真菌感染防御におけるC型レクチンの役割

• Project Area: Matrix of Infection Phenomena
• Project/Area Number: 21022016
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Chiba University (2010); The University of Tokyo (2009)
• Principal Investigator: 西城 忍 千葉大学, 真菌医学研究センター, 特任准教授 (60396877)
• Co-Investigator(Kenkyū-buntansha): 岩倉 洋一郎 東京大学, 医科学研究所, 教授 (10089120) ; 角田 茂 信州大学, ヒト環境科学研究支援センター, 助教 (80345032)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥7,600,000 (Direct Cost: ¥7,600,000); Fiscal Year 2010: ¥3,800,000 (Direct Cost: ¥3,800,000); Fiscal Year 2009: ¥3,800,000 (Direct Cost: ¥3,800,000)
• Keywords: C型レクチン / 真菌感染 / 感染免疫 / ノックアウトマウス / 自然免疫 / サイトカイン / Th17 / 疾患モデルマウス

Research Abstract

C型レクチンは膜タンパク質で、細胞外のCDRと呼ばれる領域で糖鎖を認識する。C型レクチンファミリーに分類される分子は非常に多数あるが、そのうち樹状細胞(DC)やマクロファージに発現する遺伝子は、マウスでは6番染色体のテロメア側にクラスター状に存在し、相同性も高い。これらの分子は自然免疫に関わる分子であることが予想されるが、ほとんどの分子の機能は不明である。そこで我々は、このクラスター上に存在するDectin-1(Clec7a)およびDectin-2(Clec4n)の欠損マウスを作製し、生体防御機構における役割を解析した。その結果、1)Dectin-1、Dectin-2は、それぞれ真菌細胞壁のβグルカン、αマンナンのレセプターであり、活性酸素種(ROS)やサイトカイン産生を担っていること、2)Clec7a^<-/->マウスはPneumocystis carinii感染に対し易感染性になり、野生型マウスと比較し感染後の肺でのシストの数が増加していること、3)Clec4n^<-/->マウスはCandida albicans感染に対し易感染性になり、野生型マウスと比較し感染後の生存率が低下すること、4)Dectin-2によるC.albicans感染防御には、IL-17が重要な役割を果たしており、Th17細胞の分化を優先的に促進すること、の3点を明らかにした。これらの結果は、以上の結果から、C型レクチンはサイトカイン産生やROS産生を介し生体防御に重要な役割を担っていることが示された。

Research Products

• [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
  • Peer Reviewed
• [Journal Article] The role of Syk/CARD9 coupled C-type lectins in antifungal immunity (2011)
  • Author(s): Drummond, R.A.
  • Journal Title: European journal of immunology Volume: 41 Pages: 276-81
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• [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, Mingjian
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 108 Pages: 5360-5
  • Peer Reviewed
• [Journal Article] Functional specialization of interleukin-17 family members (2011)
  • Author(s): Iwakura, Yoichiro
  • Journal Title: Immunity Volume: 34 Pages: 149-62
  • 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, Amariliz
  • Journal Title: The Journal of experimental medicine Volume: 208 Pages: 369-81
  • Peer Reviewed
• [Journal Article] Dectin-2 Recognition of α-Mannans and Induction of Th17 Cell Differentiation Is Essential for Host Defense against Candida albicans (2010)
  • Author(s): Saijo, Shinobu
  • Journal Title: Immunity Volume: 32 Pages: 681-691
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• [Journal Article] Activation of myeloid dendritic cells by deoxynucleic acids from Cordyceps sinensis via a Toll-like receptor 9-dependent pathway (2010)
  • Author(s): Xiao, Gang
  • Journal Title: Cellular Immunology Volume: 269 Pages: 241-250
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• [Journal Article] Schistosoma mansoni triggers Dectin-2, which activates the Nlrp3 inflammasome and alters adaptive immune responses (2010)
  • Author(s): Ritter, M.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 107 Pages: 20459-20464
  • Peer Reviewed
• [Journal Article] TNF, but Not IL-6 and IL-17, Is Crucial for the Development of T Cell-Independent Psoriasis-Like Dermatitis in Il1rn-/- Mice (2010)
  • Author(s): Nakajima, A.
  • Journal Title: The Journal of Immunology Volume: 185 Pages: 1887-1893
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• [Journal Article] Yersinia enterocolitica Promotes Robust Mucosal Inflammatory T-Cell Immunity in Murine Neonates (2010)
  • Author(s): Echeverry, A.
  • Journal Title: Infection and Immunity Volume: 78 Pages: 3595-3608
  • Peer Reviewed
• [Journal Article] CXC chemokine receptor 4 expressed in T cells plays an important role in the development of collagen-induced arthritis (2010)
  • Author(s): Chung, Soo-Hyun
  • Journal Title: Arthritis Research & Therapy Volume: 12
  • Peer Reviewed
• [Journal Article] Muramyldipeptide augments the actions of lipopolysacchairde in mice by stimulating macrophages to produe pro-IL-1β and by down-regulation of suppressor of cytokine signaling 1(SOCS1) (2010)
  • Author(s): Shikama, Y.
  • Journal Title: Innate Immun. (in press)
  • Peer Reviewed
• [Journal Article] Th 17 nephritogenic immunity induces autoimmune anti-MPO glomerulonephritis (2010)
  • Author(s): Gan, P.-Y.
  • Journal Title: J.Am.Soc.Nephrol. (in press)
  • Peer Reviewed
• [Journal Article] Nucleoprotein diet ameliorates arthritis symptoms in mice transgenic for human T-cell leukemia virus type I(HTLV-I) (2010)
  • Author(s): Ohtaki, H.
  • Journal Title: J.Clin.Biochem.Nutr. (in press)
  • Peer Reviewed
• [Journal Article] IFN-γ is a master regulator of endotoxin shock syndrome in mice primed with heat-killed Propionibacterium acnes (2010)
  • Author(s): Kawa, K.
  • Journal Title: Int.Immunol. (in press)
  • Peer Reviewed
• [Journal Article] Type I interferon signaling constrains IL-17A/F secretion by γδ T cells during bacterial infection (2010)
  • Author(s): Henry, T.
  • Journal Title: J.Immunol. (in press)
  • Peer Reviewed
• [Journal Article] Identification of the cellular sensor that stimulates the inflammatory response to sterile cell death (2010)
  • Author(s): Kono, H.
  • Journal Title: J.Immunol. (in press)
  • Peer Reviewed
• [Journal Article] The mechanism of lipopolysaccharide- induced human immunodeficiency virus type I activation in transgenic mouse macrophages (2010)
  • Author(s): Kadoki, M.
  • Journal Title: Int.Immunol. (in press)
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• [Journal Article] MHC-matched corneal allograft rejection in an IFN-γ/IL-17-independent manner in C57BL/6 mice (2009)
  • Author(s): Yamada, J.
  • Journal Title: Invest.Ophthalmol.Vis.Sci. 50 Pages: 2139-2146
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• [Journal Article] Biotin status affects nickel allergy via regulation of IL-1β production in mice (2009)
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  • Journal Title: J.Nutrition 139 Pages: 1031-1036
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• [Journal Article] Host-derived Interleukin-1α is important in determining the immunogenicity of 3-Methylcholantrene-tumor cells (2009)
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  • Journal Title: J.Immunol. 182 Pages: 4874-4881
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• [Journal Article] Virus sensing at the plasma membrane triggers interleukin-1α-mediated pro-inflammatory macrophage response (2009)
  • Author(s): Di Paolo, N.C.
  • Journal Title: Immunity 31 Pages: 110-121
  • Peer Reviewed
• [Journal Article] Toll-like receptor 9-dependent activation of myeloid dendritic cells by deoxynucleic acids from Candida albicans (2009)
  • Author(s): Miyazato A
  • Journal Title: Infect.Immun. 77 Pages: 3056-3064
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• [Journal Article] A protective function for interleukin 17A in T cell-mediated intestinal inflammation (2009)
  • Author(s): O'Connor, W.Jr.
  • Journal Title: Nat.Immunol. 10 Pages: 603-609
  • Peer Reviewed
• [Journal Article] IL-17 is involved in bone resorption in mouse periapical lesions (2009)
  • Author(s): Oseko, F.
  • Journal Title: Microbiol Immunol. 53 Pages: 287-294
  • Peer Reviewed
• [Journal Article] Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft versus host disease (2009)
  • Author(s): Yi, T., Chen
  • Journal Title: Blood 114 Pages: 3101-3112
  • Peer Reviewed
• [Journal Article] Interleukin-1 deficiency in combination with macrophage depletion increases susceptibility to Pseudomonas aeruginosa bacteremia (2009)
  • Author(s): Horino, T.
  • Journal Title: Microbiol.Immunol. 53 Pages: 502-511
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• [Journal Article] Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Fracisella tularensis (2009)
  • Author(s): Lin, Y.
  • Journal Title: Immunity 31 Pages: 799-810
  • Peer Reviewed
• [Journal Article] Natural occurring IL-17 producing T cells regulagte the initial phase of neutrophil mediated airway responses (2009)
  • Author(s): Tanaka, S.
  • Journal Title: J.Immunol. 183 Pages: 7523-7530
  • Peer Reviewed
• [Journal Article] Role of T cell TGFβ signaling and IL-17 in allograft acceptance and fibrosis associated with chronic rejection (2009)
  • Author(s): Faust, S.M., Lu, G., Marini, B.L., Zou, W., Gordon, D., Iwakura, Y., Laouar, Y., Bishop, D.K.
  • Journal Title: J.Immunol. 183 Pages: 7297-7306
  • Peer Reviewed
• [Journal Article] Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis (2009)
  • Author(s): Oyamada, A.
  • Journal Title: J.Immunol. 183 Pages: 7539-7546
  • Peer Reviewed
• [Journal Article] Interleukin(IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17 (2009)
  • Author(s): Munoz, M.
  • Journal Title: J.Exp.Med. 206 Pages: 3047-3059
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• [Journal Article] IFN-g regulates the requirement for IL-17 in proteoglycan-induced arthritis (2009)
  • Author(s): Doodes, P.D.
  • Journal Title: J.Immunol. 184 Pages: 1552-1559
  • Peer Reviewed
• [Presentation] C型レクチンによる真菌感染防御機構の解明 (2010)
  • Author(s): 西城忍
  • Organizer: 第31回関東医真菌懇話会
  • Place of Presentation: 東京
  • Year and Date: 2010-07-03
• [Presentation] The roles of C-type lectins in the host defense against fungal infection. (2010)
  • Author(s): Saijo, Sshinobu
  • Organizer: 14^<th> international congress of immunology
  • Place of Presentation: Kobe Japan
• [Presentation] CXCR4 expressed in T cells plays an important role in the development of autoimmune arthritis. (2010)
  • Author(s): Chung, Soo-Hyon
  • Organizer: 14^<th> international congress of immunology
  • Place of Presentation: Kobe Japan
• [Presentation] IL-17-producing gamma-delta T cells is important for the development of arthritis in a rheumatoid arthritis model. (2010)
  • Author(s): Akitsu, Aoi
  • Organizer: 14^<th> international congress of immunology
  • Place of Presentation: Kobe Japan
• [Presentation] Development of Th17-dependent arthritis in IL-6-deficient IL-1 receptor antagonist-deficient mice. (2010)
  • Author(s): Ikeda, Satoshi
  • Organizer: 14^<th> international congress of immunology
  • Place of Presentation: Kobe Japan
• [Presentation] IL-17産生性γδT細胞は自己免疫性関節炎モデルにおける関節炎発症に重要である (2010)
  • Author(s): 秋津葵
  • Organizer: 第75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: 小倉
• [Presentation] C型レクチンによるサイトカイン産生と生体防御機構 (2010)
  • Author(s): 西城忍
  • Organizer: 第75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: 小倉
• [Presentation] C型レクチン遺伝子ノックアウトライブラーの作製 (2010)
  • Author(s): 西城忍
  • Organizer: 第57回日本実験動物学会総会
  • Place of Presentation: 京都
• [Presentation] IL-17産生性γδT細胞は自己免疫性関節炎モデルにおける関節炎発症に重要である (2010)
  • Author(s): 秋津葵
  • Organizer: 第57回日本実験動物学会総会
  • Place of Presentation: 京都
• [Presentation] A C-type lectin that involved in the host defense against fungi plays an important role in the development of autoimmune arthritis. (2010)
  • Author(s): Shinobu Saijo
  • Organizer: 7^<th> International Congress on Autoimmunity
  • Place of Presentation: Ljubliana, Slovenia
• [Presentation] The roles of C-type lectins in the host defense against fungal infection. (2010)
  • Author(s): Shinobu Saijo
  • Organizer: 8^<th> Joint Meeting of the International Cytokine Society (ICS) and the International Society for Interferon and Cytokine Research (ISICR)
  • Place of Presentation: Chicago, Illinois, USA
• [Presentation] Devepoment of TH17-dependent arthritis in IL-6-deficient IL-1 receptor antagonist-deficient mice. (2010)
  • Author(s): Satoshi Ikeda
  • Organizer: 8^<th> Joint Meeting of the International Cytokine Society (ICS) and the International Society for Interferon and Cytokine Research (ISICR)
  • Place of Presentation: Chicago, Illinois, USA
• [Presentation] CXCR4 expressed in T cells plays an important role in the development of autoimmune arthritis. (2010)
  • Author(s): Soo-hyon Chung
  • Organizer: 8^<th> Joint Meeting of the International Cytokine Society (ICS) and the International Society for Interferon and Cytokine Research (ISICR)
  • Place of Presentation: Chicago, Illinois, USA
• [Presentation] IL-17-producing γδ cells are important for the development of arthritis in a rheumatoid arthritis model. (2010)
  • Author(s): Aoi Akitsu
  • Organizer: 8^<th> Joint Meeting of the International Cytokine Society (ICS) and the International Society for Interferon and Cytokine Research (ISICR)
  • Place of Presentation: Chicago, Illinois, USA
• [Presentation] The roles of C-type lectins in the host defense against fungal infection (2009)
  • Author(s): Shinobu Saijo
  • Organizer: International Society for Interferon and Cytokine Research
  • Place of Presentation: Lisbon, Portugal
• [Presentation] The roles of C-type lectins in the host defense against fungal infection (2009)
  • Author(s): Yoichiro Iwakura
  • Organizer: ISHAM 2009
  • Place of Presentation: Tokyo
• [Presentation] The Roles of IL-17A and IL-17F in Inflammation and Host Defense against Bacteria (2009)
  • Author(s): Yoichiro Iwakura
  • Organizer: The 9^<th> World Congress on Inflammation
  • Place of Presentation: Tokyo