摘要
CsgD作为沙门氏菌生物膜形成的核心调控蛋白,通过调控生物膜的关键组成成分——纤维素和卷曲菌毛的表达,进而影响生物膜的形成。近年来,科学界在剖析沙门氏菌CsgD蛋白的调控网络及其复杂影响因素方面取得了较大进展。本文聚焦于CsgD在沙门氏菌生物膜形成过程中的调控功能,系统梳理了环境因素如何影响CsgD的功能表达,并全面分析了多种调控因子对CsgD的多层次调控作用,旨在加深对沙门氏菌生物膜形成机制及其调控网络的理解,并为后续研究提供可能的方向。
沙门氏菌(Salmonella)属于肠杆菌科,是一种革兰阴性杆状细
在沙门氏菌生长过程中,随着环境中营养物质的消耗,其生长速度减慢,并伴随有细胞外聚合物(extracellular polymeric substances, EPS)的分泌,这些EPS促使沙门氏菌形成复杂的多细胞聚集体,即生物膜(biofilm),该结构以细胞间紧密交织、增强长期存活能力和耐药性为显著特
CsgD,作为一个核心调控蛋白,主要通过激活csgB、csgA和adrA基因从而影响生物膜中的关键成分卷曲菌毛(curli)和纤维素(cellulose)的表达,在生物膜的形成过程中发挥着至关重要的调控作
1 CsgD调控沙门氏菌生物膜形成
1.1 CsgD的核心调控作用
生物膜的核心组成成分之一为EPS,该复合物关键组成因素为卷曲菌毛、纤维素、生物膜相关蛋白(biofilm associated proteins, Bap)和O抗原多糖

图1 csgD对生物膜形成的调控网络和影响csgD表达的细胞内外部因素。csgD调控纤维素和卷曲菌毛的合成,以及影响csgD表达的细胞内外因素(温度、营养、氧分压、渗透压、pH等)和OmpR、IHF、H-NS等细胞内调控因子。
Figure 1 Regulatory network of csgD on biofilm formation and intracellular and external factors affecting csgD expression. csgD regulates cellulose and curli, as well as the intracellular and extracellular factors that affect csgD expression, including extracellular factors such as temperature, nutrition, oxygen partial pressure, osmolal pressure, pH, and intracellular regulators such as OmpR, IHF, and H-NS.
1.1.1 卷曲菌毛表达途径
卷曲菌毛作为一种独特的淀粉样蛋白纤维结构,在细菌表面形成并广泛参与细菌与环境的相互作用。这些复杂的纤维结构由特定的基因簇——csgBAC-csgDEFG操纵子编码,体现了基因表达与细胞外基质构建之间的高度协
1.1.2 纤维素合成途径
纤维素即αβ-1,4-d-葡萄糖聚合物,与生物膜中的其他胞外基质成分相互交织,共同构建了一个复杂的三维网络结构,促进细胞间相互作用,保护细胞使其免受不利环境的影响;纤维素的合成受到bcsABZC-bcsEFG操纵子的编码控制,这一操纵子的精确表达对于细菌在特定生态位(如支持生物膜生长的环境)中构建稳定且功能性的纤维素支架至关重
纤维素的生物合成也受到CsgD的正向调控。CsgD激活adrA的转录后,AdrA通过与细菌纤维素合成操纵子bcsABZC-bcsEFG的一个或多个基因产物的直接相互作用,在转录后水平上激活纤维素的合成;或通过其C末端的GGDEF结构域产生c-di-GMP,从而激活纤维素合成酶BcsA,激活纤维素的生物合
1.2 CsgD表达的双稳态特征
CsgD在生物膜细菌群落中的表达存在双稳态特征,即CsgD的表达水平在细菌群体中呈现出显著的异质性,细菌群落内自然分化为高表达与低表达CsgD的2个亚群,这一独特的表达模式不仅体现了细菌在能量利用上的高效策略,还可能为细菌群落赋予额外的适应性和进化上的优
这种双稳态的CsgD表达模式为沙门氏菌生物膜构建了一种精细的资源分配机制,它确保了生物膜结构的稳固性,同时保留了细菌群落的多样性和适应性,使得整个群落能够更灵活地应对环境变
2 影响csgD表达的环境因素
环境因素如温度、营养、氧分压、渗透压和pH等对生物膜EPS的产生及其化学组成的调控具有显著作
Factors | Regulation of csgD | References | |
---|---|---|---|
Positive regulation | Negative regulation | ||
Extracellular factors | |||
Temperature | Below 30 °C | Higher than 30 °C |
[ |
Nutritional conditions | Nutritional limitation | Glucose |
[ |
Partial pressure of oxygen | Microoxygen condition | Aerobic and anaerobic conditions |
[ |
pH | Alkaline condition (pH 8.5) | Acidic conditions (pH 5.5) |
[ |
Osmotic pressure | Low osmotic pressure | High osmotic pressure |
[ |
Intracellular factors | |||
OmpR | D1 and D2 binding sites | D3-D7 binding sites |
[ |
MltE and MltC | Up-regulation of transcriptional activity | - |
[ |
IHF | IHF1 binding sites | IHF3 binding site |
[ |
H-NS | - | Repression of transcription |
[ |
- means there are no reference.
2.1 温度
在沙门氏菌和大肠杆菌中,csgD基因的表达模式与生物膜构建过程紧密关联于环境温度的变化,具体而言,当环境温度降至30 ℃以下时,csgD基因的表达被显著激活,进而促进生物膜的形成;相反,在较高温度条件下,此过程则受到明显的抑
Römling
2.2 营养
葡萄糖在体外环境中被确认为是抑制csgD表达和生物膜形成的重要因素,其存在显著削弱了这些过程的启动,相反,营养限制状态被视为激活csgD转录的早期信号之
2.3 氧分压
在沙门氏菌中,氧分压对csgD转录活性的影响在细菌生物学中展现出复杂的环境依赖性:在无盐LB培养基中,当菌株在微氧条件下培养时,csgD的转录活性达到最大,这表明有限的氧气供应对csgD的表达和沙门氏菌生物膜形成具有的促进作用;而在好氧和厌氧环境下,csgD的转录活性明显降低,仅有0-30%的活性,揭示了氧气浓度对csgD转录的双向调控作
2.4 pH值
在沙门氏菌中,pH值对CsgD的表达和生物膜的形成具有重要影响。研究表明,碱性环境(pH 8.5)显著增强了csgD启动子的活性,进而促进了生物膜相关基因的表达,这对于沙门氏菌在碱性条件下的生存和适应至关重要;相反,在酸性环境(pH 5.5)中,csgD启动子的活性受到抑制,导致生物膜形成减弱,这反映了沙门氏菌在面对不利pH条件时的一种适应性策
值得注意的是,在酸性条件下,细菌csgD启动子的活性受到抑制的具体机制尚未完全明确,但研究发现插入点突变会改变酸性环境对其活性的抑制作用,如在野生型鼠伤寒沙门氏菌株14028-4r的csgD启动子区域-17后插入单个T,将高度调控的野生型启动子转化为半组成型启动子(emiconstitutive promoter, scPcsgD),这种半组成型启动子在酸性条件下(pH 5.5)表现出较高的活性,而在碱性条件下(pH 8.5)活性相对较低,同时,由于scPcsgD的固有活性较高,即使在不利的环境pH下,CsgD和生物膜形成也能保持一定程度的表
2.5 渗透压
在沙门氏菌中,渗透压是一个关键的环境因素,它通过EnvZ/OmpR和CpxA/CpxR双组分信号系统来精细调控csgD及其相关基因(如csgBAC)的表达,这种调控机制在细菌的不同生长阶段展现出不同的效
在细菌生长的迟缓期和对数期,渗透压对CsgD的表达有显著影响:当处于低渗透压环境时,EnvZ的活性降低,导致外膜蛋白R (outer membrane protein R, OmpR)保持低磷酸化状态,低水平的OmpR-P激活ompF的转录,OmpF的较大孔隙有利于外部环境中较低浓度营养物质向细胞内部扩散,同时低水平的OmpR-P结合到csgD转录起始位点上游的高亲和力结合位点(-50.5 bp),从而促进csgD的转录,随后激活csgDEFG表达,进而增加csgBA的表达,这种机制有助于细菌在低渗透压条件下增强生物膜的形成能力,以更好地适应环境;相反,在高渗透压条件下,CpxA/CpxR和EnvZ/OmpR这2个信号系统均被激活,从而导致OmpR-P和CpxR-P水平升高,OmpR-P的水平升高可以抑制ompF的转录,并激活ompC的转录,此时,OmpC的较小孔隙会阻碍细胞外大分子的进入,CpxR-P和OmpR-P分别结合到csgD启动子的不同位点,这种结合模式会干扰RNA聚合酶的结合,从而导致csgD的转录受到抑
随着细菌的生长进入稳定期(如生长18 h后),渗透压对CsgD及其相关基因表达的影响变得有限,虽然高渗透压仍然能够激活CpxA/CpxR信号系统,但这种激活并不再进一步影响csgD和csgBAC的表
同时,在EnvZ/OmpR和CpxA/CpxR双组分信号系统中,也存在一定的相互作用。CpxA对OmpR有弱磷酸化作用,但在EnvZ存在时,与EnvZ的强磷酸化作用相比,CpxA对OmpR的弱磷酸化作用不显现,此时,EnvZ激酶和磷酸酶活性之间的平衡能够使OmpR的磷酸化速度和去磷酸化过程都保持在高水平,使得OmpR-P处于中间水平;当EnvZ不存在、CpxR与CpxA同时存在时,CpxA可对CpxR和OmpR进行磷酸化,由于CpxR能够与OmpR竞争,从而导致CpxA磷酸化OmpR的过程被抑制,OmpR-P水平降
3 多种调节因子调控csgD表达
在细菌生物膜的构建过程中,多种调节因子发挥着关键作用,这些调节因子不仅可诱导生物膜的形成,还深刻影响着关键调控基因csgD的表达水平。csgD的表达机制复杂且精细,受到一系列细胞内调节蛋白的严密监控,每种调节蛋白专门响应特定的环境参数或条件变
在沙门氏菌中,csgBAC和csgDEFG操纵子之间的基因间区即是csgD的启动子,也为多个转录因子提供了结合位点,这一区域因此成为了一个信息整合的中心,能够汇集并整合来自不同环境源头的信号,协调调控生物膜形成相关基因的表达。截至目前,已发现至少有48个转录因子与csgD启动子区域强结合,其中OmpR、裂解性转糖基酶E (lytic transglycosylase E, MltE)、裂解性转糖基酶C (lytic transglycosylase C, MltC)、整合作用宿主因子(integration host factor, IHF)和组蛋白样类核结构蛋白(histone-like nucleoid structuring protein, H-NS)等转录因子的调控作用目前已较为明确(
3.1 OmpR
反应调节因子OmpR,作为EnvZ/OmpR双组分系统中的核心响应元件,其磷酸化状态直接调控着csgD基因的转录活性,在面临如低渗透压和酸性环境等外部刺激时,OmpR经历磷酸化修饰,随后与csgD启动子区域的特定序列紧密结合,显著促进该基因的转录增
在特定环境条件下,如有氧环境中,高水平的OmpR通过与位于csgD启动子上游-34 bp至-220 bp区间内的4个额外结合位点(D3-D6)的相互作用,转而抑制CsgD的表达,新近发现的D7位点在微需氧条件下也展现出类似的抑制作用,这种复杂的调控机制使得细菌能够精准且灵活地根据外界环境的变化调整csgD基因的表达水平,以优化其生存策略和适应能
3.2 MltE和MltC
MltE和MltC作为2种关键的裂解性转糖基酶(lytic transglycosylase, LTG),通过调控csgD的表达来影响生物膜的生成,在沙门氏菌ΔmltE和ΔmltC双突变体的研究中发现,相较于野生型菌株,这些突变体中的csgD的mRNA水平下降至约为野生型的47%,且在刚果红琼脂平板上生长24 h后出现白色光滑的菌落外观,这一结果明确指出了这2种酶在csgD表达调控中的重要作
尽管已知RpoS和OmpR是调控沙门氏菌生物膜生成的重要因素,但研究发现RpoS和OmpR的过表达未恢复ΔmltEΔmltC双突变体的CsgD表达,所以它们并未直接参与MltE和MltC介导的csgD表达调控路径;然而,在ΔmltEΔmltC突变体中过表达二鸟苷酸环化酶时,CsgD表达上调,表明细胞内第二信使c-di-GMP的积累能够补偿部分ΔmltEΔmltC双突变体对rdar形态及CsgD表达的影响,这表明了c-di-GMP信号传导可能位于MltE和MltC调控路径的下游,其作为关键的调控节点,在调节生物膜相关基因如csgD的表达中发挥着不可替代的作
Son
3.3 IHF
IHF作为一种在细菌中广泛存在且高度丰富的组蛋白样异二聚体蛋白,由2-10 kDa的同源亚基构成,是多种细菌生理活动不可或缺的结构成分,IHF通过与csgD启动子区内的特定DNA序列特异性结合,从而调控csgD基因的转录激活或抑制状态,进而影响生物膜的形
针对鼠伤寒沙门氏菌的IHF突变体研究表明,与野生型相比,突变体在刚果红琼脂上展现出rdar形态的细菌数量显著减少,且这一现象在不同温度条件下均保持稳定,近年的一些的研究还揭示了IHF在不同氧气浓度条件下的特定作用模式,即在液体微氧环境中,IHF突变株的csgD转录活性显著下降至野生型菌株的1/3,而在充分有氧的培养条件下,其活性则未见明显变
3.4 H-NS
H-NS是一种分子量为15.4 kDa的DNA结构蛋白,它在细菌(特别是革兰氏阴性菌)中扮演着基因表达调控的重要角色,主要通过转录水平的沉默机制来实
H-NS对csgD基因的调控可能是细菌适应不同环境条件的一种机制,并且可能因具体环境条件的不同而有所差异;在细菌生长稳定期,IHF水平的增加可能会抵消H-NS的抑制作用,从而增加csgD的转录;细菌中的第二信使c-di-GMP能够通过与H-NS结合,封闭其部分DNA结合位点,从而解除H-NS对csgD基因表达的抑制作
4 csgD启动子区突变的影响
当前研究表明,沙门氏菌csgBAC-csgDEFG操纵子基因间区的755 bp核苷酸序列内存在多个位点的点突变现象,这些突变对csgD基因的转录活性产生了显著影响,具体而言,-80A>C和-189A>G双突变导致了csgD转录活性的降低,-80A>C和-189A>G双突变株在刚果红琼脂培养基中培养后形成淡红色菌落,菌落表面有不完整的皱纹图案;-47T>C突变直接失活了csgD的启动子,在刚果红琼脂培养基中培养后呈现rdar阴性,形成白色光滑型菌落;-17至-18位之间的T插入突变以及-44G>T突变均被证实能够显著上调csgD的转录活性,在刚果红琼脂培养基中培养后表现出明显的菌落形态类型,呈现出较野生株更为巨大的rdar菌落形态,这种上调不受温度和σ因子RpoS表达的影
csgD基因启动子区-44G>T点突变是由Römling等在1998年首次发现的,这种与沙门氏菌生物膜形成能力增强有关点突变先前仅在极个别的菌株中被发现,但近期有研究报道,携带此点突变的菌株近年来在我国多地广泛流行并已形成独立的流行克隆,具有国际传播的潜力,且该克隆的耐多药能力和生物膜形成能力均显著增
5 总结与展望
沙门氏菌生物膜的形成是一个高度复杂的分子过程,这一过程涵盖了纤维素、卷曲菌毛等多种关键组分的参与。其中,CsgD作为调控生物膜形成的核心转录因子,其表达受到多种环境因素的精密调控,这些环境因素通过直接或间接的方式作用于CsgD的表达,从而显著影响生物膜的结构与功能。
尽管当前已有诸多研究揭示了环境因素和多种调控因子对CsgD表达的影响,但大多研究局限于作用的现象层面,缺少调控作用的具体通路的研究。这些因素之间的相互作用模式以及由此构建的复杂调控网络架构,仍缺乏全面而深入的理解。因此,为了透彻阐明沙门氏菌生物膜形成的分子调控机制,并以此为基础探索针对生物膜相关疾病的新型预防与治疗策略,迫切需要开展更为系统、深入的科学研究,这些研究应聚焦于解析调控因子间的互作机制,构建详尽的调控网络模型,以及阐明这些网络如何动态响应环境变化以调控生物膜的形成与功能。
作者贡献声明
黄颖:整体构思与设计,负责收集和整理相关文献,参与文献筛选和数据整理工作,并对文献中的相关数据进行综合分析;彭玉倩:参与相关文献的筛选与整理,在论点构建过程中提供重要支持;王琪:负责图表设计和排版,协助进行校对和语言润色;邱少富:提供专业建议,协助审稿和修改,确保内容的科学性和准确性;向莹:提供专业建议,协助审稿和修改,确保内容的科学性和准确性。
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