2. 江苏省动物重要疫病与人兽共患病防控协同创新中心, 扬州 225009;
3. 广西园丰牧业集团股份有限公司, 钦州 535400
, WANG Heng1,2, CHEN Yanfei1,2, PAN Xiayu3, YUAN Tianmei3, ZHU Guoqiang1,2
, MENG Xia1,2
2. Jiangsu Co-Innovation for Important Animal Infectious Diseases and Zoonose, Yangzhou 225009, China;
3. Guangxi YUANFENG Animal Husbandry Group Co. LTD, Qinzhou 535400, China
沙门菌是一群寄生于人和动物肠道的革兰阴性杆菌，绝大多数沙门菌对人和动物有致病性，引起多种不同临床表现的沙门菌病，是人类食物中毒的主要病原之一，对医学、兽医学和公共卫生均十分重要[1]。沙门菌多种毒力因子(如毒力岛Ⅰ和耐药基因等)受非编码小RNA(small non-coding RNA, sRNA)调控[2-4]。细菌sRNA是一类由50~500个核苷酸组成，在基因组中被转录但不编码蛋白质的RNA分子[5-6]。RyhB是细菌中一种参与调控胞内铁代谢的主要调控元件[7]，当铁匮乏时，RyhB可促进细菌铁摄取蛋白(如shiA和iucD编码的铁载体等含铁蛋白)表达，加快铁元素的摄取[8]，同时限制胞内非必需含铁蛋白生成[9]以及加快铁硫蛋白的储存[10-11]。RyhB最初在大肠杆菌中发现[12]，其大小约为90 bp[13]。之后在沙门菌发现有两种同源性较高、功能类似的sRNA:RyhB-1(又名RyhB或RfrA)和RyhB-2(又名IsrE或RfrB)[14-15]，其大小分别为96和98 bp[16]。最新研究发现，Poly(A)聚合酶可通过添加Poly(A)尾促进外切核糖核酸酶将RNA降解，减少非特异性靶标与RyhB结合，有助于稳定RyhB sRNA及其功能的发挥[17]。沙门菌RyhB除了参与铁代谢调控[16, 18]，还参与抗氧化应激[19-20]、耐酸性[16]、硝酸盐稳态[21-22]以及细菌运动性[23]等多种生命活动过程。本文就沙门菌RyhB生理特征及其调控机制和功能进行阐述。
1 沙门菌RyhB基本特征沙门菌ryhB-1位于yhhX和yhhY基因之间，以与yhhX相反的方向转录。ryhB-2在STM1273下游，与STM1273部分重叠。两种RyhB具有遗传稳定性[24]。研究发现，不同环境压力下沙门菌两种ryhB基因表达机制不同——低铁[25]和氧化应激[19]诱导沙门菌ryhB-1大量表达，而生长稳定期是诱导ryhB-2大量表达的首要因素(图 1A)[16]。沙门菌两种ryhB之间相似性为65%，二者均含有一段33 bp完整保守的同源序列(ACGACATTGCTCACATTGCTTCCAGTATTATTT)[16]，推测两种RyhB可调控同一靶标的转录(如sodB)。研究发现，沙门菌两种RyhB在不同环境下调控不同基因的表达，如acnB、safA和rbsK仅受RyhB-1调控[24]，而参与运动性和趋化性的基因(flgJ、cheY和fliF)仅受RyhB-2调控[23]，表明两种RyhB功能不冗余(图 1B、D)。
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图 1 沙门菌RyhB介导的调控机制 Figure 1 Model of RyhB-mediated regulations in Salmonella |
沙门菌RyhB发挥生物学功能需要以下几种调控因子协助：1)Fur(ferric uptake regulator)蛋白，一种细菌重要的全局性铁感应调控蛋白[26]。高铁条件下，受Fe2+活化Fur蛋白与ryhB基因上“fur盒”序列结合，抑制ryhB的转录[14]。“fur盒”是细菌ryhB启动子区上一段大小为19 bp(GATAATGATAATCATTATC)的保守序列[27]。当细菌胞内铁浓度下降时，Fur-Fe2+活性降低，不再结合“fur盒”序列，使RyhB表达增加。2)Hfq蛋白(Sm-like host factor I)——一种1998年在大肠杆菌中发现的高度保守的RNA伴侣蛋白[28]，其与RyhB结合后，可诱导RyhB二级结构发生改变[29-30]，增加RyhB稳定性，有助于RyhB与靶标mRNA碱基互补配对，抑制靶mRNA翻译[31-32]。3)当RyhB识别靶标形成mRNA-Hfq-RyhB复合体后，细菌核糖核酸酶(ribonucleases)便可将其降解[33]。沙门菌有三种核糖核酸酶可催化sRNA-靶mRNA复合体水解，分别是RNaseE[34-35]、RNaseⅢ[36]和PNPase[37-38]。有报道称，大肠杆菌即使缺失RNaseE，RyhB依然可以抑制sodB mRNA的转录，表明RyhB与靶标mRNA碱基互补配对后可以降低其转录效率[39-40]，但目前在沙门菌还未发现类似的报道。
2 沙门菌RyhB功能研究沙门菌RyhB不仅对维持自身的铁代谢平衡起至关重要的全局性调控作用，还参与沙门菌氧化应激、耐酸性、维持硝酸盐稳态、细菌运动性等方面的调控，在沙门菌致病过程中起重要作用。
2.1 RyhB调控铁代谢铁对于所有形式的生命都是绝对必需的，可参与三羧酸循环、DNA生物合成等重要的生物过程[41-42]。细菌侵袭宿主后，宿主体内的低铁环境是限制病原菌增殖的重要因素，病原菌通过调控一系列铁吸收相关蛋白或调控因子维持体内铁平衡，RyhB在此过程中发挥了重要的调控作用[9, 43]。研究表明，RyhB通过感应环境中可用铁含量的变化，调节铁摄入量，以适应环境变化[44]。沙门菌RyhB调控铁代谢的机制与大肠杆菌相似：当细菌胞内铁匮乏时，Fur蛋白与Fe2+分离后失活，RyhB不受Fur蛋白的抑制而快速表达，与Hfq相结合后，稳固了二级结构使其不易被RNA酶降解，且有助于RyhB识别靶标mRNA并与其结合，从而活化铁载体蛋白的表达。铁载体蛋白合成并分泌到细胞外鳌合铁离子后，被细胞膜上的铁转运蛋白运送到细胞质中，补充胞内铁含量[45-47]。RyhB还可与胞内非必需含铁蛋白等靶标mRNA碱基互补配对，阻抑核糖体结合到mRNA上，降低其翻译效率[48]；被RNA酶识别后形成一个称为RNA降解体的ryhB-靶标mRNA-RNA酶的复合物，随后被RNA酶降解，减少铁消耗。除此之外，RyhB分子还可加快胞内铁储存蛋白如Fe-S蛋白的翻译[10]，将铁储存或加以利用，以维持细菌胞内的铁平衡(图 1C)。
2.2 RyhB调控氧化应激有氧条件下，铁元素以Fe3+的形式存在，既不易获得也不具有毒性。但Fe3+易与氧气产生Haber-Weiss/Fenton反应生成有害的活性氧自由基(ROS)，如超氧化物O2-、H2O2和游离的羟基自由基OH-[9, 49]，可破坏DNA、RNA和细胞膜等[42]。因此，细菌必须根据自身需要，既要维持充足的供应，调控细胞内游离铁达到有效的铁稳态，又要防止铁含量过多产生铁诱导性毒性[43, 50]。研究表明，沙门菌RyhB可参与这种氧化应激调控——用H2O2分别作用于鼠伤寒沙门菌ryhB-1、ryhB-2、ryhB-1/ryhB-2缺失株后，均表现出生长缺陷，且细菌内活性氧物质及蛋白质羟基化的水平升高，NADH/NAD+比例发生改变，这种新陈代谢紊乱表明RyhB-1和RyhB-2在抗H2O2作用过程中具有重要作用。进一步研究表明，此过程中ryhB-1和ryhB-2表达具有OxyR依赖性。OxyR通过与ryhB-1和ryhB-2的启动子区直接相互作用促进ryhB-1和ryhB-2表达，起到抗H2O2处理的作用[19]。沙门菌fur缺失株中，ryhB缺失可增强fur缺失株抗H2O2的能力，表明RyhB-1和RyhB-2抗氧化应激的作用受到Fur蛋白的影响，推测与ryhB缺失引起含铁蛋白表达下调，导致细胞内游离铁含量增加有关[51]。
氧化应激时，需氧菌通过呼吸链减少NADH的产生，可限制ROS物质的生成，降低对细胞的损伤[52]。而RyhB可调控NADH/NAD+的比例起抗氧化应激作用。因为沙门菌两种RyhB都参与调控与三羧酸循环相关蛋白(如sdhCDAB，编码琥珀酸脱氢酶)的mRNA(图 1C)[13, 53]。研究发现，H2O2作用后，沙门菌中ryhB的缺失可引起NADH水平增加[19]。因此，推测RyhB通过调控电子通量平衡和细胞内ROS水平相关的基因发挥抗氧化作用。
2.3 RyhB调控耐酸性有报道称，fur缺失的福氏志贺菌RyhB可抑制耐酸性所必需的ydeP基因(编码氧化还原酶)[54]。鼠伤寒沙门菌fur缺失后在酸性环境中的存活率与野生株相比明显降低；但同时缺失fur和ryhB-1可轻微提高细菌的存活率，同时缺失fur和ryhB-2可进一步提高这种存活率；而同时缺失fur、ryhB-1和ryhB-2则可显著提高细菌的存活率[16]，表明在鼠伤寒沙门菌fur缺失株中，RyhB-1和RyhB-2可抑制细菌在酸性环境中存活。值得一提的是，fur、ryhB-1和ryhB-2 同时缺失可显著提高细菌的存活率，但其存活率依然明显低于野生株，表明鼠伤寒沙门菌中存在受Fur蛋白调控对耐酸性起重要作用的非RyhB依赖性相关基因。
2.4 RyhB调控硝酸盐稳态当细菌厌氧呼吸时，硝酸盐(NO3-)、亚硝酸盐(NO2-)等无机化合物可作为末端电子受体[55-56]。研究表明，沙门菌硝酸盐稳态不仅受到Fur蛋白的调控，还与RyhB密切相关。在fur缺失株中，两种ryhB失活可显著提高narP基因的表达，显著下调narL基因的表达；只缺失一种ryhB基因，narP和narL基因表达没有变化[21]，表明两种RyhB在Fur蛋白调控narP和narL基因的机制中影响硝酸盐代谢平衡。
2.5 RyhB影响细菌运动性Kim和Kwon[23]对鼠伤寒沙门菌ryhB缺失株的转录组进行比较分析发现，与野生组相比，缺失ryhB-2后参与细菌运动性和趋化性的flgJ、cheY和fliF的三个基因表达下调(图 1D)。运动性试验结果证明，ryhB-2缺失可降低细菌的运动性，而过表达ryhB-2时，细菌运动性可恢复至野生株水平。而在肠炎沙门菌中，ryhB单缺失均可降低细菌的运动性，ryhB双缺失则细菌运动能力下降更为明显。qRT-PCR比较发现，与野生株相比参与细菌运动能力相关的鞭毛亚单位基因fliC表达下调[57]，表明肠炎沙门菌ryhB-1和ryhB-2缺失均可下调fliC的表达，降低细菌的运动性。
2.6 RyhB影响沙门菌毒力细菌生物被膜在耐药性以及抵御宿主免疫等方面具有重要作用，是细菌毒力的重要组成[58-59]。本实验室的研究表明肠炎沙门菌RyhB-1和RyhB-2可影响肠炎沙门菌生物被膜的形成能力，且ryhB双缺失株的生物被膜形成能力比ryhB单缺失株明显降低[57]，推测沙门菌RyhB-1和RyhB-2可影响沙门菌的毒力。同时肠炎沙门菌ryhB-1和ryhB-2缺失导致对肠上皮细胞的黏附和侵袭能力减弱[57]，表明RyhB可增强沙门菌的侵袭力进而调控沙门菌的毒力。动物试验表明，ryhB-1和ryhB-2缺失后肠炎沙门菌对1日龄清远麻鸡半数致死量显著升高，毒力减弱，且ryhB双缺失株比单缺失毒力减弱更明显[60]，表明两种RyhB均可影响沙门菌毒力。
3 展望沙门菌是一类重要的人畜共患致病菌，其血清型众多，宿主谱广泛，研究沙门菌的致病机制以及防治沙门菌病具有重要的公共卫生意义。探索了解沙门菌RyhB调控机制，有助于为以后开发针对sRNA药物提供理论基础。目前针对沙门菌RyhB的研究还停留在RyhB参与的铁稳态调控、抗氧化应激、耐酸性、维持硝酸盐稳态和细菌运动性等功能，未来针对沙门菌RyhB的研究可集中在继续深入挖掘RyhB-1和RyhB-2调控的靶标基因方面，揭示其调控机制。此外，根据细菌所处环境变化不同，沙门菌诱导RyhB表达机制也不同，填补环境信号因子对沙门菌诱导RyhB表达机制的研究也是未来的一个研究热点；除此之外，沙门菌RyhB-1和RyhB-2可调控同一靶标但功能不冗余，二者的相互关系也有待深入研究。相信随着高通量测序技术的不断发展和sRNA研究手段的不断进步，沙门菌RyhB调控机制会越来越清晰，RyhB参与其他转录后加工和翻译调控的生命过程也会不断地被发现和认识。
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