衣原体致病机制研究进展
舒明艺, 李忠玉
南华大学病原生物学研究所,衡阳 421001
通讯作者:李忠玉, Email: lzhy1023@hotmail.com; ORCID: 0000-0001-8342-3997
摘要

衣原体是一类具有独特两相发育周期的专性胞内寄生菌,可引起人类多种疾病。衣原体致病主要依赖菌体脂多糖、膜蛋白、质粒编码蛋白、分泌的效应因子等,其或介导衣原体黏附和入侵宿主、引起炎症和病理损伤,或调控宿主细胞功能以利衣原体胞内生长,或抑制宿主免疫细胞以便衣原体逃逸免疫杀伤。这些发现在分子水平上阐述了衣原体的致病机制,为更好地诊断、治疗、预防衣原体感染提供新的理论基础。

关键词: 衣原体; 致病物质; 细胞调控; 免疫逃逸
中图分类号:R374 文献标志码:A 文章编号:1002-2694(2021)06-0542-06
Research progress on the pathogenesis of Chlamydia
SHU Ming-yi, LI Zhong-yu
Institute of Pathogenic Microorganism of University of South China, Hengyang 421001, China
Corresponding author: Li Zhong-yu,Email: lzhy1023@hotmail.com
Abstract

Chlamydia is an obligate intracellular parasite with a unique biphasic development cycle that can cause various diseases in humans. The pathogenicity of Chlamydia depends mainly on lipopolysaccharides, membrane proteins, plasmid-encoded proteins, and secreted effectors, which may mediate adhesion and invasion of the host to cause inflammation and pathological damage or regulate the functions of host cells to facilitate intracellular growth, or suppress host immune cells to evade the immune system. These findings explain the pathogenic mechanisms of Chlamydia at the molecular level and provide a new theoretical basis for better diagnosis, treatment, and prevention of Chlamydia infection.

Key words: Chlamydia; pathogenic substances; cell regulation; immune evasion

衣原体是一类专性宿主细胞内寄生和具有独特发育周期的小革兰阴性菌。在衣原体目(Chlamydiales)中, 衣原体属(Chlamydia)研究最多, 因其包含多种重要的人兽共患病原体[1], 致病性衣原体主要包括引起沙眼和女性生殖道感染的沙眼衣原体(Chlamydia trachomatis, Ct), 引起肺炎、动脉粥样硬化、反应性关节炎等疾病的肺炎衣原体(Chlamydia pneumoniae, Cpn), 引起肺炎的鹦鹉热衣原体(Chlamydia psittaci, Cps)[2]。衣原体具有独特的两相发育周期, 产生具有感染性的小而致密的原体(elementary body, EB)和非感染性的大而疏松的始体( reticulate body, RB)。感染性EB侵入宿主细胞发育为RB, RB在宿主细胞内经二分裂繁殖的子代发育为EB, EB从宿主细胞中释放出来后再感染新的宿主细胞[3]。虽然抗生素能够有效治疗衣原体感染, 但衣原体感染初期往往无明显症状, 导致诊断延迟和治疗不及时, 使得感染发展, 引起患者心血管、呼吸道、生殖系统等损伤。本文从衣原体致病物质、调控宿主细胞凋亡、逃逸宿主免疫杀伤和干扰宿主细胞转录等方面综述衣原体的分子致病机制, 为衣原体感染的临床和基础研究提供新的思路。

1 致病物质
1.1 脂多糖(LPS)

衣原体LPS是由一种截断的三糖(3-脱氧-D-甘露-辛-2-酮糖)和脂质A组成。脂质A结构特殊, 具有高疏水性, 脂肪酸链较长, 且存在与糖链相连的非羟基脂肪酸脂, 是导致衣原体LPS内毒素毒性低的原因[4]。杨春福等采用Ct LPS刺激小鼠骨髓源巨噬细胞(BMDM), 与大肠埃希菌LPS刺激相比, Ct LPS刺激的BMDM不能促进TLR4/MD-2聚合或内吞, 且IL-6、TNF、I型干扰素和IL-beta分泌减少。提示衣原体LPS可避免经典和非经典先天免疫信号途径的识别, 这可能是衣原体无症状感染者多见的一个原因[5]。此外, A.M.O’ Doherty等用Ct和流产衣原体(Chlamydia abortus)的LPS刺激牛输卵管上皮细胞, 发现LPS不能引起经典TLR4信号通路的活化, 但可导致子宫内精子活力减低和灭活[6], 这可能与衣原体引发无症状感染和女性不孕有关。

1.2 III型分泌系统效应子(T3SS)

衣原体T3SS效应子能够调控宿主细胞的多种生理和生化功能, 有利于衣原体在宿主细胞内的生存和复制[7]。Ct的易位性肌动蛋白转移招募磷蛋白(Tarp)、CT694/TmeA和TepP等效应子, 在感染早期由原体分泌至宿主细胞胞质, 通过调节肌动蛋白细胞骨架运动去介导衣原体的入侵[8, 9, 10]。Ct包涵体膜蛋白(Inc)效应子通过双叶疏水基序插入包涵体膜上, 干扰宿主细胞的囊泡和非囊泡运输、代谢、信号传递和调亡等[11]; Ct非Inc蛋白CT105/CteG是一个与高尔基体相关的T3SS效应子, 其可能参与干扰宿主细胞囊泡运输[12]。另外, 研究发现Ct T3SS效应子可能参与干扰宿主细胞染色质重塑和组蛋白甲基化[13]以及Cpn T3SS干扰宿主细胞泛素化[14]等(表1)。T3SS效应子数量多、功能多样, 其在衣原体致病中的作用尚有待研究阐明。

表1 III型分泌系统效应子及相关功能 Tab.1 T3SS effectors and their functions
1.3 质粒编码蛋白

大部分衣原体携带一个大小为7.5 kb、含有8个开放阅读框(pORF1-8)的质粒, 可促进衣原体定植、入侵、诱发炎症反应和组织损伤等, 为衣原体重要的毒力因子[15, 16]。衣原体质粒编码蛋白1-8(pGP1-8), 可参与衣原体的致病过程。研究发现Ct pGP1、2、6、8与质粒的维持和复制有关[17]; Ct pGP7与整合酶具有同源性[17]; Ct 和鼠衣原体(Chlamydia muridarum, Cm)pGP4、5可参与质粒与基因的转录调控, pGP4调控pGP3和染色体上编码GIgA、EUO基因[17, 18, 19]; Ct pGP3可分泌到宿主细胞胞质中, 参与调控宿主细胞自噬、凋亡、免疫应答等[20, 21, 22], 此外, 研究发现Ct pGP3通过阻断抗菌肽的活性抑制宿主先天免疫, 导致衣原体持续性感染[22, 23]

1.4 表面蛋白

研究发现Cpn的粘附蛋白CPn0473可粘附在上皮细胞的质膜上, 并诱导磷脂酰丝氨酸易位, 促进衣原体入侵宿主细胞[24]; Ct则用Ctad1与宿主细胞表面整合素β 1受体结合侵入宿主细胞[25]; Ct和Cpn表面多形态膜蛋白(Pmps)可与宿主上皮或内皮细胞表面受体结合, 如Pmp21粘附细胞表面生长因子受体[26]。Ct外膜蛋白OmcB和主要外膜蛋白(MOMP)则可结合宿主糖胺聚糖(GAG)硫酸肝素粘附宿主细胞[27]。这些蛋白介导衣原体粘附、入侵宿主细胞, 但具体机制尚不清楚。

2 致病机制
2.1 调控宿主细胞凋亡

细胞凋亡是细胞的自主反应, 涉及一系列基因和蛋白的激活、表达和调控, 并有许多调节通路参与, 是一个复杂的过程。天冬氨酸特异性半胱氨酸蛋白水解酶(Caspase)家族和B淋巴细胞瘤-2(Bcl-2)家族在调节细胞凋亡中起重要作用, Bcl-2家族控制内源性凋亡途径, 促凋亡Bcl-2蛋白Bax和Bak可透过线粒体外膜, 然后启动Caspase级联, 导致细胞凋亡[28]。研究发现Cps可促进抗凋亡蛋白Mcl-1并抑制促凋亡蛋白tBid和Bim的表达, 也可通过JAK/STAT3信号通路抑制Bax蛋白表达, 与此同时对细胞内促凋亡酶(Caspase-3、Caspase-7、Caspase-9、PARP)的活性也有抑制作用以阻止细胞凋亡[29, 30]。此外, Ct通过磷酸肌醇依赖性蛋白激酶(PDPK1)-MYC途径导致细胞产生大量的己糖激酶( HKII), 增加线粒体与己糖激酶( HKII)的结合以抑制宿主细胞凋亡[31]。CD95作为肿瘤坏死因子(TNF)/神经生长因子(NGF)分子受体超家族成员, 主要从Caspase的激活和线粒体途径来调节细胞凋亡, 研究表明, Ct和Cpn感染细胞后可产生相同的抗凋亡活性, 如阻断CD95诱导的凋亡途径, 从而抑制Caspase3和Caspase9的活性、阻止线粒体中细胞色素C的释放, 但这种活性不影响死亡受体凋亡通路的激活[32, 33]。因此, Mcl-1和CD95是衣原体抑制宿主细胞凋亡的重要分子。衣原体感染抑制宿主细胞凋亡, 有利于其利用宿主细胞生长繁殖。此外, 研究发现Cpn通过细胞外调节蛋白激酶1/2(ERK1/2)通路可上调血凝素样氧化低密度脂蛋白受体(LOX-1)的表达来诱导人脐静脉内皮细胞凋亡[34]

2.2 抑制宿主免疫应答

2.2.1 破坏免疫细胞 CD4+和CD8+ T淋巴细胞通过分泌干扰素IFN-γ 在抗衣原体免疫中起主要作用[35], 因此, 损害T淋巴细胞有利于衣原体在宿主中存活。Fankhauser等在Ct感染小鼠生殖道的研究中, 发现程序性细胞死亡蛋白-1(PD-1)和其配体PD-L1可抑制粘膜CD8+ T细胞的抗Ct应答, 抑制PD-1/PD-L1信号通路则能增强CD8+ T细胞清除衣原体的能力[36]。此外Shekhar等在体外用PD-1抗体阻断PD-1/PD-L1信号, 发现CD4+ T细胞产生和分泌IFN-γ 和IL-17的作用明显增强[37]。这些发现表明PD-1/PD-L1信号的活化可抑制T细胞的抗衣原体免疫应答。然而, 彭等发现PD-L1在Cm感染小鼠生殖道中具有相反的作用, 阻断PDL-1并不能增强抗衣原体免疫保护作用, 反而会导致鼠输卵管积水增加和炎症反应加重[38]。因此, PD-1/PD-L1信号在衣原体感染过程中的作用仍有待进一步探索。

最近的一项研究发现, Ct感染过程中宿主分泌过量的促炎细胞因子IFN-γ 和IL-12, 其通过调节T盒子转录因子(T-bet)的表达来抑制CD8+ T淋巴细胞成熟, T-bet是调节CD8+ T淋巴细胞成熟的关键转录因子[39], 另外, Ct感染巨噬细胞分泌肿瘤坏死因子TNF-α 去介导T细胞凋亡[40], Cm感染激活PI3K/AKT通路来介导CD4+ T细胞凋亡[41]。中性粒细胞清除体内细菌主要通过吞噬作用和释放防御素以及形成中性粒细胞胞外陷阱(NET)等方式来实现。然而, 衣原体在感染过程中可阻止NET的形成和抑制中性粒细胞激活等来逃逸宿主免疫杀伤; 衣原体蛋白酶活性因子(CPAF)在此过程中扮演着重要作用, CPAF直接影响多形核白细胞(PMN)的表面甲基肽受体2(FPR2)的裂解和释放, 干扰FPR2激活PMN[42]。衣原体通过破坏T淋巴细胞和中性粒细胞等免疫活性细胞来抑制机体的特异性免疫应答, 使其得以在宿主中长期存活并造成宿主反复感染。

2.2.2 抑制MHC分子的表达 主要组织相容性复合体(MHC)将抗原呈递给T细胞和NK细胞, 激活T细胞和NK细胞, 经典的MHC-Ⅰ 和MHC-Ⅱ 类分子分别识别CD8+和CD4+ T细胞受体。除此之外, 一些非经典的MHC分子或称为MHC样分子, 如CD1和MR1直接结合NK细胞受体[43]。已有许多研究证明细胞内病原体可以抑制MHC分子的表达或表面呈递, 以避免获得性免疫应答的追踪, 如触染性软疣动物病毒(MCV)和I型疱疹病毒(HSV-1), MCV编码的一种MC80蛋白, 通过结合TAP结合蛋白可使其泛素化, 然后经过ERAD(内质网相关性降解)途径降解, 降解的TAP结合蛋白可抑制MHC-Ⅰ 的抗原呈递[44], HSV-1则是通过Us3病毒基因产物靶向MR1分子, 抑制MR1分子的表达[45]。衣原体作为胞内病原体, 也有可能通过干扰MHC分子作用来逃逸宿主的免疫监视。研究发现衣原体CPAF可与MHC样分子CD1d的重链相互作用, 导致其泛素化和降解。在衣原体感染过程中, 人阴茎尿道上皮细胞表达的CD1d重链与CPAF一起定位在胞浆和衣原体包涵体中, 并不在细胞表面, 使CD1d无法呈递抗原[46]

2.3 干扰转录因子功能

核因子激活的B细胞的κ -轻链增强(NF-κ B)是控制DNA转录的蛋白复合物, 为炎症反应、免疫应答、细胞凋亡、应急反应等基因转录的中心调节因子。NF-κ B家族由p50、p52、p65(也称Rel-A)、c-Rel和Rel-B组成, 在胞质中与抑制蛋白Iκ B结合处于非活跃状态, 其信号途径的激活至少涉及到3个步骤:1)转化生长因子TGF-β 激酶(TAKI)和Iκ B蛋白激酶(IKK)的活化; 2)抑制蛋白Iκ B的磷酸化后降解Iκ B; 3)NF-κ B前体加工组装[47]。Iκ B蛋白家族是调控NF-κ B信号最常见的蛋白质, 其中最主要的是Iκ Bα 蛋白, 当大量的IkBα 与NF-κ B蛋白结合时, 可阻止NF-κ B激活和进入胞核, 起到负调控NF-κ B信号的作用[48]

衣原体可利用多种机制干扰NF-κ B信号的功能, 例如感染衣原体可阻止Iκ Bα 蛋白的降解和NF-κ B 的核转位[49]。 研究证明Ct的ChlaDub1蛋白可抑制IkBα 蛋白的泛素化和降解[50], ChlaDub1蛋白是Ct 的cdu1(CT868)基因编码的一种具有去泛素化和去甲基化活性的蛋白酶, 此外, Ct cdu2(CT867)基因编码的ChlaDub2蛋白也具有去泛素化和去甲基化活性[51]。ChlaDub1蛋白不影响Iκ Bα 的磷酸化水平, 但直接与Iκ Bα 相互作用、阻止该蛋白的泛素化和降解, 通过干扰Iκ Bα 激酶(IKK)复合物下游途径来发挥抑制活性[50]。衣原体CT441(Tsp蛋白酶)可选择性裂解p65, 使p65裂解为p40和p22片段, CT441蛋白酶和p40裂解片段可抑制NF-κ B的激活[49]。Christian等人提出衣原体CPAF在感染过程中可降解p65, 从而抑制NF-κ B的激活[52]。此外, 衣原体CPAF也与转录因子USF-1蛋白和RFX5蛋白的降解有关, 降解USF-1和RFX5可分别抑制MHC-Ⅱ 和MHC-Ⅰ 分子的表达[53, 54]

2.4 持续性感染状态应对不利环境因素

在不利生长条件下, 如抗生素、细胞因子或营养缺乏等, 衣原体转变为新陈代谢降低的特殊感染状态, 即持续性感染状态[55]。此时的衣原体不具有感染性, 可逃逸宿主免疫反应, 引起机体严重并发症和慢性后遗症。Claudia等通过比较正常感染Ct的发育周期和青霉素诱导的持续性感染状态Ct发育周期, 发现在持续性感染状态下, 宿主上皮细胞表面的脂质磷脂酰丝氨酸暴露、吞噬细胞/白细胞募集的信号受阻、caspase1和caspase3/7的活性受抑、毒性消失、感染细胞活性氧产生增加等[56], 表明衣原体在持续性感染状态下可对宿主细胞造成许多有害作用, 更加需要认真对待。

3 小 结

近年来, 衣原体致病性的研究取得很大的进展, 发现衣原体T3SS效应子等新的致病物质。在感染过程中, 衣原体通过分泌效应子与宿主细胞相互作用来调控宿主细胞功能, 以利于衣原体的生长繁殖和致病。这些发现在分子水平上阐述衣原体致病机制, 为更好地诊断、治疗和预防衣原体感染提供新的理论基础。

利益冲突:

引用本文格式: 舒明艺, 李忠玉. 衣原体致病机制研究进展[J]. 中国人兽共患病学报, 2021, 37(6):542-547. DOI:10.3969/j.issn.1002-2694.2021.00.066

编辑: 张智芳

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