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. 2017 Apr 25;46(2):218–224. [Article in Chinese] doi: 10.3785/j.issn.1008-9292.2017.04.16

病原菌对NOD样受体及Toll样受体信号通路介导的固有免疫逃逸机制研究进展

Progress on mechanisms for pathogensto evade NOD-like receptor and Toll-like receptor signaling pathways

Yujie HE 1,2, Jianping PAN 1,*
PMCID: PMC10396992  PMID: 28752716

Abstract

作为机体抵抗病原微生物的第一道防线，固有免疫细胞通过模式识别受体（PRR）识别病原体相关模式分子（PAMP）继而启动下游信号通路，以发挥固有免疫效应，清除入侵的病原体和异物。固有免疫细胞主要的信号通路有NOD样受体（NLR）及Toll样受体（TLR）信号通路，病原菌经过长期的选择进化产生了针对NLR及TLR信号通路的对抗机制，以利于其在宿主体内的生存增殖。病原菌主要通过产生毒力因子或降低刺激炎症小体活化的PAMP的表达，干扰、抑制或避免固有免疫细胞内炎症小体的活化，实现对NLR介导的信号通路的免疫逃逸。而对TLR信号通路的免疫逃逸主要通过产生毒力因子，抑制丝裂原活化蛋白激酶级联反应、抑制NF-κB活化以及通过产生含有TIR结构域的蛋白，直接与TLR或者TLR信号通路中的接头蛋白结合，干扰下游信号转导三种机制。

作为与生俱来的一种免疫方式，当病原体入侵时，固有免疫细胞可以通过其表面的或者胞质中的模式识别受体(pattern recognition receptor，PRR)识别病原体的相关模式分子(pathogen-associated molecular patterns，PAMP)，PRR与PAMP结合后即可迅速激活效应细胞并启动下游免疫反应。根据功能，PRR可以分为可溶型PRR、细胞吞噬型PRR以及信号转导型PRR。可溶型PRR可以识别结合游离分布于体液中的效应分子；细胞吞噬型PRR是表达于固有免疫细胞表面的多种跨膜受体，有识别PAMP并介导病原体的吞噬作用；信号转导型PRR与PAMP结合后则可以通过相应信号转导途径诱导不同基因的表达，活化固有免疫细胞并产生相应的效应分子，在固有免疫中具有重要作用 [ 1] 。信号转导型PRR又可以根据结构分为Toll样受体家族(Toll-like receptors, TLR)、RIG-I样受体家族(RIG-I-like receptors, RLR)以及NOD样受体家族[nucleotide-binding, oligomerization domain (NOD)-like receptors, NLR]等。

NLR主要由三个结构域组成，C端为LRR结构域(leucine-rich repeat)，主要负责识别和特异性结合PAMP；中间为NOD结构域(又称为NACHT结构域)，是NLR家族成员共有的特征性结构域，可以促进NLR分子相互聚合，改变其构型；N端为效应结构域，主要由半胱天冬酶激活与募集结构域(caspase activation and recruitment domain，CARD)、热蛋白结构域(pyrin domain，PYD)或杆状病毒凋亡抑制重复序列(baculovirus inhibitor of apoptosis protein repeat domain，BIR)组成，主要负责向下游传递信号。根据效应结构域的种类和结构特征，NLR可以划分为多个亚家族，包括NLRP、NLRC、PYHIN等。NLR受体分子的特点是全部处于胞质溶胶中，可以通过LRR的折叠使其靠近NACHT结构域，抑制自身多聚体化而处于非活化状态。LRR识别配体将引起自身构象变化，从而解除LRR对NACHT结构域寡聚化的抑制，NACHT寡聚化引起效应结构域暴露 [ 2] ，继而通过PYD-PYD相互作用募集凋亡相关微粒蛋白(apoptosis-associated speck-like protein containing a CARD, ASC)接头分子，形成炎症小体(inflammasome)。炎症小体的形成导致caspase-1的活化，继而引起IL-1β的前体分子pro-IL-1β和IL-18的前体分子pro-IL-18水解，并进一步导致IL-1β和IL-18成熟和分泌，其可参与许多炎症反应如巨噬细胞活化、中性粒细胞迁移以及组织修复等，从而使机体对入侵的病原体做出应答 [ 3] 。

TLR是一类跨膜或位于胞内的受体，跨膜型TLR的结构可分为胞外区、跨膜区和胞内区三个部分，跨膜区是富含半胱氨酸的结构域，胞内区含有与Toll以及IL-1R同源的TIR结构域。TIR结构域含有三个保守基序，称为小盒，是起始下游信号转导的核心元件 [ 4] 。TLR主要以同源或者异源二聚体的形式发挥作用，二聚体化后TLR迁移到一些脂类含量特别丰富的亚细胞信号位点，除TLR3以外的其它TLR家族成员胞内区含TIR结构域的TIRAP蛋白(又称MAL)募集下游髓样分化基础应答蛋白MyD88(myeloid differentiation primary response protein 88) 向下传导信号并形成高度特异有序的超分子形成中心(supramolecular organizing center，SMOC)复合物 [ 5] 。Myddosome便是SMOC复合物中的典型代表，其组成主要包括MyD88蛋白、TIRAP以及IL受体相关激酶(interleukin receptor-associated kinase，IRAK)，myddosome的形成激活E3泛素连接酶TNF受体相关因子6(TNFR-associated factor 6，TRAF6)，与E2泛素结合酶Ubc13(ubiquitin-conjugating enzyme 13) 和泛素结合酶变体1A(ubiquitin-conjugating enzyme variant1A, Uev1A)一起对其自身及其它底物进行泛素化修饰。TRAF6自我多聚泛素化后与下游的TGF-β活化激酶1(TGF-β activated kinase 1, TAK1) 以及TAK1结合蛋白2/3(TAK1-binding protein2/3，TAB 2/3) 形成复合物激活TAK1，TAK1继续活化下游不同途径的信号转导通路。一条途径是激活IκB激酶(IκB kinase，IKK)复合体，引起κB抑制物(inhibitor of κB, IκB)被泛素化降解，并释放出与其结合的NF-κB二聚体(IKKα、IKKβ)；另一条途径是激活丝裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)，后者磷酸化并进一步促进ERK、JNK及P38的活化，从而激活转录因子AP-1。两条途径分别通过核转录因子NF-κB及AP-1启动靶基因的表达，介导促炎症细胞因子、趋化因子的产生。另一类SMOC称为内体，主要由含TIR结构域的分子TRIF相关接头分子(TRIF-related adaptor molecule，TRAM)结合含有TIR结构域的可诱导产生IFN-β的接头蛋白(TIR domain -containing adaptor protein inducing IFN-β, TRIF)形成，TRIF再通过TBK1诱导干扰素调节因子3(interferon-regulatory factor 3，IRF3) 的表达进而调控Ⅰ型干扰素的产生 [ 6] 。

因为RLR在大多数组织细胞中表达量均较低且可直接结合病毒RNA，目前有关RLR的研究大多集中在其与病毒的相互作用。而病原菌干扰宿主细胞信号转导机制的研究则主要集中在NLR和TLR方面，所以本文主要从NLR及TLR这两个方面介绍一些病原菌的免疫逃逸机制研究进展。

沙门氏菌( Salmonella)是一种常见的食源性致病菌，在其入侵B细胞的过程中，B细胞的Yap蛋白(P73分子转录的共激活分子)第127位丝氨酸残基在AKT激酶的作用下发生磷酸化，促进Yap蛋白与Hck的结合，导致Yap蛋白无法与P73分子(P53家族的转录因子，调节细胞周期及细胞凋亡等过程)形成异二聚体继而影响与NLRC4启动子区的结合，通过阻止NLRC4的转录活化进而抑制炎症小体及IL-1β的生成，从而在感染过程中更利于沙门氏菌在B细胞内的存活和在宿主体内的扩散 [ 7] 。鼠疫耶尔森菌( Yersinia pestis)俗称鼠疫杆菌，是鼠疫的病原菌，其T3SS分泌的效应分子YopE、YopT是Rho-GTPase的负调节因子，可以干扰Rho-GTPase介导的细胞骨架动力学过程，从而抑制炎症小体形成过程中的寡聚化过程和半胱天冬酶1(caspase-1) 的活化 [ 8] ；其T3SS分泌的另一效应分子YopM在其裸露环中有一段四个氨基酸的序列YLTD，这段序列与caspase-1的底物YVAD结构类似，故YopM可以作为假底物直接与caspase-1结合，抑制caspase-1的活性从而导致炎症小体无法活化，故在鼠疫耶尔森菌感染巨噬细胞时，这种机制利于其在细胞内感染定植 [ 9] 。军团菌( Legionella)是一类可以引起上呼吸道感染及发热症状、严重时可导致呼吸衰竭和肾衰竭的细菌。在其入侵巨噬细胞的过程中，军团菌存活于一个泡状结构(legionella-containing vacuole, LCV)中，LCV泡状结构完整性的维持需要Dot/Icm type Ⅳ B分泌系统的效应分子SdhA；SdhA具有一个功能性的、可与高尔基体相互作用的GRIP结构域，可以帮助LCV抵抗与溶酶体的融合，阻止军团菌DNA的释放并进一步抑制caspase-1活化、IL-1β的分泌，抑制炎症小体的活化从而利于军团菌在巨噬细胞中的感染扩散 [ 10] 。尿路致病性大肠埃希菌( Uropathogenic Escherichia coli, UPEC)是引起尿路感染的主要细菌，在其CFT073菌株感染巨噬细胞的过程中，CFT073菌株具有的毒力因子含 E. coli编码蛋白的TIR结构域TcpC(TIR domain containing protein encoded by E. coli, TcpC), 其虽然会诱导NLRP3炎症小体表达且不影响胞内Pro-IL-1β水平，但会抑制caspase-1切割及成熟IL-1β释放，导致炎症小体无法活化，所以对于CFT073菌株来说，TcpC有利于其在宿主细胞内存活 [ 11] 。

在感染机体过程中，鼠疫耶尔森菌的毒力因子YopK可以作为T3SS的一种“看门人”，以控制鞭毛蛋白或T3SS的成孔蛋白YopB、YopD释放至宿主胞质溶胶而避免NLRP3、NLRC4激活，从而使耶尔森菌逃避机体免疫应答，更利于其在宿主体内存活 [ 8, 12- 13] 。金黄色葡萄球菌( Staphylococcus aureus)是人类化脓性炎症中最常见的病原菌，可引起局部化脓性炎症，严重时可导致败血症、脓毒症等全身感染。在入侵宿主细胞时，其细胞壁的肽聚糖可以在O-乙酰基转移酶A( oatA)的作用下发生O-乙酰化，从而更容易抵抗被溶酶体水解成小颗粒物质，使NLRP3炎症小体对其监测的敏感性降低，进一步避免NLRP3炎症小体激活及IL-1β生成。IL-1β在抵抗金黄色葡萄球菌所致的化脓性炎症中发挥重要作用，抑制IL-1β生成将更利于金黄色葡萄球菌侵染 [ 14- 15] 。

由此可见，病原菌在感染过程中，一方面通过产生毒力因子，干扰和抑制固有免疫细胞内炎症小体的活化；另一方面，通过降低PAMP的表达或减少进入胞质溶胶的PAMP量，避免炎症小体以及IL-1β生成，从而实现对NLR信号途径介导的固有免疫的逃逸。

MAPKs是一组能被不同的细胞外刺激激活的丝氨酸—苏氨酸蛋白激酶，主要包括MAPK激酶激酶(MAP kinase kinase kinase，MKKK)、MAPK激酶(MAP kinase kinase，MKK)和MAPK，这三种激酶能依次激活，共同调节着细胞的生长、分化、对环境的应激反应以及炎症反应等多种重要的细胞生理病理过程。最早关于病原体抑制MAPK的发现是炭疽芽孢杆菌( B. anthracis)产生的炭疽致死毒素(lethal factor，LF)。LF可以直接切割MAPKK1、MAPKK2的氨基端，从而阻断MAPK信号通路，导致感染炭疽芽孢杆菌的动物死亡 [ 16] 。后来研究发现鼠疫耶尔森菌的T3SS分泌的蛋白YopJ也可以抑制MAPK信号通路的激活。YopJ具有的乙酰基转移酶活性可以利用辅酶A分子共价修饰MAPKK6活化的关键分子丝氨酸和苏氨酸残基，导致MAPKK6激酶无法磷酸化下游的激酶，从而在鼠疫耶尔森菌感染机体过程中阻止MAPK介导的细胞因子转录激活反应 [ 17- 18] 。在入侵果蝇( Drosophila)时，YopJ也可以利用这一机制作用于果蝇的TAK1，导致MAPK信号通路下游分子C-Jun NH2端激酶(C-Jun NH2-terminal kinase，JNK)及NF-κB均无法激活 [ 19] 。同样作用机制的还有沙门菌的效应分子AvrA，其乙酰基转移酶活性也可以抑制JNK的激活，并抑制巨噬细胞凋亡从而促进感染过程中沙门菌的定植 [ 20] 。福氏志贺菌( Shigella flexneri)是志贺菌属的细菌，是人类细菌性痢疾的病原菌，其T3SS分泌的蛋白OspF具有磷酸苏氨酸裂解酶活性，在入侵机体过程中，OspF可以催化MAPKs中的P38激酶 [ 21] 及ERK [ 22] 不可逆地脱去磷酸基团。MAPKs的去磷酸化导致H3组蛋白的第十位丝氨酸残基无法磷酸化，而这一磷酸化过程对于染色质的集聚组装是必需的。染色质无法组装导致NF-κB分子入核后无法与之结合，故MAPK及NF-κB信号通路均被抑制 [ 23] 。爱德华菌属杀鱼巴斯德菌( Edwardsiella piscicida)是一类可以引起细菌性鱼病的病原菌，其T3SS分泌的一种蛋白EseH也具有磷酸苏氨酸裂解酶活性，作用方式与OspF相同，在侵染宿主细胞过程中可使ERK1/2、P38α、JNK无法磷酸化，从而抑制下游信号通路。杀鱼巴斯德菌野生型菌株与敲除EseH基因的菌株相比致病性明显增强，侵染机体时可进一步抑制宿主细胞分泌TNF-α、IL-12、IL-10、干扰素等，从而更加有利于细菌在宿主内的生存和扩散，促使鱼类的感染性症状加剧 [ 24] 。

福氏志贺菌( Shigella flexneri)T3SS分泌的蛋白Osp1具有脱酰胺酶的活性，可选择性脱去E2泛素结合酶Ubc13第100位谷氨酰胺的酰胺基，使其变成谷氨酸从而导致其失活。而Ubc13对于下游TRAF6的自我多聚泛素化是必需的，TRAF6因无法活化从而进一步沉默NF-κB信号通路 [ 25] 。志贺菌T3SS的另一效应分子OspG可以通过泛素分子表面的疏水区与E2泛素结合酶结合来激活其ATP激酶活性。在感染HeLa细胞的过程中，OspG可抑制IκBα降解，IκBα因无法与NF-κB二聚体(IKKα、IKKβ)分离从而抑制NF-κB激活，进一步促进志贺菌的存活和扩散 [ 26] 。

Tcps蛋白(Toll/IL-1 receptor containing proteins)是一些细菌分泌的一类含有TIR结构域的蛋白，其结构与TLR的TIR结构域类似，故可以直接结合TLR或者与TLR下游接头蛋白结合从而干扰正常的信号转导过程 [ 27- 28] 。尿路致病性大肠埃希菌CFT073菌株(uropathogenic E. coli strain CFT073, E. coli CFT073) 分泌的含TIR结构域的蛋白称为TcpC。TcpC基因位于 E. coli CFT073菌株的serU岛中，在岛的中央位置有TcpC操纵子的两个基因，紧挨其serU岛的5’端附着位点处有整合酶基因。TcpC氨基酸序列分析显示，其TIR结构域中的TLR同源区包含一个Box1基序，而真核生物的TIR结构域中也有此基序，所以在 E. coli CFT073菌株入侵宿主的过程中，TcpC可以与宿主细胞的MyD88接头蛋白结合，造成宿主细胞的MyD88无法与TLR4的TIR结构域结合，或直接与宿主细胞TLR4结合干扰下游信号传递过程，进一步抑制巨噬细胞分泌IL-6及TNF，改变宿主固有免疫应答功能状态，从而逃避机体免疫效应，更利于该大肠埃希菌在宿主体内的存活和增殖 [ 29- 33] 。布氏杆菌( B. melitensis)分泌的此类蛋白为TcpB，又称为BtpA/Btp1 [ 34] ，TcpB通过干扰TLR2信号通路可以抑制被感染树突状细胞成熟，降低其抗原提呈能力，抑制促炎症因子的分泌 [ 35] ；同时，TcpB也可与MAL蛋白以及TLR4结合，通过干扰MAL蛋白与TLR4的结合来抑制NF-κB信号通路 [ 36] ，并增强磷酸化的MAL蛋白的多聚泛素化，加速MAL蛋白的降解从而阻断下游信号通路 [ 37] 。粪肠球菌( Enterococcus faecalis)是一类在免疫功能正常的人体中不会引起疾病，但在免疫力低下的患者中可以引起泌尿道感染、肝胆脓毒症等疾病的革兰阳性菌。其V583基因组可编码TcpF蛋白，TcpF的TIR结构域位于其N端，其C端基序KVRFKLKK与TcpB的功能基序相似。过表达纯化的TcpF蛋白在体外可与MyD88蛋白特异性结合，这一作用依赖于TcpF Box2基序的BB loop；哺乳动物细胞中过表达TcpF会抑制脂磷壁酸引起的NF-κB的激活。与TcpF基因敲除株相比，野生株在巨噬细胞中的存活率高，并可以使被侵染的巨噬细胞分泌的细胞因子的量显著降低，同时使NF-κB的分子之一P65的表达降低，推测这可能是粪肠球菌在免疫力低下患者体内引起各种感染的一种机制 [ 38] 。金黄色葡萄球菌分泌的蛋白TirS是TcpC的同源蛋白，但其N端与TcpC差异较大，TirS会干扰TLR2信号途径，通过与MyD88、TIRAP蛋白结合来降低促炎症因子G-CSF和MCP-1的分泌，从而促进金黄色葡萄球菌在宿主体内的感染定植 [ 39] 。

由以上可知，病原菌可以通过抑制TLR信号通路中MAPK及NF-κB的活化或者直接与TLR信号通路中必需的接头蛋白结合而干扰、阻断TLR信号通路正常的信息传递，从而实现对TLR信号通路介导的免疫应答的逃逸。

免疫系统依靠复杂的、高度动态的信号转导系统来调节机体的固有免疫应答，所以，对病原菌来说，干扰固有免疫信号转导、抑制固有免疫细胞的活化，是其逃避固有免疫应答、利于其在宿主体内生存和增殖的有效方式。除了上述干扰信号通路抑制免疫细胞活化之外，病原菌还可以通过多种方式如分泌毒素分子至宿主细胞、逃避吞噬作用、抑制补体效应功能、修饰其PAMP等来逃逸机体固有免疫。深入研究病原菌逃逸机体固有免疫应答机制，不仅可以帮助我们更好地理解病原菌与机体之间的相互作用，为进一步阐明病原菌的致病机制提供新的实验依据，而且能为相应感染性疾病的预防和治疗措施的设计提供新的思路和理论指导，具有重要的意义。

Funding Statement

国家自然科学基金（31671613）；杭州市科技发展计划（20150633B44）

References

  • 1.BROZ P, MONACK D M. Newly described pattern recognition receptors team up against intracellular pathogens. Nat Rev Immunol. 2013;13(8):551–565. doi: 10.1038/nri3479. [BROZ P, MONACK D M. Newly described pattern recognition receptors team up against intracellular pathogens[J]. Nat Rev Immunol, 2013, 13(8):551-565.] [DOI] [PubMed] [Google Scholar]
  • 2.NG T M, KORTMANN J, MONACK D M. Policing the cytosol—bacterial-sensing inflammasome receptors and pathways. Curr Opin Immunol. 2013;25(1):34–39. doi: 10.1016/j.coi.2012.11.009. [NG T M, KORTMANN J, MONACK D M. Policing the cytosol—bacterial-sensing inflammasome receptors and pathways[J]. Curr Opin Immunol, 2013, 25(1):34-39.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.FRANCHI L, MUNOZ-PLANILLO R, NUNEZ G. Sensing and reacting to microbes via the inflammasomes. Nat Immunol. 2012;13(4):325–332. doi: 10.1038/ni.2231. [FRANCHI L, MUNOZ-PLANILLO R, NUNEZ G. Sensing and reacting to microbes via the inflammasomes[J]. Nat Immunol, 2012, 13(4):325-332.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.JIMENEZ-DALMARONI M J, GERSWHIN M E, ADAMOPOULOS I E. The critical role of toll-like receptors-from microbial recognition to autoimmunity:a comprehensive review. Autoimmun Rev. 2016;15(1):1–8. doi: 10.1016/j.autrev.2015.08.009. [JIMENEZ-DALMARONI M J, GERSWHIN M E, ADAMOPOULOS I E. The critical role of toll-like receptors-from microbial recognition to autoimmunity:a comprehensive review[J]. Autoimmun Rev, 2016, 15(1):1-8.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.KAGAN J C, MAGUPALLI V G, WU H. SMOCs:supramolecular organizing centres that control innate immunity. Nat Rev Immunol. 2014;14(12):821–826. doi: 10.1038/nri3757. [KAGAN J C, MAGUPALLI V G, WU H. SMOCs:supramolecular organizing centres that control innate immunity[J]. Nat Rev Immunol, 2014, 14(12):821-826.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.DE NARDO D. Toll-like receptors:activation, signalling and transcriptional modulation. Cytokine. 2015;74(2):181–189. doi: 10.1016/j.cyto.2015.02.025. [DE NARDO D. Toll-like receptors:activation, signalling and transcriptional modulation[J]. Cytokine, 2015, 74(2):181-189.] [DOI] [PubMed] [Google Scholar]
  • 7.PEREZ-LOPEZ A, ROSALES-REYES R, ALPUCHE-ARANDA C M, et al. Salmonella downregulates nod-like receptor family CARD domain containing protein 4 expression to promote its survival in B cells by preventing inflammasome activation and cell death. J Immunol. 2013;190(3):1201–1209. doi: 10.4049/jimmunol.1200415. [PEREZ-LOPEZ A, ROSALES-REYES R, ALPUCHE-ARANDA C M, et al. Salmonella downregulates nod-like receptor family CARD domain containing protein 4 expression to promote its survival in B cells by preventing inflammasome activation and cell death[J]. J Immunol, 2013, 190(3):1201-1209.] [DOI] [PubMed] [Google Scholar]
  • 8.PHA K, NAVARRO L. Yersinia type Ⅲ effectors perturb host innate immune responses. World J Biol Chem. 2016;7(1):1–13. doi: 10.4331/wjbc.v7.i1.1. [PHA K, NAVARRO L. Yersinia type Ⅲ effectors perturb host innate immune responses[J]. World J Biol Chem, 2016, 7(1):1-13.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.LAROCK C N, COOKSON B T. The Yersinia virulence effector YopM binds caspase-1 to arrest inflammasome assembly and processing. Cell Host Microbe. 2012;12(6):799–805. doi: 10.1016/j.chom.2012.10.020. [LAROCK C N, COOKSON B T. The Yersinia virulence effector YopM binds caspase-1 to arrest inflammasome assembly and processing[J]. Cell Host Microbe, 2012, 12(6):799-805.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.GE J, GONG Y N, XU Y, et al. Preventing bacterial DNA release and absent in melanoma 2 inflammasome activation by a Legionella effector functioning in membrane trafficking. Proc Natl Acad Sci U S A. 2012;109(16):6193–6198. doi: 10.1073/pnas.1117490109. [GE J, GONG Y N, XU Y, et al. Preventing bacterial DNA release and absent in melanoma 2 inflammasome activation by a Legionella effector functioning in membrane trafficking[J]. Proc Natl Acad Sci U S A, 2012, 109(16):6193-6198.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.WALDHUBER A, PUTHIA M, WIESER A, et al. Uropathogenic escherichia coli strain CFT073 disrupts NLRP3 inflammasome activation. J Clin Invest. 2016;126(7):2425–2436. doi: 10.1172/JCI81916. [WALDHUBER A, PUTHIA M, WIESER A, et al. Uropathogenic escherichia coli strain CFT073 disrupts NLRP3 inflammasome activation[J]. J Clin Invest, 2016, 126(7):2425-2436.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.BRODSKY I E, PALM N W, SADANAND S, et al. A Yersinia secreted effector protein promotes virulence by preventing inflammasome recognition of the type Ⅲ secretion system. Cell Host Microbe. 2010;7(5):376–387. doi: 10.1016/j.chom.2010.04.009. [BRODSKY I E, PALM N W, SADANAND S, et al. A Yersinia secreted effector protein promotes virulence by preventing inflammasome recognition of the type Ⅲ secretion system[J]. Cell Host Microbe, 2010, 7(5):376-387.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.ZWACK E E, SNYDER A G, WYNOSKY-DOLFI M A, et al. Inflammasome activation in response to the Yersinia type Ⅲ secretion system requires hyperinjection of translocon proteins YopB and YopD. http://mbio.asm.org/content/6/1/e02095-14.full. mBio. 2015;6(1):e02095–14. doi: 10.1128/mBio.02095-14. [ZWACK E E, SNYDER A G, WYNOSKY-DOLFI M A, et al. Inflammasome activation in response to the Yersinia type Ⅲ secretion system requires hyperinjection of translocon proteins YopB and YopD[J/OL]. mBio, 2015, 6(1):e02095-14.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.SHIMADA T, PARK B G, WOLF A J, et al. Staphylococcus aureus evades the lysozyme-based digestion of peptidoglycan that links phagocytosis and macrophage IL-1β secretion. Cell Host Microbe. 2010;7(1):38–49. doi: 10.1016/j.chom.2009.12.008. [SHIMADA T, PARK B G, WOLF A J, et al. Staphylococcus aureus evades the lysozyme-based digestion of peptidoglycan that links phagocytosis and macrophage IL-1β secretion [J]. Cell Host Microbe, 2010:7(1):38-49.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.PUSHKARAN A C, NATARAJ N, NAIR N, et al. Understanding the structure-function relationship of lysozyme resistance in staphylococcus aureus by peptidoglycan o-acetylation using molecular docking, dynamics, and lysis assay. J Chem Inf Model. 2015;55(4):760–770. doi: 10.1021/ci500734k. [PUSHKARAN A C, NATARAJ N, NAIR N, et al. Understanding the structure-function relationship of lysozyme resistance in staphylococcus aureus by peptidoglycan o-acetylation using molecular docking, dynamics, and lysis assay[J]. J Chem Inf Model, 2015:55(4):760-770.] [DOI] [PubMed] [Google Scholar]
  • 16.DUESBERY N S, WEBB C P, LEPPLA S H, et al. Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science. 1998;280(5364):734–737. doi: 10.1126/science.280.5364.734. [DUESBERY N S, WEBB C P, LEPPLA S H, et al. Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor[J]. Science, 1998:280(5364):734-737.] [DOI] [PubMed] [Google Scholar]
  • 17.MUKHERJEE S, KEITANY G, LI Y, et al. Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation. Science. 2006;312(5777):1211–1214. doi: 10.1126/science.1126867. [MUKHERJEE S, KEITANY G, LI Y, et al. Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation[J]. Science, 2006, 312(5777):1211-1214.] [DOI] [PubMed] [Google Scholar]
  • 18.MA K W, MA W. YopJ family effectors promote bacterial infection through a unique acetyltransferase activity. Microbiol Mol Biol Rev. 2016;80(4):1011–1027. doi: 10.1128/MMBR.00032-16. [MA K W, MA W. YopJ family effectors promote bacterial infection through a unique acetyltransferase activity[J]. Microbiol Mol Biol Rev, 2016, 80(4):1011-1027.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.PAQUETTE N, CONLON J, SWEET C, et al. Serine/threonine acetylation of TGFβ-activated kinase (TAK1) by Yersinia pestis YopJ inhibits innate immune signaling. Proc Natl Acad Sci U S A. 2012;109(31):12710–12715. doi: 10.1073/pnas.1008203109. [PAQUETTE N, CONLON J, SWEET C, et al. Serine/threonine acetylation of TGFβ-activated kinase (TAK1) by Yersinia pestis YopJ inhibits innate immune signaling[J]. Proc Natl Acad Sci U S A, 2012, 109(31):12710-12715.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.WU H X, JONES R M, NEISH A S. The Salmonella effector AvrA mediates bacterial intracellular survival during infection in vivo . Cell Microbiol. 2012;14(1):28–39. doi: 10.1111/cmi.2012.14.issue-1. [WU H X, JONES R M, NEISH A S. The Salmonella effector AvrA mediates bacterial intracellular survival during infection in vivo[J]. Cell Microbiol, 2012, 14(1):28-39. ] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.REITERER V, GROSSNIKLAUS L, TSCHON T, et al. Shigella flexneri type Ⅲ secreted effector OspF reveals new crosstalks of proinflammatory signaling pathways during bacterial infection. Cell Signal. 2011;23(7):1188–1196. doi: 10.1016/j.cellsig.2011.03.006. [REITERER V, GROSSNIKLAUS L, TSCHON T, et al. Shigella flexneri type Ⅲ secreted effector OspF reveals new crosstalks of proinflammatory signaling pathways during bacterial infection[J]. Cell Signal, 2011, 23(7):1188-1196.] [DOI] [PubMed] [Google Scholar]
  • 22.KIM D W, CHU H, JOO D H, et al. OspF directly attenuates the activity of extracellular signal-regulated kinase during invasion by shigella flexneri in human dendritic cells. Mol Immunol. 2008;45(11):3295–3301. doi: 10.1016/j.molimm.2008.02.013. [KIM D W, CHU H, JOO D H, et al. OspF directly attenuates the activity of extracellular signal-regulated kinase during invasion by shigella flexneri in human dendritic cells[J]. Mol Immunol, 2008, 45(11):3295-3301.] [DOI] [PubMed] [Google Scholar]
  • 23.ARBIBE L, KIM D W, BATSCHE E, et al. An injected bacterial effector targets chromatin access for transcription factor NF-kappaB to alter transcription of host genes involved in immune responses. Nat Immunol. 2007;8(1):47–56. doi: 10.1038/ni1423. [ARBIBE L, KIM D W, BATSCHE E, et al. An injected bacterial effector targets chromatin access for transcription factor NF-kappaB to alter transcription of host genes involved in immune responses[J]. Nat Immunol, 2007, 8(1):47-56.] [DOI] [PubMed] [Google Scholar]
  • 24.HOU M, CHEN R, YANG D, et al. Identification and functional characterization of EseH, a new effector of the type Ⅲ secretion system of edwardsiella piscicida. Cell Microbiol. 2017;19(1):e12638. doi: 10.1111/cmi.12638. [HOU M, CHEN R, YANG D, et al. Identification and functional characterization of EseH, a new effector of the type Ⅲ secretion system of edwardsiella piscicida[J/OL]. Cell Microbiol, 2017, 19(1), e12638.] [DOI] [PubMed] [Google Scholar]
  • 25.SANADA T, KIM M, MIMURO H, et al. The shigella flexneri effector ospI deamidates UBC13 to dampen the inflammatory response. Nature. 2012;483(7391):623–626. doi: 10.1038/nature10894. [SANADA T, KIM M, MIMURO H, et al. The shigella flexneri effector ospI deamidates UBC13 to dampen the inflammatory response[J]. Nature, 2012, 483(7391):623-626.] [DOI] [PubMed] [Google Scholar]
  • 26.ZHOU Y, DONG N, HU L, et al. The Shigella type three secretion system effector OspG directly and specifically binds to host ubiquitin for activation. PLoS One. 2013;8(2):e57558. doi: 10.1371/journal.pone.0057558. [ZHOU Y, DONG N, HU L, et al. The Shigella type three secretion system effector OspG directly and specifically binds to host ubiquitin for activation[J/OL]. PLoS One, 2013, 8(2):e57558.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.RANA R R, ZHANG M, SPEAR A M, et al. Bacterial TIR-containing proteins and host innate immune system evasion. Med Microbiol Immunol. 2013;202(1):1–10. doi: 10.1007/s00430-012-0253-2. [RANA R R, ZHANG M, SPEAR A M, et al. Bacterial TIR-containing proteins and host innate immune system evasion[J]. Med Microbiol Immunol, 2013, 202(1):1-10.] [DOI] [PubMed] [Google Scholar]
  • 28.PATTERSON N J, WERLING D. To con protection:TIR-domain containing proteins (Tcp) and innate immune evasion. Vet Immunol Immunopathol. 2013;155(3):147–154. doi: 10.1016/j.vetimm.2013.06.017. [PATTERSON N J, WERLING D. To con protection:TIR-domain containing proteins (Tcp) and innate immune evasion[J]. Vet Immunol Immunopathol, 2013, 155(3):147-154.] [DOI] [PubMed] [Google Scholar]
  • 29.CIRL C, WIESER A, YADAV M, et al. Subversion of toll-like receptor signaling by a unique family of bacterial toll/interleukin-1 receptor domain-containing proteins. Nat Med. 2008;14(4):399–406. doi: 10.1038/nm1734. [CIRL C, WIESER A, YADAV M, et al. Subversion of toll-like receptor signaling by a unique family of bacterial toll/interleukin-1 receptor domain-containing proteins[J]. Nat Med, 2008, 14(4):399-406.] [DOI] [PubMed] [Google Scholar]
  • 30.SNYDER G A, CIRL C, JIANG J S, et al. Molecular mechanisms for the subversion of MyD88 signaling by TcpC from virulent uropathogenic escherichia coli. Proc Natl Acad Sci U S A. 2013;110(17):6985–6990. doi: 10.1073/pnas.1215770110. [SNYDER G A, CIRL C, JIANG J S, et al. Molecular mechanisms for the subversion of MyD88 signaling by TcpC from virulent uropathogenic escherichia coli[J]. Proc Natl Acad Sci U S A, 2013, 110(17):6985-6990.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.YADAV M, ZHANG J Y, FISCHER H, et al. Inhibition of TIR domain signaling by TcpC: MyD88-dependent and independent effects on escherichia coli virulence. PLoS Pathog. 2010;6(9):e1001120. doi: 10.1371/journal.ppat.1001120. [YADAV M, ZHANG J Y, FISCHER H, et al. Inhibition of TIR domain signaling by TcpC: MyD88-dependent and independent effects on escherichia coli virulence[J/OL]. PLoS Pathog, 2010, 6(9):e1001120.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.SCHUBERT S, NORENBERG D, CLERMONT O, et al. Prevalence and phylogenetic history of the TcpC virulence determinant in escherichia coli. Int J Med Microbiol. 2010;300(7):429–434. doi: 10.1016/j.ijmm.2010.02.006. [SCHUBERT S, NORENBERG D, CLERMONT O, et al. Prevalence and phylogenetic history of the TcpC virulence determinant in escherichia coli[J]. Int J Med Microbiol, 2010, 300(7):429-434.] [DOI] [PubMed] [Google Scholar]
  • 33.WALDHUBER A, SNYDER G A, ROMMLER F, et al. A comparative analysis of the mechanism of toll-Like receptor-disruption by TIR-containing protein c from uropathogenic escherichia coli. Pathogens. 2016;5(1):25. doi: 10.3390/pathogens5010025. [WALDHUBER A, SNYDER G A, ROMMLER F, et al. A comparative analysis of the mechanism of toll-Like receptor-disruption by TIR-containing protein c from uropathogenic escherichia coli[J]. Pathogens, 2016, 5(1):25.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.SNYDER G A, DEREDGE D, WALDHUBER A, et al. Crystal structures of the toll/interleukin-1 receptor (TIR) domains from the brucella protein tcpB and host adaptor TIRAP reveal mechanisms of molecular mimicry. J Biol Chem. 2014;289(2):669–679. doi: 10.1074/jbc.M113.523407. [SNYDER G A, DEREDGE D, WALDHUBER A, et al. Crystal structures of the toll/interleukin-1 receptor (TIR) domains from the brucella protein tcpB and host adaptor TIRAP reveal mechanisms of molecular mimicry[J]. J Biol Chem, 2014, 289(2):669-679.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.SALCEDO S P, MARCHESINI M I, LELOUARD H, et al. Brucella control of dendritic cell maturation is dependent on the TIR-containing protein btp1. PLoS Pathog. 2008;4(2):e21. doi: 10.1371/journal.ppat.0040021. [SALCEDO S P, MARCHESINI M I, LELOUARD H, et al. Brucella control of dendritic cell maturation is dependent on the TIR-containing protein btp1[J/OL]. PLoS Pathog, 2008, 4(2):e21.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.ALAIDAROUS M, VE T, CASEY L W, et al. Mechanism of bacterial interference with TLR4 signaling by brucella toll/interleukin-1 receptor domain-containing protein TcpB. J Biol Chem. 2014;289(2):654–668. doi: 10.1074/jbc.M113.523274. [ALAIDAROUS M, VE T, CASEY L W, et al. Mechanism of bacterial interference with TLR4 signaling by brucella toll/interleukin-1 receptor domain-containing protein TcpB[J]. J Biol Chem, 2014, 289(2):654-668.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.SENGUPTA D, KOBLANSKY A, GAINES J, et al. Subversion of innate immune responses by brucella through the targeted degradation of the TLR signaling adapter, mal. J Immunol. 2010;184(2):956–964. doi: 10.4049/jimmunol.0902008. [SENGUPTA D, KOBLANSKY A, GAINES J, et al. Subversion of innate immune responses by brucella through the targeted degradation of the TLR signaling adapter, mal[J]. J Immunol, 2010, 184(2):956-964.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.ZOU J, BAGHDAYAN A S, PAYNE S J, et al. A TIR domain protein from E. faecalis attenuates MyD88-mediated signaling and NF-kB activation. PLoS One. 2014;9(11):e112010. doi: 10.1371/journal.pone.0112010. [ZOU J, BAGHDAYAN A S, PAYNE S J, et al. A TIR domain protein from E. faecalis attenuates MyD88-mediated signaling and NF-kB activation[J/OL]. PLoS One, 2014, 9(11):e112010.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.ASKARIAN F, VAN SORGE N M, SANGVIK M, et al. A Staphylococcus aureus TIR domain protein virulence factor blocks TLR2-mediated NF-kB signaling. J Innate Immun. 2014;6(4):485–498. doi: 10.1159/000357618. [ASKARIAN F, VAN SORGE N M, SANGVIK M, et al. A Staphylococcus aureus TIR domain protein virulence factor blocks TLR2-mediated NF-kB signaling[J]. J Innate Immun, 2014, 6(4):485-498.] [DOI] [PMC free article] [PubMed] [Google Scholar]

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