真菌感染防御におけるC型レクチンの役割

2009 Fiscal Year Annual Research Report

• Project Area: Matrix of Infection Phenomena
• Project/Area Number: 21022016
• Research Institution: The University of Tokyo
• Principal Investigator: 西城 忍 The University of Tokyo, 医科学研究所, 助教 (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 東京大学, 医科学研究所, 助教 (80345032)
• 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

Candida albicans (C. albicans)は、健常人には病原性を持たず共生菌として皮膚や粘膜、あるいは環境中に常在するが、免疫不全患者にとっては生命を脅かす存在となる真菌である。C. albicansに対する感染防御機構としては主に自然免疫が関与していると考えられており、この真菌を認識する宿主因子も多数報告されている。他方、IL-17が真菌感染防御に重要であるという報告もあり、自然免疫、獲得免疫の両方が関与していると考えられている。C. albicansを認識する宿主因子の一つとして、C型レクチンが知られている。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。申請者らは、先にこの遺伝子クラスター上に存在するDectin-1ノックアウト(KO)マウスを作製し、Dectin-1が真菌の細胞壁構成成分であるβ-グルカンを認識し、サイトカインや活性酸素種(ROS)の産生に関与していることを見出した。本研究では、このDeetin-1KOマウスを用いて真菌感染防御における役割を明らかにすると共に、新規KOマウスを作製し、C型レクチンによる真菌感染防御機構を解明することを目的とした。その結果、新規KOマウスはC. albicans感染に対し、易感受性になっていること、この時、C. albicansの細胞壁構成成分を認識し、T細胞を優先的にTh17に分化させる機能があることが明らかとなった。

Research Products

• [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)
  • Peer Reviewed
• [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
  • Peer Reviewed
• [Journal Article] Biotin status affects nickel allergy via regulation of IL-1β production in mice (2009)
  • Author(s): Kuroishi, T.
  • Journal Title: J.Nutrition 139 Pages: 1031-1036
  • Peer Reviewed
• [Journal Article] Host-derived Interleukin-1α is important in determining the immunogenicity of 3-Methylcholantrene-tumor cells (2009)
  • Author(s): Elkabets, M.
  • Journal Title: J.Immunol. 182 Pages: 4874-4881
  • Peer Reviewed
• [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
  • Peer Reviewed
• [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
  • Peer Reviewed
• [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
  • Peer Reviewed
• [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] 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
  • Year and Date: 20091017-20091021
• [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
  • Year and Date: 20090706-20090709
• [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
  • Year and Date: 20090525-20090529