The role of C-type lectins in the host defense against fungal infections

• Project/Area Number: 23390101
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Bacteriology (including Mycology)
• Research Institution: Chiba University
• Principal Investigator: SAIJO Shinobu 千葉大学, 真菌医学研究センター, 特任准教授 (60396877)
• Co-Investigator(Kenkyū-buntansha): IWAKURA Yoichiro 東京理科大学, 生命医科学研究所, 教授 (10089120) ; YONEYAMA Mitsutoshi 千葉大学, 真菌医学研究センター, 教授 (40260335)
• Project Period (FY): 2011-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000); Fiscal Year 2013: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2012: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2011: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
• Keywords: ｻｲﾄｶｲﾝ / C型レクチン / 真菌感染防御 / 遺伝子改変マウス / ノックアウトマウス / サイトカイン / 感染免疫 / 真菌感染 / 細菌感染 / 感染防御 / 自然免疫 / 獲得免疫 / 炎症反応 / 樹状細胞 / マウス

Outline of Final Research Achievements

The C-type lectin is a large group of transmembrane and extracellular proteins and is characterized by the extracellular domain called CRD (carbohydrate binding domain). Although C-type lectins expressed in dendritic cells (DCs) and macrophages had been suggested to be members of pattern recognition receptors (PRRs), their functions have long been remained unclear. Therefore, we aimed to clarify the molecular mechanisms of C-type lectins in the host defense against microbial infections. In this study, we found that Dectin-1 is a receptor for fungal cell wall beta-glucans and Dectin-2 is a receptor for another fungal cell wall carbohydrate alpha-mannans as well as bacterial cell wall component. More importantly, these C-type lectins are crucial for the host defense against fungal and bacterial infections. Thus, the studies clearly showed that both Dectin-1 and Dectin-2 are PRRs that control microbial infections.

Research Products

• [Journal Article] α-Mannan induces Th17-mediated pulmonary graft-versus-host disease in mice. (2015)
  • Author(s): Uryu H, Hashimoto D, Kato K, Hayase E, Matsuoka S, Ogasawara R, Takahashi S, Maeda Y, Iwasaki H, Miyamoto T, Saijo S, Iwakura Y, Hill GR, Akashi K, Teshima T.
  • Journal Title: Blood. Volume: in press
  • Peer Reviewed
• [Journal Article] Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus. (2015)
  • Author(s): Herbst S, Shah A, Mazon Moya M, Marzola V, Jensen B, Reed A, Birrell MA, Saijo S, Mostowy S, Shaunak S, Armstrong-James D.
  • Journal Title: EMBO Mol Med. Volume: 7 Issue: 3 Pages: 240-258
  • DOI: 10.15252/emmm.201404556
  • Peer Reviewed
• [Journal Article] Dectin-2 deficiency promotes Th2 response and mucin production in the lungs after pulmonary infection with Cryptococcus neoformans. (2015)
  • Author(s): Nakamura Y, Sato K, Yamamoto H, Matsumura K, Matsumoto I, Nomura T, Miyasaka T, Ishii K, Kanno E, Tachi M, Yamasaki S, Saijo S, Iwakura Y, Kawakami K.
  • Journal Title: Infect Immun. Volume: 83 Issue: 2 Pages: 671-681
  • DOI: 10.1128/iai.02835-14
  • Peer Reviewed
• [Journal Article] The pH-responsive PacC transcription factor of Aspergillus fumigatus governs epithelial entry and tissue invasion during pulmonary aspergillosis. (2014)
  • Author(s): Bertuzzi M, Schrettl M, Alcazar-Fuoli L, Cairns TC, Munoz A, Walker LA, Herbst S, Safari M, Cheverton AM, Chen D, Liu H, Saijo S, Fedorova ND, Armstrong-James D, Munro CA, Read ND, Filler SG, Espeso EA, Nierman WC, Haas H, Bignell EM.
  • Journal Title: PLoS Pathog. Volume: 10 Issue: 10 Pages: e1004413-e1004413
  • DOI: 10.1371/journal.ppat.1004413
  • Peer Reviewed
• [Journal Article] Dectin-2 is a direct receptor for mannose-capped lipoarabinomannan of mycobacteria. (2014)
  • Author(s): Yonekawa A, Saijo S, Hoshino Y, Miyake Y, Ishikawa E, Suzukawa M, Inoue H, Tanaka M, Yoneyama M, Oh-Hora M, Akashi K, Yamasaki S.
  • Journal Title: Immunity Volume: 41 Issue: 3 Pages: 402-13
  • DOI: 10.1016/j.immuni.2014.08.005
  • Peer Reviewed / Open Access
• [Journal Article] Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses. (2014)
  • Author(s): Chiba S, Ikushima H, Ueki H, Yanai H, Kimura Y, Hangai S, Nishio J, Negishi H, Tamura T, Saijo S, Iwakura Y, Taniguchi T.
  • Journal Title: eLife Volume: 04177 Pages: 04177-04177
  • DOI: 10.7554/elife.04177
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dectin-1 pathway activates robust autophagy-dependent unconventional protein secretion in human macrophages. (2014)
  • Author(s): Ohman T, Teirila L, Lahesmaa-Korpinen AM, Cypryk W, Veckman V, Saijo S, Wolff H, Hautaniemi S, Nyman TA, Matikainen S.
  • Journal Title: J Immunol. Volume: 192 Issue: 12 Pages: 5952-5962
  • DOI: 10.4049/jimmunol.1303213
  • Peer Reviewed
• [Journal Article] Rag2-deficient IL-1 Receptor Antagonist-deficient Mice Are a Novel Colitis Model in Which Innate Lymphoid Cell-derived IL-17 Is Involved in the Pathogenesis. (2014)
  • Author(s): Akitsu A, Kakuta S, Saijo S, Iwakura Y.
  • Journal Title: Exp Anim. Volume: 63 Pages: 235-246
  • NAID: 130003391627
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CTRP3 plays an important role in the development of collagen-induced arthritis in mice. (2014)
  • Author(s): Murayama MA, Kakuta S, Maruhashi T, Shimizu K, Seno A, Kubo S, Sato N, Saijo S, Hattori M, Iwakura Y.
  • Journal Title: Biochem Biophys Res Commun. Volume: 443 Issue: 1 Pages: 42-48
  • DOI: 10.1016/j.bbrc.2013.11.040
  • Peer Reviewed
• [Journal Article] C-type lectin receptors differentially induce th17 cells and vaccine immunity to the endemic mycosis of North America. (2014)
  • Author(s): Wang H, LeBert V, Hung CY, Galles K, Saijo S, Lin X, Cole GT, Klein BS, Wüthrich M.
  • Journal Title: J Immunol. Volume: 192 Issue: 3 Pages: 1107-1109
  • DOI: 10.4049/jimmunol.1302314
  • Peer Reviewed
• [Journal Article] Excess IL-1 signaling enhances the development of Th17 cells by downregulating TGF-β-induced Foxp3 expression. (2014)
  • Author(s): Ikeda S, Saijo S, Murayama MA, Shimizu K, Akitsu A, Iwakura Y.
  • Journal Title: J Immunol. Volume: 192 Issue: 4 Pages: 1449-1458
  • DOI: 10.4049/jimmunol.1300387
  • Peer Reviewed
• [Journal Article] Dectin-2 regulates the effector phase of house dust mite-elicited pulmonary inflammation independently from its role in sensitization. (2014)
  • Author(s): Parsons MW, Li L, Wallace AM, Lee MJ, Katz HR, Fernandez JM, Saijo S, Iwakura Y, Austen KF, Kanaoka Y, Barrett NA.
  • Journal Title: J Immunol. Volume: 192 Issue: 4 Pages: 1361-1371
  • DOI: 10.4049/jimmunol.1301809
  • Peer Reviewed
• [Journal Article] Nonagonistic Dectin-1 ligand transforms CpG into a multitask nanoparticulate TLR9 agonist. (2014)
  • Author(s): Kobiyama K, Aoshi T, Narita H, Kuroda E, Hayashi M, Tetsutani K, Koyama S, Mochizuki S, Sakurai K, Katakai Y, Yasutomi Y, Saijo S, Iwakura Y, Akira S, Coban C, Ishii KJ.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 111 Issue: 8 Pages: 3086-3091
  • DOI: 10.1073/pnas.1319268111
  • Peer Reviewed
• [Journal Article] Dectin-2 promotes house dust mite-induced Th2 and Th17 cell differentiation and allergic airway inflammation in mice. (2014)
  • Author(s): Norimoto A, Hirose K, Iwata A, Tamachi T, Yokota M, Takahashi K, Saijo S, Iwakura Y, Nakajima H.
  • Journal Title: Am J Respir Cell Mol Biol. Volume: Epub ahead of print
  • Peer Reviewed
• [Journal Article] Identification of distinct ligands for the C-type lectin receptors Mincle and Dectin-2 in the pathogenic fungus Malassezia. (2013)
  • Author(s): Ishikawa T, Itoh F, Yoshida S, Saijo S, Matsuzawa T, Gonoi T, Saito T, Okawa Y, Shibata N, Miyamoto T, Yamasaki S.
  • Journal Title: Cell Host Microbe. Volume: 13 Issue: 4 Pages: 477-488
  • DOI: 10.1016/j.chom.2013.03.008
  • Peer Reviewed
• [Journal Article] Dectin-2-dependent NKT cell activation and serotype-specific antibody production in mice immunized with pneumococcal polysaccharide vaccine. (2013)
  • Author(s): Miyasaka T, Akahori Y, Toyama M, Miyamura N, Ishii K, Saijo S, Iwakura Y, Kinjo Y, Miyazaki Y, Oishi K, Kawakami K.
  • Journal Title: PLoS One. Volume: 8 Issue: 10 Pages: e78611-e78611
  • DOI: 10.1371/journal.pone.0078611
  • Peer Reviewed
• [Journal Article] Rapid host defense against Aspergillus fumigatus involves alveolar macrophages with a predominance of alternatively activated phenotype. (2011)
  • Author(s): Bhatia S
  • Journal Title: PLoS One Volume: 6 Issue: 1 Pages: e15943-e15943
  • DOI: 10.1371/journal.pone.0015943
  • Peer Reviewed
• [Journal Article] The role of Syk/CARD9 coupled C-type lectins in antifungal immunity (2011)
  • Author(s): Drummond RA
  • Journal Title: Eur J Immunol Volume: 41 Issue: 2 Pages: 276-81
  • DOI: 10.1002/eji.201041252
  • Peer Reviewed
• [Journal Article] TNF-{alpha} from inflammatory dendritic cells (DCs) regulates lung IL-17A/IL-5 levels and neutrophilia versus eosinophilia during persistent fungal infection (2011)
  • Author(s): Fei, M.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 13 Issue: 13 Pages: 5360-5
  • DOI: 10.1073/pnas.1015476108
  • Peer Reviewed
• [Journal Article] Functional specialization of interleukin-17 family members (2011)
  • Author(s): Iwakura, Y.
  • Journal Title: Immunity Volume: 34 Issue: 2 Pages: 149-62
  • DOI: 10.1016/j.immuni.2011.02.012
  • Peer Reviewed
• [Journal Article] Differential pathways regulating innate and adaptive antitumor immune responses by particulate and soluble yeast-derived ss-glucans (2011)
  • Author(s): C.Qi
  • Journal Title: Blood Volume: 117 Issue: 25 Pages: 6825-6836
  • DOI: 10.1182/blood-2011-02-339812
  • Peer Reviewed
• [Journal Article] Dectin-1 diversifies Aspergillus fumigatus-specific T cell responses by inhibiting T helper type 1 CD4 T cell differentiation (2011)
  • Author(s): Rivera, A.
  • Journal Title: J Exp Med Volume: 208 Issue: 2 Pages: 369-81
  • DOI: 10.1084/jem.20100906
  • Peer Reviewed
• [Journal Article] Dectin-1 and Dectin-2 in innate immunity against fungi (2011)
  • Author(s): S.Saijo
  • Journal Title: Int Immunol Volume: 23 Issue: 8 Pages: 467-472
  • DOI: 10.1093/intimm/dxr046
  • Peer Reviewed
• [Presentation] 真菌感染防御機構におけるC型レクチンの役割 (2014)
  • Author(s): 西城忍
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都国際会館（京都府京都市左京区岩倉大鷺町422番地）
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] 真菌感染防御機構におけるC型レクチンの役割 (2014)
  • Author(s): 西城忍
  • Organizer: 第26回微生物シンポジウム
  • Place of Presentation: 都市センターホテル（東京千代田区平河町2-4-1）
  • Year and Date: 2014-09-19 – 2014-09-20
  • Invited
• [Presentation] Their roles in innate and acquired immunity. (2011)
  • Author(s): Saijo S
  • Organizer: JSICR-MMCB
  • Place of Presentation: Osaka
  • Invited
• [Presentation] C型レクチンによる真菌感染防御機構の解明 (2011)
  • Author(s): 西城忍
  • Organizer: 第22回日本生体防御学会学術総会
  • Place of Presentation: 沖縄
  • Invited
• [Presentation] C型レクチンによる真菌感染防御機構 (2011)
  • Author(s): 西城忍
  • Organizer: 第55回日本医真菌学会学術集会
  • Place of Presentation: 東京
  • Invited
• [Remarks] 千葉大学真菌医学研究センター
  • URL: http://www.pf.chiba-u.ac.jp
• [Remarks] 感染免疫分野
  • URL: http://www.pf.chiba-u.ac.jp/bunya_kansenmeneki/bunya_kansenmeneki/Mol._Immunol._jpn.html