生物技术通报 ›› 2022, Vol. 38 ›› Issue (9): 72-83.doi: 10.13560/j.cnki.biotech.bull.1985.2022-0687
• 细菌耐药性专题(专题主编: 刘雅红 教授 孙坚 教授) • 上一篇 下一篇
刘理慧1(), 储锦华1, 隋雨欣1, 陈杨1, 程古月1,2()
收稿日期:
2022-06-04
出版日期:
2022-09-26
发布日期:
2022-10-11
作者简介:
刘理慧,硕士研究生,研究方向:抗菌药耐药性;E-mail: 基金资助:
LIU Li-hui1(), CHU Jin-hua1, SUI Yu-xin1, CHEN Yang1, CHENG Gu-yue1,2()
Received:
2022-06-04
Published:
2022-09-26
Online:
2022-10-11
摘要:
沙门氏菌是一种最常见的食源性致病菌,是全球细菌性胃肠炎的主要病因之一。其血清型众多,目前已报道超过2 600种,不同血清型沙门氏菌对人和动物的致病性不同。其致病性与毒力因子密切相关。本文系统介绍了沙门氏菌主要的毒力因子以及各自编码的分泌系统和/或毒力基因及其功能,进一步分析了毒力基因与毒力的关系,同时讨论了全基因组测序(WGS)预测毒力水平的可行性,有助于探究沙门氏菌中各种毒力因子与宿主相互作用的机制,从基因层面上理解沙门氏菌病,在源头上控制沙门氏菌,从而为沙门氏菌病预防和治疗提供新思路。
刘理慧, 储锦华, 隋雨欣, 陈杨, 程古月. 沙门氏菌中主要毒力因子的研究进展[J]. 生物技术通报, 2022, 38(9): 72-83.
LIU Li-hui, CHU Jin-hua, SUI Yu-xin, CHEN Yang, CHENG Gu-yue. Research Progress of Main Virulence Factors in Salmonella[J]. Biotechnology Bulletin, 2022, 38(9): 72-83.
毒力岛 SPI | 分泌系统 Secretion system | 主要基因 Major gene | 功能 Function | 参考文献 Reference |
---|---|---|---|---|
SPI-1 | T3SS1 | iacB | 与沙门氏菌入侵宿主上皮细胞引起肠病有关 Associated with host epithelial cell invasion and enteropathy | [ |
avrA | 抑制促炎因子的激活、诱导细胞凋亡以及促进肠上皮细胞增殖及肿瘤形成 Inhibit the activation of proinflammatory factor,induce apoptosis,and promote intestinal epithelial cell proliferation and tumor formation | [ | ||
sipA | 与细胞内入侵有关、促进caspase-3的激活和释放 Associated with intracellular invasion and promote activation and release of caspase-3 | [ | ||
sipB | 促进沙门氏菌诱导的caspase-1依赖型细胞的凋亡、促进IL-18的释放 Promote Salmonella-induced caspase-1-dependent apoptosis and the release of IL-18 | [ | ||
sipC | 与沙门氏菌的易位蛋白有关、促进病原体内化 Associated with translocated proteins in Salmonella,and promote pathogen internalization | [ | ||
sptP | 破坏宿主细胞骨架、促进沙门氏菌在宿主细胞内复制 Destroy host cellular actin cytoskeleton,and promote Salmonella intracellular replication | [ | ||
sopA | E3泛素连接酶,泛素化细菌和/或宿主细胞底物 E3 ubiquitin ligase,ubiquitinating bacterial and/or host cell substrates | [ | ||
sopE | 诱导快速的肌动蛋白细胞骨架重排、膜皱褶和随后的病原体巨胞饮,促进细菌侵袭 Induce rapid actin cytoskeletal rearrangement,membrane ruffling,and subsequent pathogen macropinocytosis,and facilitate bacterial invasion | [ | ||
sopE2 | Cdc42 的鸟嘌呤核苷酸交换因子(通过SPI-1-TTSS) Guanine nucleotide exchange factor for Cdc42(via SPI-1-TTSS) | [ | ||
invB | 维持SopA蛋白的稳定性和易位 Maintain the stability and translocation of SopA protein | [ | ||
sicA | 维持分子伴侣InvF的活动 Maintain the activity of chaperone InvF | [ | ||
sicP | 其编码的蛋白SicP是SptP蛋白的分子伴侣 Its encoded protein SicP is a chaperone of the SptP protein | [ | ||
SPI-2 | T3SS2 | ssrB | 其编码的SsrB蛋白激活转录和解除H-NS介导的抑制作用 Its encoded SsrB protein activates transcription and relieves H-NS-mediated repression | [ |
ssaB | 分泌 sseB 和 sseC 所需 Required for the secretion of sseB and sseC | [ | ||
ssaE | 能识别转运体sseB并通过SPI-2的T3SS控制其分泌 Recognize the transporter sseB and controls its secretion through the T3SS of SPI-2 | [ | ||
sscA | sseC易位子的伴侣 Partner of the sseC translocon | [ | ||
sscB | 诱导沙门氏菌上皮细胞连续丝形成、其编码的蛋白sscB是效应子sseF的伴侣 Induce the continuous filament formation in Salmonella epithelial cells,its encoded protein sscB is a partner of the effector sseF | [ | ||
sseC | SPI-2 转座子 SPI-2 transposon | [ | ||
sseL | 抑制宿主炎性作用,对巨噬细胞具有杀伤作用 Inhibit host inflammatory effects and has killing effect on macrophages | [ | ||
sseFG | 将沙门氏菌液泡(SCV)运输到高尔基网络 Transport Salmonella vacuole(SCV)to the Golgi network | [ | ||
ttr | 与四硫酸还原酶的产生有关 Associated with the production of tetrasulfate reductase | [ | ||
SPI-3 | - | mgtCB | 与菌体在宿主细胞内存活以及在宿主肠道定殖有关 Associated with bacterial survival in host cells and the colonization of the host gut | [ |
misL | 编码自体转运蛋白MisL Code autotransporter MisL | [ | ||
SPI-4 | T1SS | siiE | 会对小鼠和牛产生毒力,与宿主肠道上皮细胞的黏附和侵袭有关 Host virulent in mice and cattle,associated with the adhesion and invasion of host intestinal epithelial cells | [ |
SPI-5 | - | pipA | 刺激促炎细胞因子的信号转导 Stimulate signal transduction of pro-inflammatory cytokines | [ |
pipB | 把kinesin-1募集到SCV中 Recruitment of kinesin-1 into SCV | [ | ||
pipC | 与肠上皮侵袭有关 Associated with the invasion of intestinal epithelium | [ | ||
sopB | 具有抗凋亡活性、与细胞内复制有关、损害宿主的肠上皮屏障功能 Having anti-apoptotic activity,associated with intracellular replication,and impair intestinal epithelial barrier function in the host | [ | ||
sigD | 促进中性粒细胞募集、具有抗凋亡活性、与细胞内复制有关 Facilitate neutrophil recruitment,have anti-apoptotic activity,and associated with intracellular replication | [ | ||
sigE | 与肠上皮侵袭有关 Associated with the invasion of intestinal epithelium | [ | ||
SPI-6 | T6SS | saf | 介导细胞间寡聚体机制、促进细菌聚集、定殖和最终生物膜的形成 Mediate cell-cell oligomer mechanisms,and promote bacterial aggregation,colonization,and ultimately biofilm formation | [ |
tcf | 编码功能性菌毛并作为黏附素、有助于伤寒期间的定殖 Encode functional pili and act as an adhesin,and contribute to colonization during typhoid fever | [ | ||
SPI-19 | T6SS | 无 | 与细菌在宿主巨噬细胞内存活以及鸡的定殖有关 Associated with bacterial survival within host macrophages,colonization of chickens | [ |
表1 沙门氏菌毒力岛及其编码的分泌系统、主要基因以及基因功能
Table 1 Salmonella pathogenicity island and encoded secretion system,major gene,and gene function
毒力岛 SPI | 分泌系统 Secretion system | 主要基因 Major gene | 功能 Function | 参考文献 Reference |
---|---|---|---|---|
SPI-1 | T3SS1 | iacB | 与沙门氏菌入侵宿主上皮细胞引起肠病有关 Associated with host epithelial cell invasion and enteropathy | [ |
avrA | 抑制促炎因子的激活、诱导细胞凋亡以及促进肠上皮细胞增殖及肿瘤形成 Inhibit the activation of proinflammatory factor,induce apoptosis,and promote intestinal epithelial cell proliferation and tumor formation | [ | ||
sipA | 与细胞内入侵有关、促进caspase-3的激活和释放 Associated with intracellular invasion and promote activation and release of caspase-3 | [ | ||
sipB | 促进沙门氏菌诱导的caspase-1依赖型细胞的凋亡、促进IL-18的释放 Promote Salmonella-induced caspase-1-dependent apoptosis and the release of IL-18 | [ | ||
sipC | 与沙门氏菌的易位蛋白有关、促进病原体内化 Associated with translocated proteins in Salmonella,and promote pathogen internalization | [ | ||
sptP | 破坏宿主细胞骨架、促进沙门氏菌在宿主细胞内复制 Destroy host cellular actin cytoskeleton,and promote Salmonella intracellular replication | [ | ||
sopA | E3泛素连接酶,泛素化细菌和/或宿主细胞底物 E3 ubiquitin ligase,ubiquitinating bacterial and/or host cell substrates | [ | ||
sopE | 诱导快速的肌动蛋白细胞骨架重排、膜皱褶和随后的病原体巨胞饮,促进细菌侵袭 Induce rapid actin cytoskeletal rearrangement,membrane ruffling,and subsequent pathogen macropinocytosis,and facilitate bacterial invasion | [ | ||
sopE2 | Cdc42 的鸟嘌呤核苷酸交换因子(通过SPI-1-TTSS) Guanine nucleotide exchange factor for Cdc42(via SPI-1-TTSS) | [ | ||
invB | 维持SopA蛋白的稳定性和易位 Maintain the stability and translocation of SopA protein | [ | ||
sicA | 维持分子伴侣InvF的活动 Maintain the activity of chaperone InvF | [ | ||
sicP | 其编码的蛋白SicP是SptP蛋白的分子伴侣 Its encoded protein SicP is a chaperone of the SptP protein | [ | ||
SPI-2 | T3SS2 | ssrB | 其编码的SsrB蛋白激活转录和解除H-NS介导的抑制作用 Its encoded SsrB protein activates transcription and relieves H-NS-mediated repression | [ |
ssaB | 分泌 sseB 和 sseC 所需 Required for the secretion of sseB and sseC | [ | ||
ssaE | 能识别转运体sseB并通过SPI-2的T3SS控制其分泌 Recognize the transporter sseB and controls its secretion through the T3SS of SPI-2 | [ | ||
sscA | sseC易位子的伴侣 Partner of the sseC translocon | [ | ||
sscB | 诱导沙门氏菌上皮细胞连续丝形成、其编码的蛋白sscB是效应子sseF的伴侣 Induce the continuous filament formation in Salmonella epithelial cells,its encoded protein sscB is a partner of the effector sseF | [ | ||
sseC | SPI-2 转座子 SPI-2 transposon | [ | ||
sseL | 抑制宿主炎性作用,对巨噬细胞具有杀伤作用 Inhibit host inflammatory effects and has killing effect on macrophages | [ | ||
sseFG | 将沙门氏菌液泡(SCV)运输到高尔基网络 Transport Salmonella vacuole(SCV)to the Golgi network | [ | ||
ttr | 与四硫酸还原酶的产生有关 Associated with the production of tetrasulfate reductase | [ | ||
SPI-3 | - | mgtCB | 与菌体在宿主细胞内存活以及在宿主肠道定殖有关 Associated with bacterial survival in host cells and the colonization of the host gut | [ |
misL | 编码自体转运蛋白MisL Code autotransporter MisL | [ | ||
SPI-4 | T1SS | siiE | 会对小鼠和牛产生毒力,与宿主肠道上皮细胞的黏附和侵袭有关 Host virulent in mice and cattle,associated with the adhesion and invasion of host intestinal epithelial cells | [ |
SPI-5 | - | pipA | 刺激促炎细胞因子的信号转导 Stimulate signal transduction of pro-inflammatory cytokines | [ |
pipB | 把kinesin-1募集到SCV中 Recruitment of kinesin-1 into SCV | [ | ||
pipC | 与肠上皮侵袭有关 Associated with the invasion of intestinal epithelium | [ | ||
sopB | 具有抗凋亡活性、与细胞内复制有关、损害宿主的肠上皮屏障功能 Having anti-apoptotic activity,associated with intracellular replication,and impair intestinal epithelial barrier function in the host | [ | ||
sigD | 促进中性粒细胞募集、具有抗凋亡活性、与细胞内复制有关 Facilitate neutrophil recruitment,have anti-apoptotic activity,and associated with intracellular replication | [ | ||
sigE | 与肠上皮侵袭有关 Associated with the invasion of intestinal epithelium | [ | ||
SPI-6 | T6SS | saf | 介导细胞间寡聚体机制、促进细菌聚集、定殖和最终生物膜的形成 Mediate cell-cell oligomer mechanisms,and promote bacterial aggregation,colonization,and ultimately biofilm formation | [ |
tcf | 编码功能性菌毛并作为黏附素、有助于伤寒期间的定殖 Encode functional pili and act as an adhesin,and contribute to colonization during typhoid fever | [ | ||
SPI-19 | T6SS | 无 | 与细菌在宿主巨噬细胞内存活以及鸡的定殖有关 Associated with bacterial survival within host macrophages,colonization of chickens | [ |
其他毒力因子 Other virulence factor | 主要基因 Major gene | 功能 Function | 参考文献 Reference |
---|---|---|---|
毒力质粒 Virulence plasmid | spvR | 激活毒力操纵子spvABCD的转录 Activate the transcription of the virulence operon spvABCD | [ |
spvA | 与细菌的多重耐药有关 Associated with multidrug resistance in bacteria | [ | |
spvB | 干扰巨噬细胞铁代谢、促进沙门氏菌的存活和细胞内复制 Interfer with macrophage iron metabolism,and promote Salmonella survival and intracellular replication | [ | |
spvC | 显著促进小鼠早期肠外传播 Significantly promote early parenteral transmission in mice | [ | |
spvD | 负性调节NF-κB信号通路并促进鼠伤寒沙门氏菌血清型的毒力 Negatively regulate NF-κB signaling pathway and promote the virulence of Salmonella typhimurium serotypes | [ | |
鞭毛 Flagella | fliC | 编码沙门氏菌的抗原亚基鞭毛蛋白第一相 Encode the phase 1 flagellar antigens of Salmonella | [ |
fljB | 编码沙门氏菌的抗原亚基鞭毛蛋白第二相 Encode the phase 2 flagellar antigens of Salmonella | [ | |
flpA | 编码沙门氏菌的抗原亚基鞭毛蛋白第三相 Encode the phase 3 flagellar antigens of Salmonella | [ | |
菌毛 Pili | agf | 编码卷曲型聚集性菌毛、促进细菌的黏附和入侵 Encode curly clustered pili,and promote bacterial adhesion and invasion | [ |
bfp | 编码Ⅳ型菌毛、促进感染早期在宿主上皮表面形成黏附菌落 Encode type Ⅳ pili,and promote the formation of adherent colonies on host epithelial surfaces early in infection | [ | |
pil | 编码Ⅳ型菌毛 Encode type Ⅳ pili | [ | |
fim | 影响宿主趋性 Impact host chemotaxis | [ | |
肠毒素 Enterotoxin | stn | 与细菌细胞膜的完整性相关 Associated with integrity of bacterial membrane membranes | [ |
表2 沙门氏菌其他毒力因子中主要的基因及功能
Table 2 Major genes and functions in other virulence factors of Salmonella
其他毒力因子 Other virulence factor | 主要基因 Major gene | 功能 Function | 参考文献 Reference |
---|---|---|---|
毒力质粒 Virulence plasmid | spvR | 激活毒力操纵子spvABCD的转录 Activate the transcription of the virulence operon spvABCD | [ |
spvA | 与细菌的多重耐药有关 Associated with multidrug resistance in bacteria | [ | |
spvB | 干扰巨噬细胞铁代谢、促进沙门氏菌的存活和细胞内复制 Interfer with macrophage iron metabolism,and promote Salmonella survival and intracellular replication | [ | |
spvC | 显著促进小鼠早期肠外传播 Significantly promote early parenteral transmission in mice | [ | |
spvD | 负性调节NF-κB信号通路并促进鼠伤寒沙门氏菌血清型的毒力 Negatively regulate NF-κB signaling pathway and promote the virulence of Salmonella typhimurium serotypes | [ | |
鞭毛 Flagella | fliC | 编码沙门氏菌的抗原亚基鞭毛蛋白第一相 Encode the phase 1 flagellar antigens of Salmonella | [ |
fljB | 编码沙门氏菌的抗原亚基鞭毛蛋白第二相 Encode the phase 2 flagellar antigens of Salmonella | [ | |
flpA | 编码沙门氏菌的抗原亚基鞭毛蛋白第三相 Encode the phase 3 flagellar antigens of Salmonella | [ | |
菌毛 Pili | agf | 编码卷曲型聚集性菌毛、促进细菌的黏附和入侵 Encode curly clustered pili,and promote bacterial adhesion and invasion | [ |
bfp | 编码Ⅳ型菌毛、促进感染早期在宿主上皮表面形成黏附菌落 Encode type Ⅳ pili,and promote the formation of adherent colonies on host epithelial surfaces early in infection | [ | |
pil | 编码Ⅳ型菌毛 Encode type Ⅳ pili | [ | |
fim | 影响宿主趋性 Impact host chemotaxis | [ | |
肠毒素 Enterotoxin | stn | 与细菌细胞膜的完整性相关 Associated with integrity of bacterial membrane membranes | [ |
报道年份 Reported Year | 国家 Country | 来源 Origin | 毒力基因检出率 Detection rate of virulence gene | 与毒力的关系 Relationship to virulence | 参考文献 Reference |
---|---|---|---|---|---|
2021 | 中国-山东(n=60) Shandong Province,China | 鸭胚 Duck embryo | 毒力岛基因:invA、sipC、sipA、sopA、ssaB、orf319、pipC、misL均为100% 毒力质粒基因:spvA、spvB、spvC、spvD、spvR均>50% 菌毛基因:sefA(38%) 肠毒素:stn为100% | 与毒力基因的数量呈正相关 Positive correlation with the number of virulence genes | [ |
2021 | 伊朗(n=27) Iran | 人 Human | 毒力岛基因:invA、sipA、sopB、sopE2和hilA均为100%;sopE、ssrA和ssaR均>90% 肠毒素基因:stn>90% | 与毒力基因呈正相关 Positive association with virulence genes | [ |
2020 | 中国-广西 (n=55) Guangxi Province,China | 鸡 Chicken | 毒力岛基因:ttrB、hilA、sopB、sopA、rhuM、siiE、spi4H、sipA、sseL和sipB均>80.00%;pipC、ssaB、misL、prgk、rmbA、iacP、ssrA、mgtC、invH 和orf319为50.00%-80.00%;sugR、avrA、sopD和siiD为20.00%-50.00%;ssaQ和sifA为0.00-20.00% 毒力质粒基因:spvR、spvA、spvB、spvC、spvD均>60.00% | 与毒力基因的数量呈正相关 Positive correlation with the number of virulence genes | [ |
2018 | 中国-四川(n=156) Sichuan Province,China | 鸭 Duck | 毒力岛基因:avr A、ssa Q和 mgt C均>90.0%;sii D和sop B均>80.0%;sop E 为0% 毒力质粒基因:spv R>80.0%;spv B 和 spv C 均>10% Virulence island genes:avr A,ssa Q and mgt C > 90.0%;sii D and sop B > 80.0%;sop E 0% Virulence plasmid genes:spv R > 80.0%;spv B and spv C > 10%; | 与毒力基因呈正相关 Positive association with virulence genes | [ |
2016 | 英国 (n=95) Britain | 鸡 Chicken | 105个毒力岛基因和毒力质粒基因中:40个为100%,2个为0%,63个为0-100% | 与毒力基因的数量呈正相关 Positive correlation with the number of virulence genes | [ |
2014 | 中国-黑龙江 (n=44) Heilongjiang Province,China | 鸡 Chicken | 毒力岛基因:sopA(95.5%)、invJ、virK、sipA、ssaB、misL、orf319和pipC为0% 毒力质粒基因:spvC(68.2%) 菌毛基因:fimA(82%) 肠毒素基因:stn(0%) | 与毒力基因的种类呈正相关 Positive correlation with species of virulence genes | [ |
2013 | 中国-安徽 (n=7) Anhui Province,China | 鸡 Chicken | 毒力岛基因:sscA、sseC、sseD和sseE为100%;sseC(51.14%) 毒力质粒基因:spvA、spvB、spvC、spvD和spvR为14.29% | 与毒力基因的分布存在相关性 Correlation with distribution of virulence genes | [ |
2013 | 中国-黑龙江 (n=44) Heilongjiang Province,China | 鸡 Chicken | 毒力岛基因:invJ、virK、sipA、ssaB、misL、orf319、pipC为100%;sopA(95.5%) 毒力质粒基因:spvC(68.2%) | 与毒力基因呈正相关 Positive association with virulence genes | [ |
表3 国内外沙门氏菌中毒力基因的流行情况及与毒力的关系
Table 3 Prevalence of Salmonella virulence genes at home and abroad and their relationship with virulence
报道年份 Reported Year | 国家 Country | 来源 Origin | 毒力基因检出率 Detection rate of virulence gene | 与毒力的关系 Relationship to virulence | 参考文献 Reference |
---|---|---|---|---|---|
2021 | 中国-山东(n=60) Shandong Province,China | 鸭胚 Duck embryo | 毒力岛基因:invA、sipC、sipA、sopA、ssaB、orf319、pipC、misL均为100% 毒力质粒基因:spvA、spvB、spvC、spvD、spvR均>50% 菌毛基因:sefA(38%) 肠毒素:stn为100% | 与毒力基因的数量呈正相关 Positive correlation with the number of virulence genes | [ |
2021 | 伊朗(n=27) Iran | 人 Human | 毒力岛基因:invA、sipA、sopB、sopE2和hilA均为100%;sopE、ssrA和ssaR均>90% 肠毒素基因:stn>90% | 与毒力基因呈正相关 Positive association with virulence genes | [ |
2020 | 中国-广西 (n=55) Guangxi Province,China | 鸡 Chicken | 毒力岛基因:ttrB、hilA、sopB、sopA、rhuM、siiE、spi4H、sipA、sseL和sipB均>80.00%;pipC、ssaB、misL、prgk、rmbA、iacP、ssrA、mgtC、invH 和orf319为50.00%-80.00%;sugR、avrA、sopD和siiD为20.00%-50.00%;ssaQ和sifA为0.00-20.00% 毒力质粒基因:spvR、spvA、spvB、spvC、spvD均>60.00% | 与毒力基因的数量呈正相关 Positive correlation with the number of virulence genes | [ |
2018 | 中国-四川(n=156) Sichuan Province,China | 鸭 Duck | 毒力岛基因:avr A、ssa Q和 mgt C均>90.0%;sii D和sop B均>80.0%;sop E 为0% 毒力质粒基因:spv R>80.0%;spv B 和 spv C 均>10% Virulence island genes:avr A,ssa Q and mgt C > 90.0%;sii D and sop B > 80.0%;sop E 0% Virulence plasmid genes:spv R > 80.0%;spv B and spv C > 10%; | 与毒力基因呈正相关 Positive association with virulence genes | [ |
2016 | 英国 (n=95) Britain | 鸡 Chicken | 105个毒力岛基因和毒力质粒基因中:40个为100%,2个为0%,63个为0-100% | 与毒力基因的数量呈正相关 Positive correlation with the number of virulence genes | [ |
2014 | 中国-黑龙江 (n=44) Heilongjiang Province,China | 鸡 Chicken | 毒力岛基因:sopA(95.5%)、invJ、virK、sipA、ssaB、misL、orf319和pipC为0% 毒力质粒基因:spvC(68.2%) 菌毛基因:fimA(82%) 肠毒素基因:stn(0%) | 与毒力基因的种类呈正相关 Positive correlation with species of virulence genes | [ |
2013 | 中国-安徽 (n=7) Anhui Province,China | 鸡 Chicken | 毒力岛基因:sscA、sseC、sseD和sseE为100%;sseC(51.14%) 毒力质粒基因:spvA、spvB、spvC、spvD和spvR为14.29% | 与毒力基因的分布存在相关性 Correlation with distribution of virulence genes | [ |
2013 | 中国-黑龙江 (n=44) Heilongjiang Province,China | 鸡 Chicken | 毒力岛基因:invJ、virK、sipA、ssaB、misL、orf319、pipC为100%;sopA(95.5%) 毒力质粒基因:spvC(68.2%) | 与毒力基因呈正相关 Positive association with virulence genes | [ |
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