抗念珠菌感染免疫现状及进展
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摘要
念珠菌为引起皮肤黏膜和系统性感染的常见机会性致病真菌,近年来宿主抗念珠菌感染免疫研究取得了长足进展。本文对念珠菌相关的固有免疫和适应性免疫反应研究进展进行介绍。前者包括主要模式识别受体Toll样受体(TLR2,4,9等)、C型凝集素受体(CLRs,包括Dectin-1,2,3,Mincle,DC-SIGN,DC-SIGN等)、核苷酸结合寡聚化结构域(NOD)蛋白样受体(NLRs,包括NLRP3和NLRC4等),与念珠菌胞壁相应的病原体相关分子模式及其相关信号通路,在诱导固有免疫效应中的作用及机制以及相关基因突变导致的易感性。适应性免疫方面,主要包括Th17,Th1和Treg免疫反应的作用机制,及Th17免疫相关分子的基因突变与慢性皮肤黏膜念珠菌病易感性,并初步提出本领域的研究展望。
Candida are the opportunistic fungal pathogen causing mucocutaneous and systemic infections. In this article,we reviewed the literatures in the field of immunity against the candida infection. Ininnate immune response,the roles,related mechanisms and genetic predisposition of major pattern recognitionreceptors( PRRs) including C-typelectin receptors,Toll-like receptors,NOD-like receptors,their pathogen-associated molecular patterns from candida cell wall components and downstream signal pathway molecules were discussed. The molecular andimmunologic mechanisms of adaptive immunty involved in anticandia l immunity were described. TH17 cells and their specific cytokines have been demonstrated to be the main players in conferring antifungalprotectionin systemic candidiasis and chronicmucocutaneous candidiasis.
Candida are the opportunistic fungal pathogen causing mucocutaneous and systemic infections. In this article,we reviewed the literatures in the field of immunity against the candida infection. Ininnate immune response,the roles,related mechanisms and genetic predisposition of major pattern recognitionreceptors( PRRs) including C-typelectin receptors,Toll-like receptors,NOD-like receptors,their pathogen-associated molecular patterns from candida cell wall components and downstream signal pathway molecules were discussed. The molecular andimmunologic mechanisms of adaptive immunty involved in anticandia l immunity were described. TH17 cells and their specific cytokines have been demonstrated to be the main players in conferring antifungalprotectionin systemic candidiasis and chronicmucocutaneous candidiasis.
引文
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[27]Gazi U,Rosas M,Singh S,et al.Fungal recognition enhances mannose receptor shedding through dectin-1 engagement[J].J Biol Chem,2011,286(10):7822-7829.
[28]Takahara K,Arita T,Tokieda S,et al.Difference in fine specificity to polysaccharides of Candida albicans mannoprotein between mouse SIGNR1 and human DC-SIGN[J].Infect Immun,2012,80(5):1699-1706.
[29]Nedovic B,Posteraro B,Leoncini E,et al.Mannose-Binding lectin codon 54 gene polymorphism and vulvovaginal candidiasis:A systematic review and Meta-Analysis[J].Bio Med Research International,2014,2014(6):1-7.
[30]Donders GG,Babula O,Bellen G,et al.Mannose-binding lectin gene polymorphism and resistance to therapy in women with recurrent vulvovaginal candidiasis[J].BJOG,2008,115(10):1225-1231.
[31]Joly S,Ma N,Sadler JJ,et al.Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome[J].J Immunol,2009,183(6):3578-3581.
[32]Tomalka J,Ganesan S,Azodi E,et al.A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans[J].PLo S Pathog,2011,7(12):e1002379.
[33]Gringhuis SI,den Dunnen J,Litjens M,et al.Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappa B activation through Raf-1 and Syk[J].Nat Immunol,2009,10(2):203-213.
[34]Johnson MD,Plantinga TS,van de Vosse E,et al.Cytokine gene polymorphisms and the outcome of invasive candidiasis:A prospective cohort study[J].Clinical Infectious Diseases,2012,54(4):502-510.
[35]Hanna S,Etzioni A.New host defense mechanisms against Candida species larify the basis of clinical phenotypes[J].J Allergy Clin Immunol,2011,127(6):1433-1437.
[36].Puel A,Cypowyj S,Bustamante J,et al.Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity[J].Science,2011,332(6025):65-68.
[37]Ling Y,Cypowyj S,Aytekin C,et al.Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis[J].J Exp Med,2015,212(5):619-631.
[38]van de Veerdonk FL,Plantinga TS,Hoischen A,et al.STAT1 mutations in autosomaldominant chronic mucocutaneous candidiasis[J].N Engl J Med,2011,365(1):54-61.
[39]Liu L,Okada S,Kong XF,et al.Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis[J].J Exp Med,2011,208(8):1635-1648.
[40]Boisson B,Wang C,Pedergnana V,et al.An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidi-asis[J].Immunity,2013,39(4):676-686.
[2]Netea MG,Brown GD,Kullberg BJ,et al.An integrated model of the recognition of Candida albicans by the innate immune system[J].Nat Rev Microbiol,2008,6(1):67-78.
[3]Netea MG,Van Der Graaf CA,Vonk AG,et al.The role of toll-like receptor(TLR)2 and TLR4 in the host defense against disseminated candidiasis[J].J Infect Dis,2002,185(10):1483-1489.
[4]Murciano C,Villamon E,Gozalbo D,et al.Toll-like receptor4 defective mice carrying point or null mutations do not show increased susceptibility to Candida albicans in a model of hematogenously disseminated infection[J].Med Mycol,2006,44(2):149-157.
[5]Weindl G,Naglik JR,Kaesler S,et al.Human epithelial cells establish direct antifungal defense through TLR4-mediated signaling[J].J Clin Invest,2007,117(12):3664-3672.
[6]Van der Graaf CA,Netea MG,MorréSA,et al.Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection[J].Eur Cytokine Netw,2006,17(1):29-34.
[7]Jouault T,Ibata-Ombetta S,Takeuchi O,et al.Candida albicans phospholipomannan is sensed through Toll-like receptors[J].J Infect Dis,2003,188(2):165-172.
[8]Li M,Chen Q,Shen YN,et al.Candida albicans phospholipomannan triggers inflammatory responses of human keratinocytes through Toll-like receptor 2[J].Exp Dermatol,2009,18(6):603-610.
[9]Li M,Chen Q,Tang R,et al.The expression ofβ-defensin-2,3 and LL-37 induced by Candida albicans phospholipomannan in human keratinocytes[J].J Dermatol Sci,2011,61(1):72-75.
[10]Netea MG,Sutmuller R,Hermann C,et al.Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells[J].J Immunol,2004,172(6):3712-3718.
[11]Rosentul DC,Delsing CE,Jaeger M,et al.Gene polymorphisms in pattern recognition receptors and susceptibility to idiopathic recurrent vulvovaginal candidiasis[J].Frontiers in Microbiology,2014,16(5):483.
[12]Miyazato A,Nakamura K,Yamamoto N,et al.Toll-like receptor 9-dependent activation of myeloid dendritic cells by Deoxynucleic acids from Candida albicans[J].Infect Immun,2009,77(7):3056-3064.
[13]Plantinga TS,Johnson MD,Scott WK,et al.Human genetic susceptibility to Candida infections[J].Med Mycol,2012,50(8):785-794.
[14]Nahum A,Dadi H,Bates A,et al.The biological significance of TLR3 variant,L412F,in conferring susceptibility to cutaneous candidiasis,CMV and autoimmunity[J].Autoimmunity Reviews,2012,11(5):341-347.
[15]Brown GD,Herre J,Williams DL,et al.Dectin-1 mediates the biological effects of beta-glucans[J].J Exp Med,2003,197(9):1119-1124.
[16]Taylor PR,Tsoni SV,Willment JA,et al.Dectin-1 is required for beta-glucan recognition and control of fungal infection[J].Nat Immunol,2007,8(1):31-38.
[17]Taylor PR,Brown GD,Reid DM,et al.The beta-glucan receptor,dectin-1,is predominantly expressed on the surface of cells of the monocyte/macrophage and neutrophil lineages[J].J Immunol,2002,169(7):3876-3882.
[18]Gantner BN,Simmones RM,Underhill DM.Dectin-1 mediates macrophage recognition of Candida albicans yeast but not filaments[J].EMBO J,2005,24(6):1277-12786.
[19]Gross O,Gewies A,Finger K,et al.Card 9 controls a nonTLR signalling pathway for innate anti-fungal immunity[J].Nature,2006,442(7103):651-656.
[20]Leibund Gut-Landmann S,Gross O,Robinson MJ,et al.Syk-and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin17[J].Nat Immunol,2007,8(6):630-638.
[21]Glocker E,Hennigs A,Nabavi M,et al.A homozygousCARD9 mutation in a family with susceptibility to fungal infections[J].New Eng J Med,2009,361(18):1727-1730.
[22]Ferwerda G,Ferwerda B,Huysamen C,et al.Human Dectin-1 deficiency and mucocutaneous fungal infections[J].New Eng J Med,2009,361(18):1760-1767.
[23]Robinson MJ,Osorio F,Rosas M,et al.Dectin-2 is a Sykcoupled pattern recognition receptor crucial for Th17 responses to fungal infection[J].J Exp Med,2009,206(9):2037-2051.
[24]Saijo S,Ikeda S,Yamabe K,et al.Dectin-2 recognition of alpha-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans[J].Immunity,2010,32(5):681-691.
[25]Zhu LL,Zhao XQ,Jiang C,et al.C-type lectin receptors Dectin-3 and Dectin-2 form a heterodimeric pattern-recognition receptor for host defense against fungal infection[J].Immunity,2013,39(2):324-334.
[26]Wells CA,Salvage-Jones JA,Li X,et al.The macrophageinducible C-type lectin,mincle,is an essential component of the innate immune response to Candida albicans[J].J Immunol,2008,180(11):7404-7413.
[27]Gazi U,Rosas M,Singh S,et al.Fungal recognition enhances mannose receptor shedding through dectin-1 engagement[J].J Biol Chem,2011,286(10):7822-7829.
[28]Takahara K,Arita T,Tokieda S,et al.Difference in fine specificity to polysaccharides of Candida albicans mannoprotein between mouse SIGNR1 and human DC-SIGN[J].Infect Immun,2012,80(5):1699-1706.
[29]Nedovic B,Posteraro B,Leoncini E,et al.Mannose-Binding lectin codon 54 gene polymorphism and vulvovaginal candidiasis:A systematic review and Meta-Analysis[J].Bio Med Research International,2014,2014(6):1-7.
[30]Donders GG,Babula O,Bellen G,et al.Mannose-binding lectin gene polymorphism and resistance to therapy in women with recurrent vulvovaginal candidiasis[J].BJOG,2008,115(10):1225-1231.
[31]Joly S,Ma N,Sadler JJ,et al.Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome[J].J Immunol,2009,183(6):3578-3581.
[32]Tomalka J,Ganesan S,Azodi E,et al.A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans[J].PLo S Pathog,2011,7(12):e1002379.
[33]Gringhuis SI,den Dunnen J,Litjens M,et al.Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappa B activation through Raf-1 and Syk[J].Nat Immunol,2009,10(2):203-213.
[34]Johnson MD,Plantinga TS,van de Vosse E,et al.Cytokine gene polymorphisms and the outcome of invasive candidiasis:A prospective cohort study[J].Clinical Infectious Diseases,2012,54(4):502-510.
[35]Hanna S,Etzioni A.New host defense mechanisms against Candida species larify the basis of clinical phenotypes[J].J Allergy Clin Immunol,2011,127(6):1433-1437.
[36].Puel A,Cypowyj S,Bustamante J,et al.Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity[J].Science,2011,332(6025):65-68.
[37]Ling Y,Cypowyj S,Aytekin C,et al.Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis[J].J Exp Med,2015,212(5):619-631.
[38]van de Veerdonk FL,Plantinga TS,Hoischen A,et al.STAT1 mutations in autosomaldominant chronic mucocutaneous candidiasis[J].N Engl J Med,2011,365(1):54-61.
[39]Liu L,Okada S,Kong XF,et al.Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis[J].J Exp Med,2011,208(8):1635-1648.
[40]Boisson B,Wang C,Pedergnana V,et al.An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidi-asis[J].Immunity,2013,39(4):676-686.