Role for novel innate immune receptors for pulmonary pathogens

• Project/Area Number: 24390256
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: Kagoshima University (2014); Saga University (2012-2013)
• Principal Investigator: HARA Hiromitsu 鹿児島大学, 医歯(薬)学総合研究科, 教授 (20392079)
• Co-Investigator(Renkei-kenkyūsha): MATSUZAKI Goro 琉球大学, 熱帯生物圏研究センター, 教授 (30229455) ; YAMASAKI Sho 九州大学, 生体防御医学研究所, 教授 (40312946)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2014: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2013: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2012: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
• Keywords: 自然免疫 / 結核 / インフルエンザ / CARD9 / 骨髄系ITAM受容体 / 感染症 / ITAM関連受容体

Outline of Final Research Achievements

We identified two novel innate immune receptors, IgMB1 and IgMB2, that recognize Mycobacterium tuberculosis. We found that IgMB1 recognizes non-glycosylated mycolates (MA) such as GroMM and free MA and induces MCP-1, but not TNF, production by macrophages, whereas the CLR Mince recognizes the glycosylated-mycolates, TDM and GMM, and induces both TNF and MCP-1 production. In addition, we found that IgMB1 inhibits the cytokine responses through Mincle in macrophages.We also identified a novel innate immune receptor, IgRF1, that recognizes influenza virus. We found that the innate cytokine response through IgRF1 contributes to influenza pneumonia.

Research Products

• [Journal Article] Clustering of CARMA1 through SH3-GUK domain interactions is required for its activation of NF-kB signaling (2015)
  • Author(s): Hara, H., Yokosuka, T., Hirakawa, H., Ishihara, C., Yasukawa, S., Yamazaki, M., Koseki, H., Yoshida, H. and Saito, T.
  • Journal Title: Nat. Commun. Volume: 6 Issue: 1 Pages: 5555-5555
  • DOI: 10.1038/ncomms6555
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 3-O-sulfo-β-d-galactose moiety of endogenous sulfoglycolipids is a potential ligand for immunoglobulin-like receptor LMIR5 (2015)
  • Author(s): Phongsisay V, Iizasa E, Hara H, Yamasaki S
  • Journal Title: Molecular Immunology Volume: 63 Issue: 2 Pages: 595-595
  • DOI: 10.1016/j.molimm.2014.07.023
  • Peer Reviewed
• [Journal Article] Defect of CARD9 leads to impaired accumulation of IFN-γ -producing memory-phenotype T cells in lungs and increased susceptibility to pulmonary infection with Cryptococcus neoformans (2014)
  • Author(s): Yamamoto H, Nakamura Y, Sato K, Takahashi Y, Nomura T, Miyasaka T, Ishii K, Hara H, Yamamoto N, Kanno E, Iwakura Y, Kawakami K
  • Journal Title: Infect. Immun Volume: 82 Issue: 4 Pages: 1606-1615
  • DOI: 10.1128/iai.01089-13
  • Peer Reviewed
• [Journal Article] An ITAM-Syk-CARD9 signaling axis triggers contact hypersensitivity by stimulating IL-1 production in dendritic cells (2014)
  • Author(s): Yasukawa. S., Miyazaki, Y., Yoshii, C., Nakaya, M., Ozaki, N., Toda, S., Kuroda, E., Ishibashi, K., Yasuda, T., Natsuaki, Y., Mi-ichi, F., Iizasa, E., Nakahara, T., Yamazaki, M., Kabashima, K., Iwakura, Y., Takai, T., Saito, T., Kurosaki, T., Malissen, B., Ohno, N., Furue, M., Yoshida, H., and Hara, H
  • Journal Title: Nature Comm Volume: 5 Issue: 1 Pages: 3755-3755
  • DOI: 10.1038/ncomms4755
  • Peer Reviewed / Open Access
• [Journal Article] LMIR5 extracellular domain activates myeloid cells through Toll-like receptor 4. (2014)
  • Author(s): Phongsisay V, Iizasa E, Hara H, Yamasaki S
  • Journal Title: Molecular Immunology Volume: 62 Issue: 1 Pages: 169-169
  • DOI: 10.1016/j.molimm.2014.06.012
  • Peer Reviewed
• [Presentation] 自然免疫による結核菌ミコール酸脂質の認識 (2015)
  • Author(s): 原博満、飯笹英一、久保田未央、植松崇之、清原秀泰、山崎晶、松崎吾朗、吉田裕樹
  • Organizer: 第88回日本細菌学会総会ワークショップ「PAMPs受容体研究の最前線」
  • Place of Presentation: 岐阜市 長良川国際会議場
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] 骨髄系ITAM受容体を介した免疫応答の制御 (2015)
  • Author(s): 原博満
  • Organizer: 第60回日本臨床検査医学会 九州地方会（第26回日本臨床化学会 九州支部総会合同開催）
  • Place of Presentation: 鹿児島市 鹿児島大学鶴陵会館
  • Year and Date: 2015-03-07
  • Invited
• [Presentation] Innate recognition of mycolic acid-containing lipids in mycobacteria (2014)
  • Author(s): Iizasa Ei’ichi, UEMATSU Takayk, KUBOTA Mio, KIYOHARA Hideyasu, CHUMA Yasushi, MATSUZAKI Goro, YAMASAKI Sho, YOSHIDA Hiroki, HARA Hiromitsu
  • Organizer: The 43rd annual meeting of the Japanese Society for Immunology
  • Place of Presentation: 京都市 国立京都国際会館
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Activation of innate immunity mediated by the IgSFR2/CARD9 pathway is involved in severe influenza pneumonia (2014)
  • Author(s): UEMATSU Takayuki, IIZASA Ei-ichi, KOBAYASHI Noritada, Yoshida Hiroki, HARA Hiromitsu
  • Organizer: The 43rd annual meeting of the Japanese Society for Immunology
  • Place of Presentation: 京都 国立京都国際会館
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] 結核菌細胞壁のミコール酸含有脂質を認識する新規自然免疫受容体 (2014)
  • Author(s): 飯笹英一, 植松崇之, 久保田未央, 清原秀泰, 中馬康志, 松崎吾朗, 山崎晶, 吉田裕樹, 原博満
  • Organizer: 第67回日本細菌学会西日本支部会
  • Place of Presentation: 鹿児島市 城山観光ホテル
  • Year and Date: 2014-09-05 – 2014-09-06
• [Presentation] インフルエンザウイルス感染における ITAM 関連受容体-CARD9シグナルを介した新規自然免疫活性化経路の解析 (2014)
  • Author(s): 植松崇之, 飯笹英一, 小林憲忠, 吉田裕樹, 原博満
  • Organizer: 第51回日本ウイルス学会九州支部総会
  • Place of Presentation: 鹿児島市 城山観光ホテル
  • Year and Date: 2014-09-05 – 2014-09-06
• [Presentation] IgSFR2は結核菌細胞壁のミコール酸含有脂質を認識する自然免疫受容体である (2014)
  • Author(s): 飯笹英一, 植松崇之, 杉田昌彦, 山崎晶, 吉田裕樹, 原博満
  • Organizer: 第79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: 札幌市 北海道大学医学部学友会館
  • Year and Date: 2014-06-19 – 2014-06-20
• [Presentation] Activation of innate immunity through the CARD9 pathway is involved in severe influenza pneumonia. (2013)
  • Author(s): T. Uematsu, E. Iizasa, N. Kobayashi, H. Yoshida, H. Hara
  • Organizer: International congress of immunology
  • Place of Presentation: Milano, Italy
• [Presentation] Identification of an ITAM-coupled pattern recognition receptor that recognizes the mycobacterium cell wall component mycolic acids. (2013)
  • Author(s): E. Iizasa, T. Uematsu, G. Matsuzaki, S. Yamasaki, H. Yoshida and H. Hara
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 幕張
• [Presentation] CARD9-mediated innate IFN-g production and host defene to cryptococcal inection. (2013)
  • Author(s): H. Yamamoto, Y. Nakamura, K. Sato, K. Matsumura, K. Ishii, H. Hara and K. Kawakami
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 幕張
• [Presentation] Identification of novel innate pattern recognition receptors for mycobacterium tuberculosis. (2013)
  • Author(s): E. Iizasa, T. Myamoto, T. Uematsu, T. Ishikawa, S. Yamasaki, G. Matsuzaki, H. Yoshida, H. Hara
  • Organizer: International congress of immunology
  • Place of Presentation: Milano, Italy
• [Presentation] Identification and analysis of two novel pattern recognition receptors for Mycobacterium tuberculosis. (2013)
  • Author(s): Ei’ichi Iizasa, Tomofumi Miyamoto, Takayuki Uematsu, Tetsuaki Ishikawa, Sho Yamasaki, Goro Matsuzaki, Hiroki Yoshida, Hiromitsu Hara
  • Organizer: 第78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: 東京
• [Presentation] Adjuvant activity of Mycobacterium tuberculosis-derived mycolic acid through activation of the ITAM receptor/CARD9-mediated innate immunity (2013)
  • Author(s): M. Kubota, E. Iizasa, K. Hideyasu, N. Yasushi, H. Hara and H. Yoshida
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 幕張
• [Presentation] Identification and functional analysis of novel mycobacterium receptors. (2012)
  • Author(s): 飯笹英一
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2012-12-05
• [Presentation] Activation of innate immunity through the CARD9 pathway is involved in severe influenza pneumonia. (2012)
  • Author(s): 植松崇之
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2012-12-05