微生物学报

Target gene	Gene function	References
gltD	Encoding glutamate synthase	[1]
csrA	RNA-binding protein, translational regulator	[25-26]
ybiI	Unknown	[27]
ydbK	Unknown	[27]
katE	Hydroperoxidase II	[28]
xthA	Exonuclease III	[28]
sodC	CuZnSOD	[28]
artI/P	Amino acid transport and metabolism	[29]
ansP	Amino acid transport and metabolism	[29]
tnaA	Amino acid transport and metabolism	[29]
ilvD	Amino acid transport and metabolism	[29]
fhuA	Iron acquisition	[30]
cirA	Uptake of iron-siderophore	[30]
fecI	Sigma19	[30]
osmB	Osmotically inducible lipoprotein	[31-32]
osmE	Osmotically inducible lipoprotein	[32]
dps	Stress response to DNA-binding protein with a ferritin-like domain	[32-33]
otsA	Trehalose-6-phosphate synthase	[33]
otsB	Trehalose-6-phosphate phosphatase, biosynthetic	[33]
sanA	Multicopy suppressor	[34]
dacA	PG carboxypeptidases	[35]
yhdP	Involved in GPL transport	[36]
gltB	Encoding glutamate synthase or glutamate-2-oxoglutarate aminotransferase, GOGAT	[37]
dnaK	Encoding heat shock proteins	[38]
osmY	Starvation and stress response	[39]
sodC	Starvation and stress response	[40]
rpsV	Protein synthesis	[41]
wrbA	Starvation and stress response	[42]
yahO	Unknown	[43]

Target gene	Gene function	References
gltD	Encoding glutamate synthase	[1]
csrA	RNA-binding protein, translational regulator	[25-26]
ybiI	Unknown	[27]
ydbK	Unknown	[27]
katE	Hydroperoxidase II	[28]
xthA	Exonuclease III	[28]
sodC	CuZnSOD	[28]
artI/P	Amino acid transport and metabolism	[29]
ansP	Amino acid transport and metabolism	[29]
tnaA	Amino acid transport and metabolism	[29]
ilvD	Amino acid transport and metabolism	[29]
fhuA	Iron acquisition	[30]
cirA	Uptake of iron-siderophore	[30]
fecI	Sigma19	[30]
osmB	Osmotically inducible lipoprotein	[31-32]
osmE	Osmotically inducible lipoprotein	[32]
dps	Stress response to DNA-binding protein with a ferritin-like domain	[32-33]
otsA	Trehalose-6-phosphate synthase	[33]
otsB	Trehalose-6-phosphate phosphatase, biosynthetic	[33]
sanA	Multicopy suppressor	[34]
dacA	PG carboxypeptidases	[35]
yhdP	Involved in GPL transport	[36]
gltB	Encoding glutamate synthase or glutamate-2-oxoglutarate aminotransferase, GOGAT	[37]
dnaK	Encoding heat shock proteins	[38]
osmY	Starvation and stress response	[39]
sodC	Starvation and stress response	[40]
rpsV	Protein synthesis	[41]
wrbA	Starvation and stress response	[42]
yahO	Unknown	[43]

Bacteria species	Mutation status	Mutation type	Phenotypic difference	References
Cronobacter sakazakii	843 bp deletion	Fragment deletion	No catalase activity	[47]
	Single-base substitution at position 601	Nonsense mutation	No catalase activity
E. coli	Premature termination of translation	Nonsense mutation	Acid sensitivity	[48]
E. coli	C97G, G377T	Missense mutation	Unknown	[49]
	T32G, G124T, T163C, ΩA269, T339C, T357G, ΩT392, C405T, T462C, ΩA518, T573C, G598T, C732T, C942T	Nonsense mutation, Frameshift mutation	Unknown
	Δnt94-nt121	Fragment deletion	Unknown
E. coli	ATG→ATA	Missense mutation	No catalase activity	[50]
Salmonella enterica	T897C, C687T, C1466T, G915A	Missense mutation	Unknown	[51]
	Single-base deletion at position 619, Single-base insertion at position 750	Frameshift mutation	Unknown
E. coli	C97G, T374A, G376T, G926A	Nonsynonymous mutation	Unknown	[52]
	A deletion at position 191, multiple base insertion at position 158	Frameshift mutation	Unknown
	Single-base variations at 39 sites	Synonymous mutation	Unknown
E. coli	96 bp deletion	Fragment deletion	Grows faster when using succinate as the carbon source, and is sensitive to acid and hydrogen peroxide	[53]
	G148A	Nonsense mutation	Grows faster when using succinate as the carbon source, and is sensitive to acid and hydrogen peroxide
	Multiple base insertion at position 32	Frameshift mutation	Grows faster when using succinate as the carbon source, and is sensitive to acid and hydrogen peroxide
E. coli	G297T, T383A	Missense mutation	Has partial glycogen synthesis capacity and catalase activity	[54]
	T515G, G814T	Nonsense mutation	Has partial glycogen synthesis capacity and catalase activity
	Δnt484-nt487, Δnt151-nt155, Δnt393-nt397, ΔA900, Δnt249-nt345	Fragment deletion	No glycogen synthesis capacity and no catalase activity

Bacteria species	Mutation status	Mutation type	Phenotypic difference	References
Cronobacter sakazakii	843 bp deletion	Fragment deletion	No catalase activity	[47]
	Single-base substitution at position 601	Nonsense mutation	No catalase activity
E. coli	Premature termination of translation	Nonsense mutation	Acid sensitivity	[48]
E. coli	C97G, G377T	Missense mutation	Unknown	[49]
	T32G, G124T, T163C, ΩA269, T339C, T357G, ΩT392, C405T, T462C, ΩA518, T573C, G598T, C732T, C942T	Nonsense mutation, Frameshift mutation	Unknown
	Δnt94-nt121	Fragment deletion	Unknown
E. coli	ATG→ATA	Missense mutation	No catalase activity	[50]
Salmonella enterica	T897C, C687T, C1466T, G915A	Missense mutation	Unknown	[51]
	Single-base deletion at position 619, Single-base insertion at position 750	Frameshift mutation	Unknown
E. coli	C97G, T374A, G376T, G926A	Nonsynonymous mutation	Unknown	[52]
	A deletion at position 191, multiple base insertion at position 158	Frameshift mutation	Unknown
	Single-base variations at 39 sites	Synonymous mutation	Unknown
E. coli	96 bp deletion	Fragment deletion	Grows faster when using succinate as the carbon source, and is sensitive to acid and hydrogen peroxide	[53]
	G148A	Nonsense mutation	Grows faster when using succinate as the carbon source, and is sensitive to acid and hydrogen peroxide
	Multiple base insertion at position 32	Frameshift mutation	Grows faster when using succinate as the carbon source, and is sensitive to acid and hydrogen peroxide
E. coli	G297T, T383A	Missense mutation	Has partial glycogen synthesis capacity and catalase activity	[54]
	T515G, G814T	Nonsense mutation	Has partial glycogen synthesis capacity and catalase activity
	Δnt484-nt487, Δnt151-nt155, Δnt393-nt397, ΔA900, Δnt249-nt345	Fragment deletion	No glycogen synthesis capacity and no catalase activity

细菌压力响应调控因子RpoS功能及多态性研究进展

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石佳丽 ¹^,² , 魏雨萌 ¹^,² , 李嘉敏 ² , 滕昕辰 ¹ , 宋凯 ² , 宋亚军 ¹^,²

微生物学报 | 综述 2026,66(5): 2091-2102

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微生物学报 | 综述 2026, 66(5): 2091-2102

细菌压力响应调控因子RpoS功能及多态性研究进展

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石佳丽¹^,², 魏雨萌¹^,², 李嘉敏², 滕昕辰¹, 宋凯², 宋亚军¹^,²

作者信息

^1.苏州大学药学院，江苏苏州

^2.军事医学研究院，病原微生物生物安全全国重点实验室，北京

Research progress in the functions and polymorphism of the bacterial stress response regulator RpoS

Jiali SHI¹^,², Yumeng WEI¹^,², Jiamin LI², Xinchen TENG¹, Kai SONG², Yajun SONG¹^,²

Affiliations

^1.College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China

^2.State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, China

出版时间: 2026-05-04 doi: 10.13343/j.cnki.wsxb.20250884

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摘要

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通用压力响应(general stress response, GSR)是细菌为应对多种外界刺激而形成的一种全局性策略，能使细菌通过协调一系列生理和代谢变化来适应不断变化的环境。替代σ因子RpoS (σ^S)是细菌GSR的核心调节蛋白，对细菌应对胁迫环境至关重要。细菌中此类关键调控因子通常具有较高的保守性，但研究发现多种细菌的自然分离株和实验室诱导株中RNA聚合酶σ^S因子(RNA polymerase sigma factor S, rpoS)存在多态性现象。该现象反映了细菌在进化过程中形成的适应性权衡机制，使RpoS成为研究此机制的关键模型之一。本文综述了细菌RpoS的重要功能及其多态性特征，并结合RpoS功能初步探讨了其多态性形成的环境驱动因素。

关键词

通用压力响应 / 适应度 / RpoS功能 / rpoS多态性

Abstract

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The general stress response (GSR) is a global regulatory strategy developed by bacteria to adapt to diverse environmental stresses by coordinating a suite of physiological and metabolic changes, thereby enabling survival in fluctuating conditions. The alternative sigma factor RpoS (σ^S) serves as a central GSR regulator in bacteria and is crucial for bacterial responses to various stress conditions. Such regulators in bacteria are conserved, while polymorphic variations in rpoS are prevalent across numerous natural isolates and acclimated strains. This polymorphism reflects the adaptive trade-off mechanism formed by bacteria during the evolutionary process, positioning RpoS as a key model for investigating fitness trade-offs in bacteria. This review summarizes the functions and polymorphisms of RpoS and explores the potential environmental drivers underlying its polymorphism.

Key words

general stress response / fitness / RpoS function / rpoS polymorphism

引用本文

石佳丽, 魏雨萌, 李嘉敏, 滕昕辰, 宋凯, 宋亚军. 细菌压力响应调控因子RpoS功能及多态性研究进展. 微生物学报, 2026 , 66 (5) : 2091 -2102 . DOI: 10.13343/j.cnki.wsxb.20250884

Jiali SHI, Yumeng WEI, Jiamin LI, Xinchen TENG, Kai SONG, Yajun SONG. Research progress in the functions and polymorphism of the bacterial stress response regulator RpoS[J]. Acta Microbiologica Sinica, 2026 , 66 (5) : 2091 -2102 . DOI: 10.13343/j.cnki.wsxb.20250884

正文

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细菌在自然环境和宿主体内生存时会面临多种胁迫环境(如高/低pH、高/低温度、高/低渗透压及营养缺乏等)，针对这些胁迫细菌会启动通用压力响应(general stress response, GSR)。RNA聚合酶σ^S因子(RNA polymerase sigma factor S, RpoS)是细菌GSR体系的重要成员，其合成受上述胁迫压力的诱导，可调节细菌多种应激反应途径，包括氨基酸分解代谢、生物膜形成和毒力等^[1]。尽管RpoS对细菌的核心代谢功能并非必需，但其在应激反应中的多种辅助功能使其在进化过程中得以保留。RpoS通过调控一系列保护性反应，帮助细菌适应多种次优生长条件，为后代群体提供了新的适应性可能^[2]。编码基因rpoS可能与其祖先基因RNA聚合酶σ^D因子(RNA polymerase sigma factor D, rpoD)的复制事件有关，在绝大多数假单胞菌门(Pseudomonadota)中保守^[1,3]。rpoD作为管家基因，主要参与基础代谢、大分子合成和转运等过程^[4]。研究表明，作为细菌适应性反应的关键调节因子，RpoS的缺失会导致细菌对多种胁迫因子抗性下降^[1,5-6]；而在营养匮乏的环境中，RpoS突变能够促进细菌生长，并上调RpoD相关基因表达，使细菌能够在有限的营养资源中充分调动增殖所需基因的优先表达，最大限度地提高细菌的环境适应性^[4]。

RpoS对细菌的压力响应具有核心作用，传统认知中，如此重要的调控蛋白应该是高度保守的，但多种细菌的自然分离株rpoS基因存在多态性，这种蛋白保守性与多态性之间的矛盾可能反映了细菌在快速生长与胁迫生存之间的适应性权衡(adaptive trade-off)策略。前期研究发现，鼠疫耶尔森菌(Yersinia pestis) rpoS同样存在多态性，进一步支持该基因是病原菌面临自然选择时适应性权衡的重要靶点。鉴于RpoS在细菌胁迫环境耐受中发挥重要作用，却存在高频变异的“矛盾”现象，系统阐释其多态性的分布规律、环境驱动机制及进化意义，不仅有助于深化对细菌应激调控网络的理解，也对揭示病原菌适应性进化规律具有重要科学价值。

本文通过系统综述RpoS的表达调控机制及其生理功能，梳理其在自然与实验种群中基因多态性普遍存在的证据，重点探讨驱动该多态性形成及维持的环境因素与进化权衡机制，以期为该领域后续研究提供清晰的理论框架，并为深入理解细菌在多样化环境中的进化策略提供新的视角。

1 RpoS概述

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1.1 RpoS表达调控

σ因子是细菌RNA聚合酶(RNA polymerase, RNAP)的重要组成部分，通过与RNA聚合酶核心酶结合，识别基因的启动子区域并启动转录。在大肠杆菌(Escherichia coli)中已鉴定出7种σ因子，包括管家因子σ⁷⁰ (RpoD)和替代σ因子(σ^E、σ^F、σ^H、σ^I、σ^N和σ^S)^[7-8]。管家σ因子RpoD主要调控细菌在营养丰富环境以及指数增长期管家基因的转录，此时替代σ因子的表达受到严格的负调控，以避免其与RpoD竞争性结合RNA聚合酶核心酶。因此，在最佳生长条件或指数增长期，RpoS表达量极低；而当细胞进入稳定期或处于胁迫环境时，RpoS被大量诱导表达以提高细菌的抗逆性^[7,9]。RpoS的表达涉及转录、翻译及翻译后修饰等多层次的调控(图1)。

细菌rpoS的转录主要受其上游新型脂蛋白D (novel lipoprotein D, nlpD)基因启动子及位于nlpD基因内启动子(rpoS_p1)的控制^[9-10]。其中，在胁迫条件下rpoS_p1受多种因子的精密调控：全局营养应激信号分子鸟苷四磷酸(guanosine 3′,5′-bispyrophosphate, ppGpp)在营养匮乏时积累，正调控rpoS转录以适应胁迫^[11]；此外，双组分系统ArcAB响应环境氧浓度，磷酸化的应答调节因子缺氧氧化还原调控蛋白A (Anoxic redox control protein A, ArcA)可直接结合并抑制rpoS_p1^[12-13]。rpoS转录本存在567个核苷酸的5′-非翻译区(5′ untranslated region, 5′-UTR)^[9]，该区域形成的茎-环结构阻碍核糖体结合，从而抑制其翻译(图1B)^[14]。RpoS调节子RNA A (RpoS regulator RNA A, RprA)、DsrA小非编码RNA (DsrA small non-coding RNA, DsrA)和小非编码RNA ArcZ (small non-coding RNA ArcZ, ArcZ)等sRNAs在分子伴侣Qβ噬菌体宿主因子I (host factor I for RNA bacteriophage Qβ, Hfq)的介导下，可与5′-UTR结合并打开茎-环结构，进而解除对翻译的抑制^[15-19]。此外，RpoS蛋白稳定性主要体现在大肠杆菌的指数增长期，σ^S接头蛋白B(regulator of sigma S protein B, RssB)协助ATP依赖型Clp蛋白酶复合物XP (ATP-dependent Clp protease complex XP, ClpXP)介导RpoS蛋白快速降解^[20-21]；而在平台期或营养限制环境下，该降解过程被抑制^[22]。抗适配体(anti-adaptor)蛋白磷酸饥饿响应RssB抑制蛋白(inhibitor of RssB activity during phosphate starvation, IraP)、镁饥饿响应RssB抑制蛋白(inhibitor of RssB activity during magnesium starvation, IraM)和DNA损伤响应RssB抑制蛋白(inhibitor of RssB activity during DNA damage, IraD)可通过隔离RssB阻断降解通路，从而提升RpoS水平^[23]。

1.2 RpoS调控靶标

在富营养条件下，大肠杆菌中约23%的基因受RpoS调控，这些靶基因根据其对RpoS浓度梯度的依赖程度，可划分为敏感性、线性和迟钝性3类响应模式，从而协调细菌在稳定期及应激条件下的转录适应^[24](表1)。在最小培养基条件下的微阵列研究表明，RpoS在指数期和稳定期分别影响200个和225个基因的差异表达，其中稳定期超过90%的靶基因为正调控，凸显了RpoS调控网络的营养依赖性特征^[25]。然而，对于其中绝大多数基因，其受RpoS直接或间接调控的机制尚未明确。

Peano等^[27]通过ChIP-seq技术在大肠杆菌中鉴定出63个已知或预测的RpoS特异性依赖的启动子区域，如渗透压诱导脂蛋白B (osmotically-inducible lipoprotein B)基因osmB、饥饿细胞DNA结合蛋白(DNA-binding protein from starved cells)基因dps、渗透压诱导脂蛋白E (osmotically-inducible protein E)基因osmE和碳储存调控因子A (carbon storage regulator A)基因csrA等，并且发现了2个新的RpoS依赖性基因未表征锌指结构域蛋白(uncharacterized zinc finger domain-containing protein)基因ybiI和推定丙酮酸-黄素氧还蛋白氧化还原酶(putative pyruvate-flavodoxin oxidoreductase)基因ydbK。大量证据表明，RpoS依赖性基因功能多样，但其核心作用在于增强细菌对各种环境胁迫的抵抗力。例如，在碳源限制条件下，RpoS通过调控万古霉素抗性蛋白SanA (vancomycin resistance protein)基因sanA、D-丙氨酰-D-丙氨酸羧肽酶A (D-alanyl-D-alanine carboxypeptidase A)基因dacA和未表征蛋白(uncharacterized protein)基因yhdP等基因介导细菌对十二烷基硫酸钠(sodium dodecyl sulfate, SDS)的抗性^[44]；关键抗氧化应激基因(如dps、过氧化氢酶HPII (catalase HPII)基因katE、外切核酸酶III (exonuclease III)基因xthA和铜锌超氧化物歧化酶[superoxide dismutase (Cu-Zn)]基因sodC的表达也显著依赖于RpoS^[28]。此外，RpoS广泛参与多种代谢途径的调控。例如，RpoS能激活编码谷氨酸合成酶的谷氨酸合酶大亚基(glutamate synthase large subunit)基因gltB和谷氨酸合酶小亚基(glutamate synthase small subunit)基因gltD的表达，该酶可利用α-酮戊二酸催化谷氨酰胺转化为谷氨酸^[1]；同样地，RpoS还能激活细菌糖酵解相关基因^[45]以及L-精氨酸代谢(转化为谷氨酰胺或经腐胺途径转化为琥珀酸)的相关基因^[24]；类似地，海藻糖合成基因[海藻糖-6-磷酸合酶(trehalose-6-phosphate synthase)基因otsA和海藻糖-6-磷酸磷酸酶(trehalose-6-phosphate phosphatase)基因otsB]也受RpoS调控^[46]。Lacour等^[29]研究了营养丰富培养基中大肠杆菌rpoS突变体的基因表达情况，发现41个基因表达水平显著降低，并鉴定到7个已知的RpoS调控基因[dps、osmE、渗透诱导蛋白Y (osmotically inducible protein Y)基因osmY、sodC、30S核糖体蛋白S22 (30S ribosomal protein S22)基因rpsV、色氨酸阻遏物结合蛋白A (tryptophan repressor binding protein A)基因wrbA和未表征蛋白(uncharacterized protein)基因yahO]，这些基因主要参与氨基酸的转运和代谢、铁的摄取和储存、蛋白质合成、碳水化合物代谢以及核苷代谢等，参与氨基酸转运[精氨酸转运基因I (arginine transport gene I, artI)、精氨酸转运ATP结合蛋白(arginine transport ATP-binding protein)基因artP和L-天冬酰胺转运蛋白(L-asparagine permease)基因ansP]或代谢[色氨酸酶A(tryptophanase A)基因tnaA和二羟基酸脱水酶(dihydroxy-acid dehydratase)基因ilvD]的基因同样依赖于RpoS。Dong等^[30]检测了大肠杆菌对数生长期内RpoS的调控作用，进一步发现大肠杆菌RpoS在对数生长期正向调控热休克蛋白编码基因[分子伴侣DnaK (DnaK chaperone protein)基因dnaK等]和铁获取相关基因[铁色素摄取蛋白A (ferrichrome uptake protein A)基因fhuA、大肠菌素I受体蛋白(colicin I receptor protein)基因cirA和柠檬酸铁σ因子FecI (ferric citrate sigma factor FecI)基因fecI等]，同时负向调节三羧酸循环(tricarboxylic acid cycle, TCA)相关基因的表达。不同靶基因对RpoS的敏感性差异，使得不同强度或性质的应激信号能诱导产生特异性的蛋白质组响应，从而极大地增强细菌适应多变环境的能力。

1.3 rpoS 基因的多态性

尽管RpoS在应激响应中的核心功能已明确，但rpoS基因在大肠杆菌和沙门菌等多种细菌的自然种群中普遍存在多态性(表2)，这反映了细菌在应对不同环境压力时的进化适应策略^[4]。例如，Alvarez-Ordóñez等^[47]对15株阪崎克洛诺斯杆菌(Cronobacter sakazakii)的rpoS基因测序发现，其中2株菌存在无义突变及碱基缺失，且这2株突变株对胁迫环境高度敏感。Waterman等^[48]在58株志贺样产毒素大肠杆菌中鉴定出13株存在耐酸性缺陷表型，对其中2株耐酸性缺陷菌株的rpoS基因测序结果显示，该基因均发生功能丧失性突变，导致RpoS蛋白失活。Lalaouna等^[55]通过对80株细菌的全基因组分析显示，假单胞菌门(Pseudomonadota) [尤其肠杆菌科(Enterobacteriaceae)]的mutS-rpoS基因簇区域长度差异显著(40 bp-13 kb)，而假单胞菌属(Pseudomonas)中这一区域结构高度保守。Bhagwat等^[56]分析了来自34个国家的82株致病性大肠杆菌分离株，发现其中20株的谷氨酸依赖酸抗性(glutamate-dependent acid-resistance, GDAR)系统的缺陷源于RpoS功能缺失。Ferenci等^[49]分析来源于大肠杆菌参考菌株集(Escherichia coli reference, ECOR)菌种保藏中心的31株大肠杆菌，其中22株菌的rpoS基因存在序列长度多态性(1.3、3.4、4.2 kb)和非同义突变或无义突变。Berger等^[50]从2011年德国大肠杆菌疫情中发现Escherichia coli O104:H4的rpoS基因起始密码子存在ATG→ATA的单核苷酸突变，且RpoS主要通过AggR依赖性机制抑制肠聚集性大肠杆菌(enteroaggregative Escherichia coli, EAEC)特异性毒力基因的表达。Jordan等^[51]分析了18株环境来源沙门菌的rpoS变异水平，发现6株菌存在序列多态性，且主要出现在基因中末端。Valencia等^[52]从Pirajuçara河流中分离出328株大肠杆菌，并对无RpoS蛋白和RpoS/RpoD比值较高的40株菌的rpoS进行测序，发现几乎所有的测序分离株均存在C97G的非同义突变。Wu等^[57]分析了3 318株鼠疫菌基因组序列，发现45个突变热区(突变率高于平均水平)，而rpoS位于第36个突变热区，其突变多为无义突变或移码突变，这表明鼠疫菌自然种群中的rpoS同样存在高度的多态性。

类似地，rpoS多态性在实验室培养条件下同样高频发生，Ratib等^[58]在长达1 200 d长期营养限制培养过程中，对1 117株大肠杆菌的全基因组分析揭示了rpoS基因的高频多态性，其中导致RpoS表达显著降低的启动子-10区的T→C突变在4个平行培养群中均受正向选择，说明RpoS活性的下降赋予了大肠杆菌碳源竞争的适应性优势。然而，Snyder等^[59]对涵盖主要谱系的96株非致病大肠杆菌RpoS蛋白产物进行了鉴定，发现仅有2株菌因碱基的插入缺失引起移码突变导致无法产生功能性RpoS蛋白，且该突变均为实验室培养过程中发生；但研究中并未对能够表达RpoS菌株的rpoS基因进行测序鉴定，因此无法排除这些菌株存在rpoS基因层面的多态性现象。

同样值得注意的是，Chiang等^[53]通过检测琥珀酸生长和过氧化氢酶活性这2种RpoS依赖的表型来鉴定环境来源的2 040株大肠杆菌中RpoS活性，仅筛选出6株RpoS功能缺失株；而对其中45株分离株的rpoS基因测序结果显示，该基因存在8种非同义突变和81种同义突变。Notley-McRobb等^[54]将野生型E. coli K-12接种至葡萄糖限制或氮源限制的培养基中培养10 d，第4天时菌落分解过氧化氢能力减弱，提示RpoS调控的过氧化氢酶-过氧化物酶 (catalase-peroxidase KatG, KatG)表达降低；进一步对18株糖原合成发生变化(RpoS调控)的分离株进行rpoS基因测序，发现所有分离株的rpoS序列均发生变异，2株完全丧失RpoS功能。综上可知，RpoS功能丧失型多态性在多种细菌的自然种群与实验室种群中均广泛存在。

2 rpoS多态性的驱动因素

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RpoS在抵抗外界环境压力中发挥着至关重要的作用，其介导的GSR可以通过不同的激活机制响应多种环境胁迫，从而增强细菌在特定环境下的适应度优势。GSR的诱导不仅能增强细菌对特定胁迫因子的抵抗力，还能提供对其他胁迫的交叉保护(如处于碳饥饿状态的细菌也会对过氧化氢、高温和酸刺激产生抵抗力)^[7]。不同细菌中rpoS多态性的普遍存在，提示RpoS的活性在特定生境下可能给细菌带来一定程度的适应度代价；在这些特殊生境下，RpoS活性降低甚至失活的菌株与野生型菌株相比具备竞争优势，因此rpoS的某些突变在细菌种群中得以固定^[4]，但这一推论还需要进一步实验数据的证实。以下重点阐述几种关键环境压力如何驱动细菌rpoS多态性的形成。

2.1 活性氧(ROS)胁迫

活性氧(如超氧化物、过氧化氢、羟基自由基等)在细菌快速生长期、磷酸盐或氮源等营养缺乏、遭遇环境压力或宿主毒素分泌时产生，高水平活性氧(reactive oxygen species, ROS)对细菌具有毒性^[60-62]。为应对氧化刺激，细菌可诱导产生解毒酶，如大肠杆菌含有3种超氧化物歧化酶(superoxide dismutase, SODs)，可将超氧化物转化为危害较小的过氧化物(如H₂O₂)；过氧化物进一步由2种过氧化氢酶(KatG和KatE)转化为水和氧气；上述ROS清除酶均属于RpoS调控子(RpoS regulon)，当细菌面临ROS刺激时，RpoS可上调其ROS防御系统以淬灭ROS^[63]。因此，在ROS胁迫环境中，功能性RpoS对细菌生存至关重要，而RpoS突变体在此选择压力下则处于明显劣势。

2.2 酸性胁迫

细菌常面临酸性环境胁迫，当细菌胞外环境pH处于中低水平时，RpoS表达水平上升，此过程通常与IraM表达水平上调有关^[23]。IraM受PhoP应答调控蛋白(PhoP response regulator, PhoP)/PhoQ感应激酶(PhoQ sensor kinase, PhoQ)双组分系统正调控，酸性胁迫可激活细菌PhoP，诱导IraM和RpoS表达水平增加^[23]。细菌的酸耐受反应涉及多种酸耐受体系(acid resistance systems, ARs)，其中AR1通路需要RpoS调控耐酸基因的转录，而RpoS的表达则受C-反应蛋白(C-reactive protein, CRP)和环腺苷酸(cyclic adenosine monophosphate, cAMP)的负调控；同时，当细菌处于极端酸性环境刺激时，cAMP水平的下降将增强RpoS的表达，进而促进AR2体系相关蛋白酶的活性，使其在谷氨酸存在时增强细菌的酸耐受能力^[64-65]。由此可知，RpoS在细菌面临酸性胁迫时同样发挥重要作用，有助于增强细菌在酸性胁迫环境下的适应度。

2.3 高渗胁迫

高渗透压会导致细菌脱水，从而造成严重损伤。大肠杆菌通过积累K⁺和相容性溶质(如甘氨酸甜菜碱和海藻糖)作为渗透保护剂以适应高渗环境^[66]。RpoS在此过程中同样发挥重要作用，其通过正调控甘氨酸甜菜碱合成相关基因的表达，同时激活海藻糖合成酶编码基因otsA和otsB来促进相容性溶质的产生，从而提高细菌在高渗透压环境中的适应度优势^[46]。因此，在高渗胁迫下，功能性RpoS对维持细菌渗透压平衡和生存至关重要。

2.4 营养限制胁迫

与上述胁迫环境相反，在特定营养(如葡萄糖)限制条件下，rpoS突变体反而表现出更强的适应度优势，在此培养条件下可快速分离得到RpoS功能缺失的突变体^[54,58]。当将大肠杆菌野生型接种于葡萄糖限制的培养基中，通过糖原表型(RpoS控制糖原的合成)筛选，并对18株糖原合成发生变化的分离株进行rpoS基因测序，发现所有分离株的rpoS序列均发生变异，其中2株完全丧失RpoS功能^[54]。此外，Ratib等^[58]在长期分批培养(1 200 d)中发现，rpoS是突变频率最高的基因之一；在该营养限制条件下，RpoS的突变一方面缓解了大肠杆菌应激反应带来的适应度代价，另一方面可能解除了RpoS对氨基酸代谢基因的抑制，通过代谢重编程增强了大肠杆菌对次级碳源(如氨基酸)的利用。以上研究表明，RpoS突变体在营养限制条件下更具适应度优势，因此RpoS的变异能够在种群中固定并形成基因的多态性。

以上研究提示，RpoS的进化命运呈现典型的环境依赖性：在急性胁迫环境(如ROS、酸、高渗)下，功能性RpoS能提供生存优势而被选择；而在营养限制胁迫环境下，RpoS的活性反而可能成为生长负担，其失活突变体因此获得选择优势而在群体中固定下来。

3 总结与展望

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通用应激反应是细菌应对外界多变环境的核心策略，而σ^S因子RpoS作为其核心调控元件，通过调控细菌内大量胁迫抗性相关基因的表达，在细菌环境适应过程中发挥重要功能^[8]。当细菌处于活性氧刺激、酸应激和高渗透压等胁迫环境中时，RpoS能够通过调控GSR提高细菌对胁迫环境的耐受性，从而为细菌提供适应度优势。传统认为，发挥重要功能的基因通常更加保守，而在多种细菌中均发现rpoS存在多态性。这一现象提示，在特定生境中RpoS活性可能反而成为细菌生存的负担，因此细菌采取rpoS突变策略来降低其带来的适应度代价，这体现了细菌在“生存”与“繁殖”这一根本进化权衡中的动态适应；此外，在实验室葡萄糖限制和氮源限制的培养条件下，同样较易获得rpoS基因突变分离株。同时，在竞争环境下，大肠杆菌野生株会被rpoS突变株取代^[2]，这也为细菌RpoS突变在特定环境中的适应度优势提供了证据。尽管目前尚未发现rpoS无义突变回复为野生型的现象，但不排除此类菌株在长期或高频暴露于急性胁迫环境下发生回复突变的可能。

由此可推测，rpoS多态性的驱动机制可能是替代性σ因子对RNA聚合酶核心酶的竞争以及细菌进化的权衡。RNA聚合酶核心酶的总量在细菌内相对恒定，因此RpoS (保护应激)和RpoD (支持生长)对核心酶的竞争性结合主导了细菌截然不同的生存策略：当细菌面临极端胁迫环境时，RpoS大量表达并激活应激保护网络，有助于细菌的抗逆性，但以牺牲最大生长速率为代价；而在营养限制等亚适宜环境中，细菌生长速率降低引发ppGpp积累并诱导RpoS表达但RpoS依赖性应激基因的转录会抢占核心酶资源，抑制RpoD主导的管家基因，导致细菌因应激响应而削弱了对稀缺营养的竞争能力^[4,63]。此时，RpoS突变体对核心酶的结合能力下降或丢失，从而解除对RpoD的竞争抑制，使细菌获得生长优势。这一现象体现了典型的拮抗多效性，即RpoS突变虽在胁迫环境下损害生存能力，却可以在营养竞争中提供适应度优势。这种环境波动驱动的“生长-生存”动态权衡，使RpoS成为细菌适应异质生境的进化开关，为细菌种群应对不可预测的环境压力提供了权衡策略。

随着技术的进步，未来关于RpoS的研究可以从以下3个层面深入。在机制层面，利用单细胞组学技术解析RpoS调控网络的动态变化及其在细菌群体异质性中的作用；在进化层面，结合多组学与实验室进化手段，直接验证不同环境下的选择压力对rpoS基因多态性的影响，阐述其多态性驱动因素和进化动力学机制；在临床微生物学应用层面，可以重点研究临床常见病原菌中rpoS多态性对其毒力与抗生素耐受性/持留性的影响，以发现基于干扰细菌“生长-生存”权衡的新型抗感染策略。

基金

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国家自然科学基金(U22A20526)

参考文献

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文献

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参考文献引证文献

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2026年第66卷第5期

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doi: 10.13343/j.cnki.wsxb.20250884

接收时间：2025-12-01
首发时间：2026-05-09
出版时间：2026-05-04

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收稿日期：2025-12-01
录用日期：2026-01-02

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The National Natural Science Foundation of China(U22A20526)

国家自然科学基金(U22A20526)

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^1.苏州大学药学院，江苏苏州

^2.军事医学研究院，病原微生物生物安全全国重点实验室，北京

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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RefWorks
TxT

Target gene	Gene function	References
gltD	Encoding glutamate synthase	[1]
csrA	RNA-binding protein, translational regulator	[25-26]
ybiI	Unknown	[27]
ydbK	Unknown	[27]
katE	Hydroperoxidase II	[28]
xthA	Exonuclease III	[28]
sodC	CuZnSOD	[28]
artI/P	Amino acid transport and metabolism	[29]
ansP	Amino acid transport and metabolism	[29]
tnaA	Amino acid transport and metabolism	[29]
ilvD	Amino acid transport and metabolism	[29]
fhuA	Iron acquisition	[30]
cirA	Uptake of iron-siderophore	[30]
fecI	Sigma19	[30]
osmB	Osmotically inducible lipoprotein	[31-32]
osmE	Osmotically inducible lipoprotein	[32]
dps	Stress response to DNA-binding protein with a ferritin-like domain	[32-33]
otsA	Trehalose-6-phosphate synthase	[33]
otsB	Trehalose-6-phosphate phosphatase, biosynthetic	[33]
sanA	Multicopy suppressor	[34]
dacA	PG carboxypeptidases	[35]
yhdP	Involved in GPL transport	[36]
gltB	Encoding glutamate synthase or glutamate-2-oxoglutarate aminotransferase, GOGAT	[37]
dnaK	Encoding heat shock proteins	[38]
osmY	Starvation and stress response	[39]
sodC	Starvation and stress response	[40]
rpsV	Protein synthesis	[41]
wrbA	Starvation and stress response	[42]
yahO	Unknown	[43]

Target gene

Gene function

References

gltD

Encoding glutamate synthase

[1]

csrA

RNA-binding protein, translational regulator

[25-26]

ybiI

Unknown

[27]

ydbK

Unknown

[27]

katE

Hydroperoxidase II

[28]

xthA

Exonuclease III

[28]

sodC

CuZnSOD

[28]

artI/P

Amino acid transport and metabolism

[29]

ansP

Amino acid transport and metabolism

[29]

tnaA

Amino acid transport and metabolism

[29]

ilvD

Amino acid transport and metabolism

[29]

fhuA

Iron acquisition

[30]

cirA

Uptake of iron-siderophore

[30]

fecI

Sigma19

[30]

osmB

Osmotically inducible lipoprotein

[31-32]

osmE

Osmotically inducible lipoprotein

[32]

dps

Stress response to DNA-binding protein with a ferritin-like domain

[32-33]

otsA

Trehalose-6-phosphate synthase

[33]

otsB

Trehalose-6-phosphate phosphatase, biosynthetic

[33]

sanA

Multicopy suppressor

[34]

dacA

PG carboxypeptidases

[35]

yhdP

Involved in GPL transport

[36]

gltB

Encoding glutamate synthase or glutamate-2-oxoglutarate aminotransferase, GOGAT

[37]

dnaK

Encoding heat shock proteins

[38]

osmY

Starvation and stress response

[39]

sodC

Starvation and stress response

[40]

rpsV

Protein synthesis

[41]

wrbA

Starvation and stress response

[42]

yahO

Unknown

[43]

Bacteria species	Mutation status	Mutation type	Phenotypic difference	References
Cronobacter sakazakii	843 bp deletion	Fragment deletion	No catalase activity	[47]
	Single-base substitution at position 601	Nonsense mutation	No catalase activity
E. coli	Premature termination of translation	Nonsense mutation	Acid sensitivity	[48]
E. coli	C97G, G377T	Missense mutation	Unknown	[49]
	T32G, G124T, T163C, ΩA269, T339C, T357G, ΩT392, C405T, T462C, ΩA518, T573C, G598T, C732T, C942T	Nonsense mutation, Frameshift mutation	Unknown
	Δnt94-nt121	Fragment deletion	Unknown
E. coli	ATG→ATA	Missense mutation	No catalase activity	[50]
Salmonella enterica	T897C, C687T, C1466T, G915A	Missense mutation	Unknown	[51]
	Single-base deletion at position 619, Single-base insertion at position 750	Frameshift mutation	Unknown
E. coli	C97G, T374A, G376T, G926A	Nonsynonymous mutation	Unknown	[52]
	A deletion at position 191, multiple base insertion at position 158	Frameshift mutation	Unknown
	Single-base variations at 39 sites	Synonymous mutation	Unknown
E. coli	96 bp deletion	Fragment deletion	Grows faster when using succinate as the carbon source, and is sensitive to acid and hydrogen peroxide	[53]
	G148A	Nonsense mutation	Grows faster when using succinate as the carbon source, and is sensitive to acid and hydrogen peroxide
	Multiple base insertion at position 32	Frameshift mutation	Grows faster when using succinate as the carbon source, and is sensitive to acid and hydrogen peroxide
E. coli	G297T, T383A	Missense mutation	Has partial glycogen synthesis capacity and catalase activity	[54]
	T515G, G814T	Nonsense mutation	Has partial glycogen synthesis capacity and catalase activity
	Δnt484-nt487, Δnt151-nt155, Δnt393-nt397, ΔA900, Δnt249-nt345	Fragment deletion	No glycogen synthesis capacity and no catalase activity

Bacteria species

Mutation status

Mutation type

Phenotypic difference

References

Cronobacter sakazakii

843 bp deletion

Fragment deletion

No catalase activity

[47]

Single-base substitution at position 601

Nonsense mutation

No catalase activity

E. coli

Premature termination of translation

Nonsense mutation

Acid sensitivity

[48]

E. coli

C97G, G377T

Missense mutation

Unknown

[49]

T32G, G124T, T163C, ΩA269, T339C, T357G, ΩT392, C405T, T462C, ΩA518, T573C, G598T, C732T, C942T

Nonsense mutation, Frameshift mutation

Unknown

Δnt94-nt121

Fragment deletion

Unknown

E. coli

ATG→ATA

Missense mutation

No catalase activity

[50]

Salmonella enterica

T897C, C687T, C1466T, G915A

Missense mutation

Unknown

[51]

Single-base deletion at position 619, Single-base insertion at position 750

Frameshift mutation

Unknown

E. coli

C97G, T374A, G376T, G926A

Nonsynonymous mutation

Unknown

[52]

A deletion at position 191, multiple base insertion at position 158

Frameshift mutation

Unknown

Single-base variations at 39 sites

Synonymous mutation

Unknown

E. coli

96 bp deletion

Fragment deletion

Grows faster when using succinate as the carbon source, and is sensitive to acid and hydrogen peroxide

[53]

G148A

Nonsense mutation

Grows faster when using succinate as the carbon source, and is sensitive to acid and hydrogen peroxide

Multiple base insertion at position 32

Frameshift mutation

Grows faster when using succinate as the carbon source, and is sensitive to acid and hydrogen peroxide

E. coli

G297T, T383A

Missense mutation

Has partial glycogen synthesis capacity and catalase activity

[54]

T515G, G814T

Nonsense mutation

Has partial glycogen synthesis capacity and catalase activity

Δnt484-nt487, Δnt151-nt155, Δnt393-nt397, ΔA900, Δnt249-nt345

Fragment deletion

No glycogen synthesis capacity and no catalase activity