Investigation of new therapeutic target against influenza virus infection

• Project/Area Number: 25860296
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Experimental pathology
• Research Institution: Nara Medical University (2014); Okayama University (2013)
• Principal Investigator: ITO TOSHIHIRO 奈良県立医科大学, 医学部, 教授 (00595712)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: エピジェネティクス / インフルエンザウィルス / 気道上皮細胞 / マクロファージ / ヒストンメチル化

Outline of Final Research Achievements

Influenza A virus causes acute respiratory infections that induce annual epidemics and occasional pandemics. Especially, the main cause of death in influenza viral infection is secondary bacterial pneumonia. Both bronchial epithelial cells and macrophages upregulated SET domain, bifurcated 2 (SETDB2) expression following influenza virus H1N1 infection. SETDB2 is a histone methyltransferase that methylates Lys-9 of histone H3 (H3K9), which is correlated with repression of transcription. SETDB2 expression is dependent on RIG-I induced type-I IFN pathway. Moreover, SETDB2 regulates TRAF2, an adaptor molecule of TNF signaling, and amphiregulin, which plays a critical role for promoting the restoration of airway epithelial integrity and lung tissue homeostasis.
These findings indicate that SETDB2 regulation might be one of the critical therapeutic target for influenza virus infection and secondary bacterial pneumonia.

Research Products

• [Journal Article] Spred-2 deficiency exacerbates lipopolysaccharide-induced acute lung inflammation in mice (2014)
  • Author(s): Xu Y, Ito T, Fushimi S, Takahashi S, Itakura J, Kimura R, Sato M, Mino M, Yoshimura A, Matsukawa A
  • Journal Title: PLoS One Volume: 9
  • Peer Reviewed / Open Access
• [Journal Article] The in vivo fibrotic role of FIZZ1 in pulmonary fibrosis (2014)
  • Author(s): Liu T, Yu H, Ullenbruch M, Jin H, Ito T, Wu Z, Liu J, Phan SH.
  • Journal Title: PLoS One Volume: 9
  • Peer Reviewed / Open Access
• [Journal Article] The in vivo fibrotic role of FIZZ1 in pulmonary fibrosis (2014)
  • Author(s): Liu T, Yu H, Ullenbruch M, Jin H, Ito T, Wu Z, Liu J, Phan SH
  • Journal Title: PLoS One Volume: 9 Issue: 2 Pages: e88362-e88362
  • DOI: 10.1371/journal.pone.0088362
  • Peer Reviewed
• [Journal Article] T helper 2 and regulatory T cell cytokine production by mast cells: A key factor in the pathogenesis of IgG4-related disease. (2014)
  • Author(s): Takeuchi, M., Sato, Y., Ohno, K., Tanaka, S., Takata, K., Gion, Y., Orita,Y., Ito, T., Tachibana, T. and Yoshino, T.
  • Journal Title: Mod. Pathol. Volume: 27 Issue: 8 Pages: 1126-1136
  • DOI: 10.1038/modpathol.2013.236
  • Peer Reviewed
• [Journal Article] MHV68 Latency Modulates the Host Immune Response to Influenza A Virus (2013)
  • Author(s): Saito F, Ito T, Connett JM, Schaller MA, Carson WF 4th, Hogaboam CM, Rochford R, Kunkel SL
  • Journal Title: Inflammation Volume: 36 Issue: 6 Pages: 1295-1303
  • DOI: 10.1007/s10753-013-9668-1
  • Peer Reviewed
• [Journal Article] Clinicopathologic analysis of IgG4-related skin disease. (2013)
  • Author(s): Sato Y, Takeuchi M, Takata K, Ohno K, Iwaki N, Orita Y, Goto N, Hida AI, Iwamoto T, Asano N, Ito T, Hanakawa H, Yanai H, Yoshino T.
  • Journal Title: Mod Pathol. Volume: 26 Issue: 4 Pages: 523-532
  • DOI: 10.1038/modpathol.2012.196
  • Peer Reviewed
• [Journal Article] Cutting needle biopsy combined with immunohistochemical study of myeloperoxidase for the diagnosis of histiocytic necrotizing lymphadenitis (2013)
  • Author(s): Hanakawa H, Orita Y, Sato Y, Takeuchi M, Ohno K, Iwaki N, Ito T, Nishizaki K, Yoshino T
  • Journal Title: Acta oto-laryngologica Volume: 133 Issue: 12 Pages: 1328-1332
  • DOI: 10.3109/00016489.2013.824112
  • Peer Reviewed
• [Journal Article] Monocyte chemoattractant protein-1/CCL2 produced by stromal cells promotes lung metastasis of 4T1 murine breast cancer cells (2013)
  • Author(s): Yoshimura T, Howard OM, Ito T, Kuwabara M, Matsukawa A, Chen K, Liu Y, Liu M, Oppenheim JJ, Wang JM
  • Journal Title: PLoS One Volume: 8 Issue: 3 Pages: e58791-e58791
  • DOI: 10.1371/journal.pone.0058791
  • NAID: 120005703799
  • Peer Reviewed
• [Presentation] The critical role of epigenetic regulation against secondary bacterial pneumonia following influenza virus infection (2014)
  • Author(s): Toshihiro Ito, Steven L. Kunkel, Akihiro Matsukawa
  • Organizer: The 13th Awaji International Forum on Infection and Immunity in Nara
  • Place of Presentation: 奈良県新公会堂
  • Year and Date: 2014-09-23 – 2014-09-26
• [Presentation] Spred-2 deficiency exacebates Influenza A Virus (H1N1)-induced Pneumonia (2013)
  • Author(s): Toshihiro Ito, Akihiko Yoshimura, and Akihiro Matsukawa
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: ミラノ（イタリア）
• [Presentation] Epigenetic regulation of secondary bacterial pneumonia following influenza virus infection (2013)
  • Author(s): ITO Toshihiro, KUNKEL L. Steven, MATSUKAWA Akihiro
  • Organizer: 第４２回日本免疫学会総会
  • Place of Presentation: 千葉市
• [Presentation] T細胞Suppressor of Cytokine Signaling 5 (SOCS5)の過剰発現はLPSトレランス効果を増強する (2013)
  • Author(s): 伊藤利洋、板倉淳哉、佐藤美和、美野愛、伏見聡一郎、松川昭博
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌市