A novel regulatory mechanism of C-type lectin receptor-mediated antifungal immunity

• Project/Area Number: 18K15195
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Osaka University
• Principal Investigator: Toyonaga Kenji 大阪大学, 微生物病研究所, 特任研究員(常勤) (90791567)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 自然免疫受容体 / 真菌感染症 / 自然免疫 / C型レクチン受容体

Outline of Final Research Achievements

Candida albicans (C. albicans), which colonize the skin and mucous membranes as a resident fungus, causes severe symptoms such as disseminated candidiasis as an opportunistic infection. For the protection against C. albicans, activation of innate immunity through the C-type lectin receptors (CLRs) such as Dectin-1/Dectin-2 and its signaling adaptor molecule CARD9 plays an important role. However, the detailed regulatory mechanism of this pathway is still unknown. In this study, we found that Trem2 (triggering receptor expressed on myeloid cells 2) might contribute to the suppression of CLR-mediated activation signals.

Academic Significance and Societal Importance of the Research Achievements

全身性カンジダ症のマウスモデルを用いた報告や、様々な疫学的知見から、C. albicansに対する感染防御には、Dectin-1/Dectin-2-CARD9経路を介した自然免疫応答の活性化が重要であることが明らかとなっている。この経路を抑制することが知られているCbl-bの阻害剤は、C. albicansの排除応答を促進することも報告されているため、Trem2-Dap12経路の阻害がカンジダ症の新規治療につながる可能性がある。

Research Products

• [Journal Article] Structural insight into the recognition of pathogen-derived phosphoglycolipids by C-type lectin receptor DCAR (2020)
  • Author(s): Omahdi Zakaria、Horikawa Yuto、Nagae Masamichi、Toyonaga Kenji、Imamura Akihiro、Takato Koichi、Teramoto Takamasa、Ishida Hideharu、Kakuta Yoshimitsu、Yamasaki Sho
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 17 Pages: 5807-5817
  • DOI: 10.1074/jbc.ra120.012491
  • Peer Reviewed
• [Journal Article] IgG immune complexes with Staphylococcus aureus protein A enhance osteoclast differentiation and bone resorption by stimulating Fc receptors and TLR2. (2020)
  • Author(s): Kamohara A, Hirata H, Xu X, Shiraki M, Yamada S, Zhang JQ, Kukita T, Toyonaga K, Hara H, Urano Y, Yamashita Y, Miyamoto H, Kukita A.
  • Journal Title: Int Immunol. 2020 Feb 7;32(2):89-104. Volume: 32 Issue: 2 Pages: 89-104
  • DOI: 10.1093/intimm/dxz063
  • Peer Reviewed
• [Journal Article] C型レクチン受容体のリガンド認識と免疫調節機構 (2019)
  • Author(s): 豊永 憲司、山﨑 晶
  • Journal Title: 医学のあゆみ Volume: 269(9) Pages: 743-748
• [Presentation] Analysis of Card9 function in Mycobacterium bovis BCG infection (2020)
  • Author(s): Kenji Toyonaga, Hiromitsu Hara, Sho Yamasaki
  • Organizer: 8th ITAM WS
• [Presentation] BCG感染におけるCard9の機能解析 (2019)
  • Author(s): 豊永 憲司、原 博満、山﨑 晶
  • Organizer: 第4回抗酸菌研究会
• [Presentation] Analysis of mycobacterial phenolic glycolipid-induced innate immune responses (2019)
  • Author(s): Kenji Toyonaga, Ei’ichi Iizasa, Hiromitsu Hara
  • Organizer: 第12回 寄生虫感染免疫研究会
• [Presentation] Analysis of PGL-mediated innate immune responses (2019)
  • Author(s): Kenji Toyonaga, Ei’ichi Iizasa, Hiromitsu Hara
  • Organizer: 7th ITAM WS
• [Presentation] Identification of innate immune receptor for the mycobacterial virulence factor phenolic glycolipid (2018)
  • Author(s): Kenji Toyonaga, Ei’ichi Iizasa, Yasushi Chuma, Hideyasu Kiyohara, Kazuhiro Matsuo, Hiromitsu Hara
  • Organizer: 第47回 日本免疫学会学術集会
• [Presentation] PGL受容体の機能解析 (2018)
  • Author(s): 豊永憲司、飯笹英一、中馬康志、清原秀泰、松尾和浩、原博満
  • Organizer: 第29回 日本生体防御学会学術総会