您好, 访客   登录/注册

金黄色葡萄球菌的群体效应研究进展

来源:用户上传      作者:

  摘要:金黄色葡萄球菌(Staphylococcus aureus)中已知的群体效应系统是Agr系统和LuxS/AI-2系统,其在细菌浓度等于或大于1×107 CFU/mL时会被激活,通过调控相应基因,间接或直接调控生物被膜的产生和降解、细菌毒素的分泌以及细菌的生长。综述了金黄色葡萄球菌的群体效应研究进展,旨在为今后对金黄色葡萄球菌的研究寻找新方向,金黄色葡萄球菌致病性及生物被膜的形成与金黄色葡萄球菌的群体效应系统之间存在必然联系。
  关键词:群体效应;金黄色葡萄球菌(Staphylococcus aureus);生物被膜
  中图分类号:R378.1+1         文献标识码:A
  文章编号:0439-8114(2020)04-0010-03
  Abstract: The known group effect systems in Staphylococcus aureus are the Agr system and LuxS/AI-2 system, which are activated when the bacterial concentration is equal to or greater than 1×107 CFU/mL, and indirectly or directly regulates the production and degradation, bacterial toxin secretion, and bacterial growth of the biofilm  by regulating the corresponding genes. The research progress of the group effects of Staphylococcus aureus were reviewed, and a new direction for future research on Staphylococcus aureus was found. There is an inevitable relationship between the pathogenicity of Staphylococcus aureus and the formation of biofilms and the quorum sensing system of Staphylococcus aureus.
  Key words: quorum sensing; Staphylococcus aureus; biofilms
  金黃色葡萄球菌(Staphylococcus aureus,SA)是造成社区和医院获得性感染的常见病原菌之一,是导致人血液感染的主要原因之一,可以感染各种器官从而引起感染性心内膜炎、化脓性关节炎和骨髓炎[1]。SA可躲避宿主的免疫系统,并不断对抗生素产生抗性[2],给治疗带来很大的阻碍。
  细菌通过对环境中信号分子的感应而进行一系列基因调控的现象,称为群体效应(QS),也称为自诱导[3]。细菌之间通过某些其自身分泌的次级代谢产物作为信号分子,在细菌达到某个阈浓度的时候通过对这些信号分子的识别而产生基因表达,从而产生一系列生理变化[4,5]。
  目前的试验表明,SA的QS系统与SA的毒性和耐药性密切相关[6,7]。因此,对SA的QS系统进行干扰从而治疗SA感染,已成为目前新兴的研究热点[8]。本研究就目前对金黄色葡萄球菌的QS系统对生物被膜及金黄色葡萄球菌的QS机制进行了综述,旨在为今后对金黄色葡萄球菌的毒性及耐药性相关研究提供参考。
  1  SA的QS调控网络
  目前发现SA至少有2个QS系统,按照其信号分子的种类划分,分为短肽类(AIPs)的Agr系统[9]和呋喃硼酸二酯(AI-2)的LuxS/AI-2系统[10]。
  Agr系统是葡萄球菌属中已知的QS系统,其与SA的毒性因子合成以及细胞表面黏附性有着密切联系[11]。agr基因座大小为3.5 kb,由RNAⅡ和RNAⅢ 2个不同的转录单位组成,其分别由P2和P3启动子激活。RNAⅡ基因座包含4个基因,分别是agrB、agrD、agrC和agrA。agrD负责编码胞外的可作为agr的QS信号分子的前肽AIPs;agrB的基因产物是一种跨膜肽链内切酶,用于引入内脂修改、C端裂解和AIP的传出;agrC和agrA基因编码1个双组分信号转导系统,包括1个组氨酸激酶传感器AgrC、1个可以结合AIP并使之磷酸化的跨膜蛋白和其相关的响应调节器AgrA[12]。在AgrC的磷酸化激活后,AgrA结合RNAⅡ上的P2启动子区域和RNAⅢ上的P3启动子区域[13],并进一步激活RNAⅢ,然后RNAⅢ翻译产生由hld编码的δ毒素[14]。
  LuxS/AI-2系统是以呋喃硼酸二酯(AI-2)为信号分子的QS系统,起初从哈氏弧菌中发现[15],随后发现广泛存在于大多数细菌中,被推测为菌种间的通用语言的1个QS系统[16]。AI-2是细菌甲基循环中的副产物。在甲基循环中,s-腺苷甲硫氨酸(SAM)被转变成S-腺苷高半胧氨酸(SAH),SAH随后被5’-甲硫腺苷/S-腺苷高半胱氨酸核苷酶(Pfs)水解成S-核糖高半胱氨酸(SRH)和腺嘌呤,AI-2的合成代谢酶LuxS将SRH催化成AI-2的前体化合物4,5-二羟基-2,3-戊二酮,即DPD。DPD自身不稳定,进一步转化生成AI-2[17]。AI-2与SA具有多种致病性,如生物被膜的形成、对抗生素敏感性以及毒性有着紧密的联系[9,18]。
  2  SA的QS系统对SA生物被膜的影响
  细菌生物被膜最早在1978年由Costerton等[19]提出,之后学界普遍认为细菌生物被膜是细菌为了适应环境而分泌的一种多糖复合物,用于黏附接触物体的表面,并保护膜中的细菌免受抗菌药物的影响,同时分泌抗生素灭活酶而使抗菌药物作用下降[20]。生物被膜的形成过程主要分为几个步骤:①细菌黏着在非生物或者宿主基质蛋白表面,然后聚集成多细胞结构,并形成膜状;②增殖并成长;③分解、扩散至其他部位,然后又从第一步开始[21]。近年来的研究表明,细菌QS系统在细菌生物被膜的生成中起重要作用[22]。具体机制是,LuxS/AI-2系统激活后会激活Agr系统,AgrA激活产生RNAⅢ,RNAⅢ进一步与其靶蛋白TRAP结合,促进SA的生物被膜生成[23]。其中,LuxS/AI-2系统可以通过对icaR作用而影响ica通路[9],从而影响生物被膜的形成及扩散;Agr系统也可以通过影响ica通路而影响生物被膜[24],还可以独立地通过agrA通路影响生物被膜[25]。   Agr系统在SA生物被膜的形成及扩散中起重要作用。Agr控制蛋白酶,在体外通过降解生物被膜黏附素的蛋白组件而影响生物被膜的扩大,并加大生物被膜的扩散程度[26]。低活性的Agr生成的少量PSM肽通过干扰生物被膜黏附素PIA和细胞表面的相互作用,使细菌集合长成大的集合体[27]。在菌浓度低时,Agr系统会抑制SA的生物被膜形成,从而增加SA的流动和数量,直至高浓度时产生毒性因子并促进生物被膜形成。进一步研究发现,Agr上有许多影响生物被膜生成的因子,如CodY、SarA等[28]。CodY是Agr系统的负调节因子,CodY间接影响Agr系统的RNAⅢ转录,CodY的增多会导致AIPⅢ堆积,从而使生物被膜生成减少[29]。SarA是影响生物被膜生成的主要因子之一,Beenken等[30]指出,在SA的生物被膜生成过程中,Agr是SarA的上级,Agr会使SarA对生物被膜的生成产生更多作用。
  AI-2通过对二元信号系统KdpDE作用,抑制kdpD和kdpE的转录水平,使和cap结合的kdpE量减少,使荚膜多糖生成减少,从而抑制生物被膜的合成[31]。Yu等[9]通过对LuxS缺失SA株添加不同剂量的DPD,LuxS缺失SA株与正常SA株中的生物被膜生成量对比,发现添加DPD后LuxS缺失SA株的生物被膜量会减少,进一步对加入DPD后LuxS缺失SA株的icaA和icaR基因的表达量研究发现,AI-2可以通过激活icaR而抑制icaADBC的表达,从而抑制了生物被膜生成。
  3  SA的QS系统对SA毒力因子的影响
  细菌的QS系统除了与生物被膜相关之外,还主要与细菌毒性有关。QS系统是一种319氨基酸组成的β-桶形成孔毒素,与宿主细胞膜上的解聚素和金属蛋白酶10(ADAM10)受体结合[25,26]。Hla与人体中的多种葡萄球菌感染有关。在葡萄球菌感染的肺炎动物模型[27,28]中发现,皮肤和软组织感染[29,30]、血管内感染[9]中,与标准型菌株相比,hla基因缺陷突变株都表现出更低的致病性。
  酚溶调制肽(PSM)是一种肽类毒素家族,在Agr控制的毒力因子中是惟一受AgrA直接控制的毒力因子[9],其在葡萄球菌的非传染性活动中起重要作用[14]。在PSM类中,在金黄色葡萄球菌的psmα基因座中编码的蛋白,尤其是PSMα3,对多种细胞类型包括嗜中性粒细胞、巨噬细胞、成骨细胞和红细胞具有较强的促炎和溶解性[32]。这导致PSMα肽类对急性金黄色葡萄球菌感染,如皮肤和软组织感染、败血症和骨髓炎等有较强的影响[33,34]。
  4  讨论
  近年来抗生素滥用,金黄色葡萄球菌的耐药性成为目前越来越棘手的治疗阻碍。对金黄色葡萄球菌QS系统的研究成为一个新的研究方向。然而QS系统十分复杂,目前尚未能绘制出完整的金黄色葡萄球菌QS系统,但已有的研究表明,金黄色葡萄球菌的致病性与其QS系统相关,说明今后對其的抗菌研究可以向其自身Agr QS系统和LuxS QS系统进行。
  参考文献:
  [1] RASMUSSEN R V,JR F V,SKOV R,et al. Future challenges and treatment of Staphylococcus aureus bacteremia with emphasis on MRSA[J].Future microbiology,2011,6(1):43-56.
  [2] ROOIJAKKERS S H,VAN KESSEL K P,VAN STRIJP J A. Staphylococcal innate immune evasion[J].Trends in microbiology,2005,13(12):596-601.
  [3] FUQUA W C,WINANS S C,GREENBERG E P. Quorum sensing in bacteria:The LuxR-LuxI family of cell density-responsive transcriptional regulators[J].Journal of bacteriology,1994, 176(2):269-275.
  [4] ENGEBRECHT J,NEALSON K,SILVERMAN M. Bacterial bioluminescence:Isolation and genetic analysis of functions from Vibrio fischeri.[J].Cell,1983,32(3):773-781.
  [5] CAO J G,MEIGHEN E A. Purification and structural identification of an autoinducer for the luminescence system of Vibrio harveyi.[J].Journal of biological chemistry,1989,264:21670-21676.
  [6] YARWOOD J M,BARTELS D J,VOLPER E M,et al. Quorum sensing in Staphylococcus aureus biofilms[J].Journal of bacteriology,2004,186(6):1838-1850.
  [7] QUECK S Y,JAMESON-LEE M,VILLARUZ A E,et al. RNAIII-independent target gene control by the quorum-sensing system:Insight into the evolution of virulence regulation in Staphylococcus aureus[J].Molecular cell,2008,32(1):150-158.   [8] CASTILLO-JU?魣REZ I,MAEDA T,MANDUJANO-TINOCO E A,et al. Role of quorum sensing in bacterial infections[J].World journal of clinical cases,2015,3(7):575-598.
  [9] YU D,ZHAO L P,XUE T,et al. Staphylococcus aureus autoinducer-2 quorum sensing decreases biofilm formation in an icaR-dependent manner[J].BMC microbiology,2012,12:288.
  [10] PENG H L,NOVICK R P,KREISWIRTH B,et al. Cloning,characterization, and sequencing of an accessory gene regulator (agr) in Staphylococcus aureus[J].Journal of bacteriology,1988, 170(9):4365-4372.
  [11] THOENDEL M,KAVANAUGH J S,FLACK C E,et al. Peptide signaling in the staphylococci[J].Chemical reviews,2011,111(1):117-151.
  [12] GRAY B,HALL P,GRESHAM H. Targeting agr-and agr-Like quorum sensing systems for development of common therapeutics to treat multiple gram-positive bacterial infections[J].Sensors,2013,13(4):5130-5166.
  [13] GEISINGER E,CHEN J,NOVICK R P. Allele-Dependent differences in quorum-sensing dynamics result in variant expression of virulence genes in Staphylococcus aureus[J].Journal of bacteriology,2012,194(11):2854-2864.
  [14] CHEUNG G Y C,JOO H S,CHATTERJEE S S,et al. Phenol-soluble modulins-critical determinants of staphylococcal virulence[J].Fems microbiology reviews,2014,38(4):698-719.
  [15] BASSLER B L,GREENBERG E P,STEVENS A M. Cross-species induction of luminescence in the quorum-sensing bacterium Vibrio harveyi.[J].Journal of bacteriology,1997,179(12):4043-4045.
  [16] WINZER K,HARDIE K R,WILLIAMS P. LuxS and autoinducer-2:Their contribution to quorum sensing and metabolism in bacteria[J].Advances in applied microbiology,2003,53(4):291-396.
  [17] 趙丽萍.金黄色葡萄球菌中AI-2群体感应系统的调控[D].合肥:中国科学技术大学,2010.
  [18] XUE T,ZHAO L P,SUN B L,et al. LuxS/AI-2 system is involved in antibiotic susceptibility and autolysis in Staphylococcus aureus NCTC 8325[J].International journal of antimicrobial agents,2013,41(1):85-89.
  [19] COSTERTON J W,GEESEY G G,CHENG K J. How bacteria stick[J].Scientific American,1978,238(1):86-95.
  [20] LI J,XIE S Y,AHMED S,et al. Antimicrobial activity and resistance:Influencing factors[J].Frontiers in pharmacology,2017, 8:364.
  [21] KUDVA I T,CORNICK N A,PLUMMER P J,et al. Virulence mechanisms of bacterial pathogens,fifth edition[M].Atlanta:American society for microbiology,2016.
  [22] TOWNSLEY L,SHANK E A. Natural-product antibiotics:Cues for modulating bacterial biofilm formation[J].Trends in microbiology,2017,25(12):1016-1026.   [23] KIRAN M D,ADIKESAVAN N V,CIRIONI O,et al. Discovery of a quorum-sensing inhibitor of drug-resistant staphylococcal infections by structure-based virtual screening[J].Molecular pharmacology,2008,73(5):1578-1586.
  [24] AUDRETSCH C,LOPEZ D,SRIVASTAVA M,et al. A semi-quantitative model of quorum-sensing in Staphylococcus aureus,approved by microarray meta-analyses and tested by mutation studies[J].Molecular biosystems,2013,9(11):2665-2680.
  [25] FOSTER T J,GEOGHEGAN J A,GANESH V K,et al. Adhesion,invasion and evasion:The many functions of the surface proteins of Staphylococcus aureus[J].Nature reviews microbiology,2014,12(1):49-62.
  [26] LAUDERDALE K J,BOLES B R,CHEUNG A L,et al. Interconnections between sigma B,agr,and proteolytic activity in Staphylococcus aureus biofilm maturation[J].Infection & immunity,2009,77(4):1623-1635.
  [27] DASTGHEYB S S,VILLARUZ A E,LE K Y,et al. Role of phenol-soluble modulins in formation of Staphylococcus aureus biofilms in synovial fluid[J].Infection & immunity,2015,83(7):2966-2975.
  [28] RUTHERFORD S T,BASSLER B L. Bacterial quorum sensing:Its role in virulence and possibilities for its control[J]. Cold spring harbor perspectives in medicine,2012,2(11):705-709.
  [29] ROUX A,TODD D A,VEL?魣ZQUEZ J V,et al. CodY-Mediated regulation of the Staphylococcus aureus agr system integrates nutritional and population density signals[J].Journal of bacteriology,2014,196(6):1184-1196.
  [30] BEENKEN K E,MRAK L N,GRIFFIN L M,et al. Epistatic relationships between sarA and agr in Staphylococcus aureus biofilm formation[J].PloS one,2010,5(5):e10790.
  [31] ZHAO L P,XUE T,SHANG F,et al. Staphylococcus aureus AI-2 quorum sensing associates with the KdpDE two-component system to regulate capsular polysaccharide synthesis and virulence[J].Infection & immunity,2010,78(8):3506-3515.
  [32] RASIGADE J P, TROUILLET-ASSANT S,FERRY T,et al. PSMs of hypervirulent Staphylococcus aureus act as intracellular toxins that kill infected osteoblasts[J].PLoS one,2013,8:e63176.
  [33] WANG R,BRAUGHTON K R,KRETSCHMER D,et al. Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA[J].Nat Med,2007,13:1510-1514.
  [34] CASSAT J E,HAMMER N D,CAMPBELL J P,et al.A secreted bacterial protease tailors the Staphylococcus aureus virulence repertoire to modulate bone remodeling during osteomyelitis[J].Cell host microbe,2013,13:759-772.
转载注明来源:https://www.xzbu.com/8/view-15235549.htm