授 (10325863) ; 高野 賢一 札幌医科大学, 医学部, 准教授 (70404689) ; 小笠原 徳子 札幌医科大学, 医学部, 助教 (00438061)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2017: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: 上気道感染 / ウイルス / RSウイルス / インターフェロン / IRF3 / 気道上皮細胞 / 上気道 / ウイルス感染 / Ⅲ型インターフェロン / マクロライド / ストレス顆粒 / 抗ウイルス活性 / 鼻粘膜 / 上皮細胞 / 鼻粘膜上皮 / 抗ウイルス作用物質 / ムンプスウイルス / 麻疹ウイルス / ウイルス受容体 / ＲＳウイルス / .インターフェロン / 呼吸器ウイルス / λインターフェロン / ウイルス持続感染

Outline of Final Research Achievements

We examined the effect of CAM on production of cytokines, CAM significantly suppressed RSV-induced production of IFN-λ1, λ2 and λ3. CAM dramatically suppressed RSV-induced promoter activity, which is an IRF3 biding element. RSV-induced phosphorylation of IRF-3 did not alter in the presence of CAM. CAM inhibits IRF3 dimerization and its subsequent nuclear translocation from cytosol upon stimulation with poly I:C or RSV.
In conclusion, CAM suppresses the production of pro-inflammatory cytokines and IFNs induced by virus-related stimuli, such as RSV and poly I:C. CAM exerts these effects by inhibiting the dimerization and subsequent nuclear translocation of IRF3 in airway epithelial cells. NIP-SNAP and MuV-induced SGs partly suppressed viral-induced type Ⅲ IFN production and suppressed the production of pro-inflammatory cytokines.

Research Products

• [Journal Article] Evaluation of consistency in quantification of gene copy number by real-time reverse transcription quantitative polymerase chain reaction and virus titer by plaque-forming assay for human respiratory syncytial virus. (2018)
  • Author(s): Yamamoto K, Ogasawara N, Yamamoto S, Takano K, Shiraishi T, Sato T, Tsutsumi H, Himi T, Yokota SI.
  • Journal Title: Microbiol Immunol. Volume: 62 Issue: 2 Pages: 90-98
  • DOI: 10.1111/1348-0421.12563
  • NAID: 40021481337
  • Peer Reviewed
• [Journal Article] The role of transcriptional factor p63 in regulation of epithelial barrier and ciliogenesis of human nasal epithelial cells (2017)
  • Author(s): Kaneko Yakuto、Kohno Takayuki、Kakuki Takuya、Takano Ken-ichi、Ogasawara Noriko、Miyata Ryo、Kikuchi Shin、Konno Takumi、Ohkuni Tsuyoshi、Yajima Ryoto、Kakiuchi Akito、Yokota Shin-ichi、Himi Tetsuo、Kojima Takashi
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 10935-10935
  • DOI: 10.1038/s41598-017-11481-w
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of claudin-4 via p63 in human epithelial cells. (2017)
  • Author(s): Kojima T, Kohno T, Kubo T, Kaneko Y, Kakuki T, Kakiuchi A, Kurose M, Takano KI, Ogasawara N, Obata K, Nomura K, Miyata R, Konno T, Ichimiya S, Himi T.
  • Journal Title: Ann N Y Acad Sci. Volume: 1405 Issue: 1 Pages: 25-31
  • DOI: 10.1111/nyas.13456
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial proteins NIP-SNAP-1 and -2 are a target for the immunomodulatory activity of clarithromycin, which involves NF-κB-mediated cytokine production. (2017)
  • Author(s): Yamamoto S, Ogasawara N, Yamamoto K, Uemura C, Takaya Y, Shiraishi T, Sato T, Hashimoto S, Tsutsumi H, Takano K, Himi T, Yokota SI.
  • Journal Title: Biochem Biophys Res Commun. Volume: 483 Issue: 3 Pages: 911-916
  • DOI: 10.1016/j.bbrc.2016.12.133
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial proteins NIP-SNAP-1 and -2 are a target for the immunomodulatory activity of clarithromycin, which involves NF-κB-mediated cytokine production. (2017)
  • Author(s): Yamamoto S, Ogasawara N, Yamamoto K, Uemura C, Takaya Y, Shiraishi T, Sato T, Hashimoto S, Tsutsumi H, Takano K, Himi T, Yokota SI.
  • Journal Title: Biochem Biophys Res Commun Volume: 483 Issue: 3 Pages: 911-916
  • DOI: 10.1016/j.bbrc.2016.12.100
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] HIV-associated cystic lesions of the parotid gland. (2017)
  • Author(s): Ogasawara N, Takano KI, Kobayashi H, Kikuchi K, Matsumiya H, Yoshioka I, Himi T.
  • Journal Title: Auris Nasus Larynx. Volume: 44 Issue: 1 Pages: 126-130
  • DOI: 10.1016/j.anl.2016.05.011
  • Peer Reviewed
• [Journal Article] Mechanism of Reduced Susceptibility to Fosfomycin in Escherichia coli Clinical Isolates (2017)
  • Author(s): Ohkoshi Y, Sato T, Suzuki Y, Yamamoto S, Shiraishi T, Ogasawara N, Yokota SI
  • Journal Title: BioMed Research International Volume: Article ID 5470241 Pages: 5470241-5470241
  • DOI: 10.1155/2017/5470241
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Tigecycline Nonsusceptibility Occurs Exclusively in Fluoroquinolone- Resistant Escherichia coli Clinical Isolates, Including the Major Multidrug-Resistant Lineages O25b:H4- ST131-H30R and O1-ST648 (2017)
  • Author(s): Sato T, Suzuki Y, Shiraishi T, Honda H, Shinagawa M, Yamamoto S, Ogasawara N, Takahashi H, Takahashi S, Tamura Y, Yokota SI
  • Journal Title: Antimicrob Agents Chemother Volume: 61 Issue: 2
  • DOI: 10.1128/aac.01654-16
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mumps Virus Induces Protein-Kinase-R-Dependent Stress Granules, Partly Suppressing Type III Interferon Production. (2016)
  • Author(s): Hashimoto S, Yamamoto S, Ogasawara N, Sato T, Yamamoto K, Katoh H, Kubota T, Shiraishi T, Kojima T, Himi T, Tsutsumi H, Yokota S
  • Journal Title: PLoS One. Volume: Aug 4;3: Issue: 8 Pages: 16023-16023
  • DOI: 10.1371/journal.pone.0161793
  • Peer Reviewed / Open Access
• [Journal Article] Clarithromycin prevents human respiratory syncytial virus-induced airway epithelial responses by modulating activation of interferon regulatory factor-3. (2016)
  • Author(s): Yamamoto K, Yamamoto S, Ogasawara N, Takano K, Shiraishi T, Sato T, Miyata R, Kakuki T, Kamekura R, Kojima T, Tsutsumi H, Himi T, Yokota S.
  • Journal Title: Pharmacol Res Volume: 111 Pages: 804-814
  • DOI: 10.1016/j.phrs.2016.07.033
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Adenovirus-Mediated ICOSIg Gene Therapy in a Presensitized Murine Model of Allergic Rhinitis. (2016)
  • Author(s): Sato J, Konno N, Murakami M, Uede T, Himi T.
  • Journal Title: Adv Otorhinolaryngol. Volume: 77 Pages: 59-66
  • DOI: 10.1159/000441876
  • ISBN: 9783318056501, 9783318056518
• [Journal Article] Measles Virus Genotype D Wild Strains Suppress Interferon-Stimulated Gene Expression More Potently than Laboratory Strains in SiHa Cells. (2016)
  • Author(s): Jinushi M, Yamamoto S, Ogasawara N, Nagano H, Hashimoto S, Tsutsumi H, Himi T, Yokota S.
  • Journal Title: Viral Immunol. Volume: 29 Issue: 5 Pages: 296-306
  • DOI: 10.1089/vim.2016.0004
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 上気道炎症と上皮バリア機能 (2016)
  • Author(s): 高野賢一，氷見徹夫
  • Journal Title: 別冊Bio Clinica:慢性炎症と疾患 Volume: 5 Pages: 1-4
• [Journal Article] 耳鼻咽喉科が依頼におけるインフルエンザに対するアプローチ (2016)
  • Author(s): 高野賢一
  • Journal Title: ENTONI Volume: 192 Pages: 189-194
• [Journal Article] 微生物学的検査のピットフォール 的確な感染症診断 耳鼻咽喉科領域における結核菌感染症 (2016)
  • Author(s): 小笠原 徳子, 高野 賢一, 氷見 徹夫
  • Journal Title: 日本耳鼻咽喉科感染症・エアロゾル学会会誌 Volume: 4 Pages: 77-81
  • NAID: 130007896187
• [Journal Article] 抗菌薬耐性菌の驚くべき進化と脅威 (2016)
  • Author(s): 横田 伸一
  • Journal Title: 日本耳鼻咽喉科感染症・エアロゾル学会会誌 Volume: 4 Pages: 7-13
  • NAID: 130007896194
• [Journal Article] Measles Virus Genotype D Wild Strains Suppress Interferon-Stimulated Gene Expression More Potently than Laboratory Strains in SiHa Cells. (2016)
  • Author(s): Jinushi M, Yamamoto S, Ogasawara N, Nagano H, Hashimoto S, Tsutsumi H, Himi T, Yokota SI.
  • Journal Title: Viral Immunol. Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Interferon-gamma increased epithelial barrier function via upregulating claudin-7 expression in human submandibular gland duct epithelium. (2016)
  • Author(s): Abe A, Takano K, Kojima T, Nomura K, Kakuki T, Kaneko Y, Yamamoto M, Takahashi H, Himi T.
  • Journal Title: J Mol Histol. Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Claudin-binder C-CPE mutants enhance permeability of insulin across human nasal epithelial cells. (2015)
  • Author(s): Kojima T, Kondoh M, Keira T, Takano KI, Kakuki T, Kaneko Y, Miyata R, Nomura K, Obata K, Kohno T, Konno T, Sawada N, Himi T.
  • Journal Title: Drug Deliv. Volume: 3 Pages: 1-8
  • Peer Reviewed
• [Journal Article] Poly(I:C) induced microRNA-146a regulates epithelial barrier and secretion of proinflammatory cytokines in human nasal epithelial cells. (2015)
  • Author(s): Miyata R, Kakuki T, Nomura K, Ohkuni T, Ogasawara N, Takano K, Konno T, Kohno T, Sawada N, Himi T, Kojima T.
  • Journal Title: Eur J Pharmacol. Volume: 761 Pages: 375-382
  • DOI: 10.1016/j.ejphar.2015.04.031
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Leukotriene E₄ induces MUC5AC release from human airway epithelial NCI-H292 cells (2015)
  • Author(s): Shirasaki H, Kanaizumi E, Seki N, Himi T.
  • Journal Title: Allergology International Volume: 64 Issue: 2 Pages: 169-174
  • DOI: 10.1016/j.alit.2014.11.002
  • NAID: 130005290288
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed
• [Journal Article] Alteration of circulating type 2 follicular helper T cells and regulatory B cells underlies the comorbid association of allergic rhinitis with bronchial asthma (2015)
  • Author(s): Kamekura R, Shigehara K, Miyajima S, Jitsukawa S, Kawata K, Yamashita K, Nagaya T, Kumagai A, Sato A, Matsumiya H, Ogasawara N, Seki N, Takano K, Kokai Y, Takahashi H, Himi T, Ichimiya S
  • Journal Title: Clinical Immunology Volume: in press Issue: 2 Pages: 120-5
  • DOI: 10.1016/j.clim.2015.02.016
  • Peer Reviewed / Open Access
• [Journal Article] Isogladine maleate regulates gap junctional intercellular communication-dependent epithelial barrier in human nasal epithelial cells. (2014)
  • Author(s): Miyata R, Nomura K, Kakuki T, Takano K, Kohno T, Konno T, Sawada N, Himi T, Kojima T.
  • Journal Title: J Membr Biol. Volume: 248(2) Issue: 2 Pages: 327-336
  • DOI: 10.1007/s00232-015-9774-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 鼻粘膜上皮におけるRSウイルス感染メカニズムと新たな予防戦略 (2014)
  • Author(s): 高野賢一，氷見徹夫
  • Journal Title: 日本鼻科学会会誌 Volume: 53 Pages: 36-38
  • NAID: 130004546200
  • Open Access
• [Journal Article] 耳鼻咽喉科とウイルス 上気道粘膜とウイルス感染 (2014)
  • Author(s): 氷見徹夫， 高野 賢一, 大國 毅, 小笠原 徳子, 山本 圭佑, 高橋 希
  • Journal Title: ＪＯＨＮＳ Volume: 30 Pages: 1533-39
• [Journal Article] ΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis. (2014)
  • Author(s): Kubo T, Kamekura R, Kumagai A, Kawata K, Yamashita K, Mitsuhashi Y, Kojima T, Sugimoto K, Yoneta A, Sumikawa Y, Yamashita T, Sato N, Himi T, Ichimiya S
  • Journal Title: PLoS One Volume: 9(8) Issue: 8 Pages: e105498-e105498
  • DOI: 10.1371/journal.pone.0105498
  • Peer Reviewed / Open Access
• [Journal Article] Pseudomonas aeruginosa elastase causes transient disruption of tight junctions and downregulation of PAR-2 in human nasal epithelial cells (2014)
  • Author(s): Nomura K, Takano K, Himi T, Kojima T. (10名, 9, 10番)
  • Journal Title: Respir Res Volume: 18 Issue: 1 Pages: 15-21
  • DOI: 10.1186/1465-9921-15-21
  • Peer Reviewed / Open Access
• [Journal Article] 鼻粘膜とウイルス感染 (2014)
  • Author(s): 氷見徹夫．柏木征三郎
  • Journal Title: インフルエンザ Volume: 15 Pages: 9-15
• [Presentation] クラリスロマイシンは軌道上秀RSVによって誘導されるインターフェロンをIRF-3を介して調節する (2017)
  • Author(s): 山本 圭佑， 高野 賢一, 小笠原 徳子, 黒瀬 誠, 野村 一顕, 宮田 遼, 角木 拓也, 氷見 徹夫
  • Organizer: 第１１８回日本耳鼻咽喉科学会総会
• [Presentation] Clarisromysin regulates production or induction of IFN and proinflammatory cytokine production by RSV infection in human airway epithelial cells via modulation nuclear translocation of IRF-3. (2016)
  • Author(s): Yamamoto K, Yamamoto S, Ogasawara N, Takano K, Ohkuni T, Kojima T, Tsutsumi H, Yokota S, Himi T
  • Organizer: 第６４回日本ウイルス学会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2016-10-23
• [Presentation] Clarithromycin and garenoxacin supress proinflammatory cytokine and chemokane induction in airway epithelial cells induced by human RSV. via different signal pathway. (2015)
  • Author(s): Yamamoto K, Hashimoto S, Himi T et al
  • Organizer: 第63回日本ウイルス学会
  • Place of Presentation: 福岡国際会議場（福岡）
  • Year and Date: 2015-11-22
• [Presentation] ヒト気道上皮細胞におけるRSウイルス感染によるサイトカイン産生誘導と抗生剤による阻害効果の検討 (2014)
  • Author(s): 山本 圭佑， 高野 賢一, 小笠原 徳子, 黒瀬 誠, 野村 一顕, 宮田 遼, 角木 拓也, 氷見 徹夫
  • Organizer: 日本鼻科学会
  • Place of Presentation: 大阪コングレコンベンションセンター
  • Year and Date: 2014-09-25 – 2014-09-27