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Toll样受体在抗白假丝酵母菌感染中的作用研究进展
周云1,2, 潘建平1     
1. 浙江大学城市学院医学院, 浙江 杭州 310015 ;
2. 浙江大学医学院病原生物学系, 浙江 杭州 310058
摘要: Toll样受体(TLR)是一类主要表达于树突状细胞和巨噬细胞等固有免疫细胞上的模式识别受体,能识别和结合白假丝酵母菌上的病原相关分子模式,并引起特定下游信号转导。TLR多态性与宿主对白假丝酵母菌的易感性有关,TLR激活后可诱导促炎性细胞因子的表达,发挥抗白假丝酵母菌感染作用;而白假丝酵母菌也可发生菌相改变以利于逃逸机体免疫反应。了解TLR和白假丝酵母菌之间的相互作用,可为阐明抗真菌感染免疫的机制提供新的实验依据。
关键词: Toll样受体     念珠菌, 白色/药物作用     细胞因子类     感染/药物疗法     综述    
Progress on the role of Toll-like receptors in Candida albicans infections
ZHOU Yun1,2, PAN Jianping1     
1. Zhejiang University City College School of Medicine, Hangzhou 310015, China ;
2. Department of Pathogen Biology, Zhejiang University School of Medicine, Hangzhou 310058, China
Corresponding author: PAN Jianping, E-mail:jppan@zucc.edu.cn; http://orchid.org/0000-0001-9636-1561
Abstract: Toll like receptors (TLRs) are expressed mainly on innate immunocytes such as dendritic cells and macrophages, and may have the potential to recognize and bind to pathogen-associated molecular patterns (PAMPs) from Candida albicans, thereby triggering the downstream signals. The genetic polymorphism of TLRs is associated with susceptibility to Candida albicans. The activation of TLRs by PAMPs from Candida albicans can induce the production of proinflammatory cytokines that play key roles in the anti-infection of Candida albicans. However, in order to evade the immune response of host, Candida albicans can also change its bacterial phase. Understanding of the interaction between TLRs and Candida albicans will provide novel evidence to further clarify the mechanisms of anti-fungal immune response.
Key words: Toll-like receptors     Candida albicans/drug effects     Cytokines     Infection/drug therapy     Review    

白假丝酵母菌(Candida albicans,C.albicans),又称白念珠菌,是人体的常居真菌之一,广泛存在于正常人体的皮肤、口腔、上呼吸道、肠道和阴道黏膜表面,同时也可在大多数哺乳动物的胃肠道中检测到[1]。白假丝酵母菌是目前所知最主要的机会致病菌之一[2-3]。在体外,不同的培养条件如酸碱度、培养基等的差异均可导致其发生菌相(即酵母相和菌丝相)转换[4]。在体内,白假丝酵母菌一般以酵母相形式存在,一旦机体免疫功能受到抑制或微生态环境失衡,它可转变为毒力更强的菌丝相黏附于宿主细胞,定植,形成生物膜,从而有效逃避机体的防御机制,引发白假丝酵母菌病(如口腔白斑口咽念珠菌病、白假丝酵母菌菌血症、复发性阴道炎[5-6])。近年来艾滋病、恶性肿瘤长期放化疗以及器官移植后长期使用免疫抑制剂患者免疫功能低下,加之广谱抗生素使用不当所致的人体正常菌群失调,导致白假丝酵母菌感染发病率逐年增高,引起学界的高度关注[7]。抗真菌,尤其是抗白假丝酵母菌感染免疫的细胞和分子生物学机制研究已成为感染免疫学研究的热点之一。表达于树突状细胞、巨噬细胞等抗原提呈细胞上的Toll样受体(Toll-like receptor,TLR)可识别和结合相应的病原体相关分子模式(pathogen-associated molecular pattern,PAMP),激活胞内信号转导途径,诱发免疫应答,不仅在树突状细胞、巨噬细胞介导的固有免疫中发挥重要作用,而且对特异性免疫应答的发生、发展、类型和强度均具有重要的调节作用[8]

TLR是一种表达于树突状细胞、巨噬细胞和中性粒细胞等固有免疫细胞的模式识别受体(pattern recognition receptor,PRR),通过识别入侵病原体上的PAMP,激活固有免疫细胞,在感染的早期发挥作用,并调节特异性免疫的发生和发展。迄今,已发现二十多种TLR,其中在鼠类有13种(TLR1~TLR13),人类有10种(TLR1~TLR10),鱼类中则有TLR18、TLR19、TLR20、TLR25、TLR27等[9-10]。TLR根据其亚细胞定位可分为膜表面TLR和内体TLR。位于膜表面的TLR1[11]、TLR2[12-13]、TLR4[13]、TLR5[14]、TLR6[11]主要识别与结合细菌细胞壁成分,而TLR3[15]、TLR7[16-17]、TLR8[16]、TLR9[17-19]、TLR10[20-21]、TLR11[22-23]、TLR12[22, 24]和TLR13[15]则存在于内体。

TLR在抗真菌感染免疫的发生和发展中占有十分重要的地位,是决定真菌感染发生、发展和转归的重要因素之一[25]。本文综述近年TLR在抗白假丝酵母菌感染中的作用研究进展。

1 Toll样受体多态性及其在抗白假丝酵母菌感染中的作用

单核苷酸多态性(single nucleotide polymorphism,SNP)是基因组变异中最常见的一种形式,可影响免疫应答,与疾病的发生发展密切相关,是导致不同个体对同一种病原体入侵产生不同反应(被感染或形成防御)的重要原因[26]。在免疫力低下患者中,TLR2多态性与真菌易感性有关。Rosentul等[27]发现虽然感染患者中C型凝集素结构域家族7中的成员A(C-type lectin domain family 7,member A,CLEC7A)、胱天蛋白酶募集区域9(caspase-associated recruitment domain-9,CARD9)、TLR1与TLR4等的SNP对复发性外阴阴道白假丝酵母菌易感性无显著影响,但是TLR2中的非同义多态性(rs5743704和Pro631His)却增加了对其的易感性。体外实验证实,rs5743704可抑制经白假丝酵母菌刺激的外周血单核细胞分泌IL-17和TNF-α,表明TLR2多态性与白假丝酵母菌的易感性有关。

吞噬作用作为固有免疫应答中清除病原体的基本属性,主要包括以下四个步骤:①吞噬细胞表面的PRR识别结合颗粒病原体上的相应配体;②在摄取部位,肌动蛋白与其相关蛋白组装,形成吞噬杯;③肌动蛋白在吞噬体中解离;④吞噬体成熟。Tafesse等[28]利用CRISPR/Cas9技术对参与鞘脂类生物合成途径的丝氨酸棕榈酰转移酶基因进行编辑,得到Sptlc2-/-(丝氨酸棕榈酰转移酶抗体2-/-)的树突状细胞系(Sptlc2-/- DC2.4),结果发现,Sptlc2-/-DC2.4表面的Dectin-1(Ⅱ型跨膜蛋白,属C型凝集素受体家族)和TLR2受体表达下降,TLR4表达无显著变化,其吞噬白假丝酵母菌功能显著降低,促炎性细胞因子IL-6、TNF-α的表达下调。这说明鞘脂类合成途径受损可导致Dectin-1和TLR2表达下调,从而阻断其与配体识别结合,最终干扰树突状细胞对白假丝酵母菌的吞噬作用及促炎性细胞因子的产生。从TLR2-/-小鼠中分离骨髓来源的肥大细胞,并在体外抑制Dectin-1表达,结果发现,与野生型小鼠来源的肥大细胞相比,TLR2-/-小鼠来源的肥大细胞吞噬功能和产生一氧化氮的能力显著减弱[29]。角质细胞分泌的IL-34可通过下调M1型巨噬细胞上的TLR2和Dectin-1的表达从而抑制其分泌TNF-α致巨噬细胞抗白假丝酵母菌感染能力减弱[30]。但是也有研究发现以脂阿拉伯甘露糖和卵泡抑素样1(follistatin-like 1,FSL-1)分别同时刺激小鼠树突状细胞系XS106上的C样凝集素树突状细胞特异性细胞间黏附分子3抗体非整合素(DC-specific ICAM3 grabbing non-integrin,DC-SIGN)同源物SIGNR1(SIGN-related 1)和TLR2,SIGNR1通路激活后,通过细胞因子信号1抑制物(suppressor of cytokine signalling-1,SOCS1)降解髓样分化因子(myeloid differentiation factor 88,MyD88)衔接蛋白,从而负调控FSL-1诱导的NF-κB通路以及以剂量依赖方式抑制TNF-α、IL-6和IL-12p40的表达[31]。此外,白假丝酵母菌激活Dectin-1后可增加分枝杆菌等细菌的感染载量,抑制TLR诱导的促炎性细胞因子的分泌[32]

上述结果表明,一方面TLR2可与其他受体协同作用,诱导促炎性细胞因子的表达,介导抗白假丝酵母菌感染;另一方面,TLR2参与识别白假丝酵母菌受体的不同和与其相互作用的受体的差异,导致不同的免疫反应。

2 Toll样受体与白假丝酵母菌感染

TLR4在抗真菌感染中发挥着重要作用。当TLR4识别白假丝酵母菌后主要通过衔接蛋白MyD88,MyD88样蛋白(MyD88 adapter-like,MaL)激活NF-κB,促进TNF-α表达;或者激活丝裂原激活蛋白激酶(mitogen-activated protein kinase,MAPK)中的p38蛋白、c-Jun氨基端激酶(c-Jun N-terminal kinase,JNK)上调IL-12以及IFN-γ表达;或者通过TIR结构域接头分子诱导的干扰素β(TIR-domain-containing adapter-inducing interferon-β,TRIF)以及与其相关的衔接分子(TRIF-related adapter molecule,TRAM)等衔接蛋白激活干扰素调节因子3(interferon regulatory factor 3,IRF3),诱导Ⅰ型干扰素分泌[25]。此外,位于皮肤和黏膜表面的黑色素细胞在受到白假丝酵母菌粗提取物刺激后,细胞表面TLR2、TLR4在72 h后达到峰值。虽然白假丝酵母菌的芽生分生孢子可以诱导TLR2、TLR4表达,但其菌丝相仅刺激TLR4表达,也就是说黑色素细胞在对抗菌丝相白假丝酵母菌感染时主要通过TLR4参与固有免疫反应,导致黑色素分泌增加,从而有利于控制感染[33]。对于不同的宿主细胞而言,白假丝酵母菌菌相转换(即从酵母相转变为菌丝相)可能更有利于其逃逸宿主防御功能,增强其在宿主中的适应性和毒力。有研究发现芽生分生孢子感染外周血单个核细胞以及脾脏淋巴细胞后,通过激活TLR4信号通路,诱导产生IFN-γ;当白假丝酵母菌由酵母相转变为菌丝相后,可干扰TLR4活化,而无法诱导产生IFN-γ,从而达到免疫逃逸的目的[34]。目前关于两菌相不同识别的报道较少,但肯定的是,TLR4可以通过诱导细胞因子产生参与抗菌丝相白假丝酵母菌感染。

此外,关于TLR2、TLR4基因敲除小鼠对真菌应答作用的研究结果,存在较多不一致性。Gasparoto等[35]研究发现,TLR4缺陷小鼠感染白假丝酵母菌ATCC 10231后感染部位中性粒细胞趋化性减弱,产生TNF-α、趋化因子1以及一氧化氮能力降低,并且该菌在淋巴结和脾脏等处散播、持续定植。TLR4基因缺陷小鼠来源的巨噬细胞,体外产生上述因子的能力以及吞噬功能均下降。而Nakamura等[36]认为,TLR2-/-以及TLR4-/-小鼠在感染新生隐球菌YC-13后其血清中IL-12p40、IL-1β、IL-6以及TNF-α增多,并可以清除肺中真菌。Netea等[37]发现,与野生型小鼠相比,TLR2-/-小鼠抵御白假丝酵母菌UC 820感染能力更强,这可能与TLR2-/-小鼠巨噬细胞趋化性和杀菌能力提高有关。虽然TLR2-/-小鼠血清中细胞因子TNF-α、IL-1α、IL-1β水平无显著变化,但是IL-10表达却显著下降,调节性T细胞数量减少。同时体外实验也证实,激动剂激活TLR2后,调节性T细胞存活率上升。这提示白假丝酵母菌另一种致病机制,即白假丝酵母菌可通过TLR2衍生的信号调控IL-10表达和调节性T细胞存活以诱导免疫耐受。2014年Zhang等[38]报道,小鼠巨噬细胞在识别三种不同的白假丝酵母菌菌株过程中,MyD88、CARD9、活性氧、IL-10以及TNF-α表达存在差异,巨噬细胞经白假丝酵母菌菌株3683刺激后表达上述分子的能力高于白假丝酵母菌菌株3630与SC5314。由此可见,这些结果的不一致性可能是因为不同研究者所研究的白假丝酵母菌菌株不同或者是菌相不同,从而激活的信号通路不同,或者由小鼠品系的差异所造成。

3 其他Toll样受体与白假丝酵母菌感染

TLR2和TLR4是目前研究发现的参与机体抗白假丝酵母菌感染的主要受体,其他TLR也发挥着一定作用。TLR1和TLR6主要与TLR2形成异源二聚体,参与对白假丝酵母菌的识别过程[39]。携带TLR3变体L412F则更易感染白假丝酵母菌[40]。而骨髓来源树突状细胞(BM-DC)中的TLR7在识别白假丝酵母菌RNA后,可激活MyD88和IRF1,产生IL-12[41]。此外,小鼠BM-DC依赖非甲基化的CpG基序通过TLR9识别白假丝酵母菌DNA,从而大量表达IL-12p40[42]。从白假丝酵母菌中分离纯化的几丁质壳,当其被分解成小颗粒时,被甘露糖受体识别结合,诱导含有核苷酸结合寡聚化结构域2(nucleotide binding oligomerzation domain 2,NOD2)和TLR9信号转导途径,分别激活CARD9/RICK以及MyD88,促进抗炎细胞因子IL-10表达,从而反馈抑制促炎性细胞因子TNF-α、IL-1β和IL-6的分泌[43]。几丁质分解颗粒可以通过NOD2和TLR9信号通路,降低白假丝酵母菌感染时的炎症反应,这一方面可能是白假丝酵母菌逃逸机体免疫效应的一种方式,另一方面也可能是机体调控白假丝酵母菌感染所致炎症反应的重要机制,使炎症反应适度,以免引起严重的组织损伤。

4 结语

迄今为止,关于参与抗白假丝酵母菌感染的TLR的生物学特征和功能已有了较深入的研究。业已证实,表达于树突状细胞、巨噬细胞等细胞上的TLR能结合识别白假丝酵母菌的β-葡聚糖、α-甘露聚糖、DNA等PAMP,激活相应的信号转导通路,诱导非特异性免疫效应分子的产生[25];TLR也可协同C型凝集素受体参与抗真菌感染。但是关于这些受体是如何选择性地识别不同的真菌PAMP尚未阐明。此外,TLR在面临白假丝酵母菌在不同环境(如不同酸碱度)中表现出的不同形态时,又怎样进行相应的识别,以及不同菌株之间的PAMP结构上是否存在差异,这些病原菌又是如何克服并逃逸宿主的防御措施等问题都有待进一步阐明。

上述科学问题的深入研究,无疑可为进一步了解宿主与白假丝酵母菌之间的相互作用,阐明机体抗白假丝酵母菌感染的细胞和分子生物学机制提供新的实验依据,为预防和治疗白假丝酵母菌感染提供新的思路,同时也可为研究抗其他真菌感染的免疫学机制提供新的线索。

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文章信息

周云, 潘建平
ZHOU Yun, PAN Jianping
Toll样受体在抗白假丝酵母菌感染中的作用研究进展
Progress on the role of Toll-like receptors in Candida albicans infections
浙江大学学报(医学版), 2016, 45(3): 302-307
Journal of Zhejiang University(Medical Sciences), 2016, 45(3): 302-307.
http://dx.doi.org/10.3785/j.issn.1008-9292.2016.05.14

文章历史

收稿日期: 2015-11-13
接受日期: 2016-01-20
基金项目: 浙江省医药卫生科技计划(2013KYA149);杭州市科技发展计划(20150633B44);杭州市高层次留学回国人员在杭创业创新项目
第一作者: 周云(1990-), 女, 硕士研究生, 主要从事感染免疫学研究; E-mail:zhyun0813@163.com; http://orcid.org/0000-0001-8394-0409
通讯作者: 潘建平(1962-), 男, 博士, 教授, 博士生导师, 从事免疫学研究; E-mail:jppan@zucc.edu.cn; http://orchid.org/0000-0001-9636-1561

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