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Article(id=1240375271828811791, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1240375270163673092, articleNumber=null, orderNo=null, doi=10.20043/j.cnki.MPM.202311202, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1699459200000, receivedDateStr=2023-11-09, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773658109862, onlineDateStr=2026-03-16, pubDate=1713974400000, pubDateStr=2024-04-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773658109862, onlineIssueDateStr=2026-03-16, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773658109862, creator=13701087609, updateTime=1773658109862, updator=13701087609, issue=Issue{id=1240375270163673092, tenantId=1146029695717560320, journalId=1227665162245664772, year='2024', volume='51', issue='8', pageStart='1345', pageEnd='1536', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773658109465, creator=13701087609, updateTime=1773658579758, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1240377242795176417, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1240375270163673092, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1240377242795176418, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1240375270163673092, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1493, endPage=1498, ext={EN=ArticleExt(id=1240375272126607381, articleId=1240375271828811791, tenantId=1146029695717560320, journalId=1227665162245664772, language=EN, title=Molecular epidemiological analyses of drug-resistant Mycobacterium tuberculosis in Zigong City, 2018-2020, columnId=1228016572065837304, journalTitle=Modern Preventive Medicine, columnName=Experimental Technology and Applications, runingTitle=null, highlight=null, articleAbstract=
Objective

To explore the clustering of drug-resistant Mycobacterium tuberculosis (MTB) in Zigong from 2018 to 2020, analyze the genetic relationship between strains, and speculate whether there is a potential correlation between drug-resistant strains isolated from different patients, so as to provide a reference for the prevention and treatment of drug-resistant tuberculosis in Zigong.

Methods

The drug-resistant MTB strains isolated from Zigong from 2018 to 2020 were used as the research objects and the standard MIRU-VNTR 12-loci method was used for typing study. The band sizes of the amplified products were analyzed by PCR and agarose gel electrophoresis to obtain the number of replicates of different loci of the strains. The data were imported into the MIRU-VNTRplus database and the SITVIT2 website to construct the phylogenetic tree diagrams and the minimum spanning trees, and the global source analysis of the isolated strains was performed. The discriminatory ability of the 12-locus method was evaluated by locus polymorphism analysis, and the local prevalence and transmission of drug-resistant TB were analyzed by calculating the cluster formation rate and recent transmission rate.

Results

The overall resolution HGI index of MIRU-VNTR standard 12-loci typing was 0.974. MIRU26 and MIRU31 showed high polymorphism; MIRU10, MIRU16, MIRU39, and MIRU40 showed moderate polymorphism, and the remaining loci showed low polymorphism. The most concentrated locus was MIRU2, and the most dispersed locus was MIRU26. The 120 drug-resistant strains contained 77 genotypes, with a clustering rate of 46.67 % and a recent transmission rate of 34.17 %. The minimum spanning tree showed that 120 drug-resistant strains could be divided into three clonal complexes, CC1, CC2, and CC3, according to the VNTR typing results. Among the 120 valid strains, 12 genotypes of 32 strains could be found on the SITVIT2 website, and the corresponding 12 MIT numbers were distributed in 14 countries on five continents worldwide.

Conclusion

The standard VNTR-12 locus method resolves drug-resistant tuberculosis strains well. There is a certain range of transmission of drug-resistant TB in Zigong, and the recent transmission rate is high, targeted surveillance is helpful in the prevention and control of tuberculosis.

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目的

探究2018—2020年自贡市耐药结核分枝杆菌的聚类情况，分析菌株之间的亲缘关系，推测不同病人中分离的耐药菌株之间是否存在潜在的相关性，为自贡市耐药结核病的防治提供参考依据。

方法

以2018—2020年自贡市结核病定点医院分离得到的120株耐药结核分枝杆菌菌株为研究对象，采用标准MIRU-VNTR 12位点法进行分型研究。用PCR和琼脂糖凝胶电泳对扩增产物的条带大小进行分析，获得菌株不同位点的重复次数；将数据导入到MIRU-VNTRplus数据库和SITVIT2网站，构建系统发育树图和最小生成树，并对分离得到的菌株进行全球来源分析；通过位点多态性分析，评价12位点法的分辨能力；通过计算成簇率和近期传播率，分析当地耐药结核病的流行和传播情况。

结果

MIRU-VNTR标准12位点分型的总体分辨力HGI指数为0.974，MIRU26和MIRU31呈现高多态性，MIRU10、MIRU16、MIRU39和MIRU40呈现中等多态性，其余位点呈现低多态性。重复次数最集中的位点是MIRU2，最为分散的位点是MIRU26。120株耐药菌株包含77个基因型，成簇率为46.67%，近期传播率为34.17%。最小生成树显示120株耐药菌株根据VNTR分型结果可以分成三个克隆复合体CC1、CC2和CC3。120份菌株中有32株菌的12个基因型可以在SITVIT2网站中找到相应的12MIT编号，12个基因型分布于全球五个洲14个国家。

结论

标准VNTR-12位点法对于耐药结核菌株有较好的分辨力，自贡市的耐药结核病存在一定的传播范围，近期传播率较高，针对性的监测有助于结核病的防治。

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汪川，E-mail：
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唐静（2000—），女，硕士在读，研究方向：疾病防控实验技术与应用

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唐静（2000—），女，硕士在读，研究方向：疾病防控实验技术与应用

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Chinese Journal of Antituberculosis, 2023, 45(1): 73-78., articleTitle=Analysis of genotype characteristics and drug resistance ofMycobacterium tuberculosis isolates in Fujian Province from 2017 to 2019, refAbstract=null)], funds=[Fund(id=1240748860507747329, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, awardId=2022-YF09-00011-SN, language=CN, fundingSource=成都市科技局重大应用示范项目(2022-YF09-00011-SN), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1240748855482970700, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, xref=1., ext=[AuthorCompanyExt(id=1240748855487165006, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, companyId=1240748855482970700, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan 610041, China), AuthorCompanyExt(id=1240748855499747921, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, companyId=1240748855482970700, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.四川大学华西公共卫生学院（华西第四医院），四川 成都 610041)]), AuthorCompany(id=1240748855604605529, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, xref=2., ext=[AuthorCompanyExt(id=1240748855621382750, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, companyId=1240748855604605529, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.自贡市疾病预防控制中心)])], figs=[ArticleFig(id=1240748858632893319, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=EN, label=Fig.1, caption=Agarose gel electrophoresis results of PCR amplification of MIRU26 locus of some strains, figureFileSmall=MBaXhDLBTlT3JrBUK6m5Uw==, figureFileBig=wRorWE/9IUv56DIeGai+TA==, tableContent=null), ArticleFig(id=1240748858771305355, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=CN, label=图1, caption=部分菌株的MIRU26位点PCR扩增琼脂糖凝胶电泳结果

注：图中M为DNA 100 bp marker，6为标准菌株H37Rv，1-5为样本菌株，重复次数从左至右依次为6、5、1、7、5。

, figureFileSmall=MBaXhDLBTlT3JrBUK6m5Uw==, figureFileBig=wRorWE/9IUv56DIeGai+TA==, tableContent=null), ArticleFig(id=1240748858905523096, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=EN, label=Fig.2, caption=Distribution of the number of strains with different MIRU sites and different repetition times, figureFileSmall=sEYX7zGJf0GSmiwRdZ861w==, figureFileBig=nv7dJTVgvAW0lXYGKX2iIA==, tableContent=null), ArticleFig(id=1240748859014575008, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=CN, label=图2, caption=不同MIRU位点不同重复次数的菌株数量分布图

注：图中蓝色色条由浅到深分别代表重复次数由0到11，色条上的数字代表菌株数。

, figureFileSmall=sEYX7zGJf0GSmiwRdZ861w==, figureFileBig=nv7dJTVgvAW0lXYGKX2iIA==, tableContent=null), ArticleFig(id=1240748859123626914, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=EN, label=Fig.3, caption=Phylogenetic tree of MIRU typing of 120 strains of drug-resistant Mycobacterium tuberculosis, figureFileSmall=98OKBiSzcq2Gbn4ALUKxxQ==, figureFileBig=Oq0MFoZSMpjU0LnOUpA3kA==, tableContent=null), ArticleFig(id=1240748859249456042, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=CN, label=图3, caption=120株耐药结核分枝杆菌的MIRU分型系统发育树图

注：成簇菌株用相同颜色的彩色阴影标注。

, figureFileSmall=98OKBiSzcq2Gbn4ALUKxxQ==, figureFileBig=Oq0MFoZSMpjU0LnOUpA3kA==, tableContent=null), ArticleFig(id=1240748859358507955, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=EN, label=Fig.4, caption=Minimum spanning tree of MIRU typing of 120 strains of drug-resistant Mycobacterium tuberculosis, figureFileSmall=Bm5CzIjQ685dOsnAitliOg==, figureFileBig=QaB8Itm5XStjCip2gVwGnQ==, tableContent=null), ArticleFig(id=1240748859459171261, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=CN, label=图4, caption=120株耐药结核分枝杆菌MIRU分型最小生成树

注：每一个圈代表一个ST，圈的颜色深浅表示一个ST型中包含的菌株数量的多少，颜色越深包含菌株菌株数量越多，相邻圈线上的数字表示两种ST差异位点数量。

, figureFileSmall=Bm5CzIjQ685dOsnAitliOg==, figureFileBig=QaB8Itm5XStjCip2gVwGnQ==, tableContent=null), ArticleFig(id=1240748859568223168, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=EN, label=Table 1, caption=

MIRU-VNTR 12-locus primer sequences

, figureFileSmall=null, figureFileBig=null, tableContent=
位点引物序列（5’-3’）H37Rv产物大小（bp）
MIRU2F: TGGACTTGCAGCAATGGACCAACT508
R: TACTCGGACGCCGGCTCAAAAT
MIRU4F: GCGCGAGAGCCCGAACTGC353
R: GCGCAGCAGAAACGTCAGC
MIRU10F: GTTCTTGACCAACTGCAGTCGTCC643
R: GCCACCTTGGTGATCAGCTACCT
MIRU16F: TCGGTGATCGGGTCCAGTCCAAGTA671
R: CCCGTCGTGCAGCCCTGGTAC
MIRU20F: GCCCTTCGAGTTAGTATCGTCGGTT375
R: CAATCACCGTTACATCGACGTCATC
MIRU23F: CTGTCGATGGCCGCAACAAAACG465
R: AGCTCAACGGGTTCGCCCTTTTGTC
MIRU24F: CGACCAAGATGTGCAGGAATACAT447
R: GGGCGAGTTGAGCTCACAGAA
MIRU26F: TAGGTCTACCGTCGAAATCTGTGAC438
R: CATAGGCGACCAGGCGAATAG
MIRU27F: TCGAAAGCCTCTGCGTGCCAGTAA657
R: GCGATGTGAGCGTGCCACTCAA
MIRU31F: ACTGATTGGCTTCATACGGCTTTA651
R: GTGCCGACGTGGTCTTGAT
MIRU39F: CGCATCGACAAACTGGAGCCAAAC646
R: CGGAAACGTCTACGCCCCACACAT
MIRU40F: GGGTTGCTGGATGACAACGTGT408
R: GGGTGATCTCGGCGAAATCAGATA
), ArticleFig(id=1240748859694052300, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=CN, label=表1, caption=

MIRU-VNTR 12位点引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
位点引物序列（5’-3’）H37Rv产物大小（bp）
MIRU2F: TGGACTTGCAGCAATGGACCAACT508
R: TACTCGGACGCCGGCTCAAAAT
MIRU4F: GCGCGAGAGCCCGAACTGC353
R: GCGCAGCAGAAACGTCAGC
MIRU10F: GTTCTTGACCAACTGCAGTCGTCC643
R: GCCACCTTGGTGATCAGCTACCT
MIRU16F: TCGGTGATCGGGTCCAGTCCAAGTA671
R: CCCGTCGTGCAGCCCTGGTAC
MIRU20F: GCCCTTCGAGTTAGTATCGTCGGTT375
R: CAATCACCGTTACATCGACGTCATC
MIRU23F: CTGTCGATGGCCGCAACAAAACG465
R: AGCTCAACGGGTTCGCCCTTTTGTC
MIRU24F: CGACCAAGATGTGCAGGAATACAT447
R: GGGCGAGTTGAGCTCACAGAA
MIRU26F: TAGGTCTACCGTCGAAATCTGTGAC438
R: CATAGGCGACCAGGCGAATAG
MIRU27F: TCGAAAGCCTCTGCGTGCCAGTAA657
R: GCGATGTGAGCGTGCCACTCAA
MIRU31F: ACTGATTGGCTTCATACGGCTTTA651
R: GTGCCGACGTGGTCTTGAT
MIRU39F: CGCATCGACAAACTGGAGCCAAAC646
R: CGGAAACGTCTACGCCCCACACAT
MIRU40F: GGGTTGCTGGATGACAACGTGT408
R: GGGTGATCTCGGCGAAATCAGATA
), ArticleFig(id=1240748859798909908, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=EN, label=Table 2, caption=

Product length comparison of different site repetition times (bp)

, figureFileSmall=null, figureFileBig=null, tableContent=
重复次数MIRU2MIRU4MIRU10MIRU16MIRU20MIRU23MIRU24MIRU26MIRU27MIRU31MIRU39MIRU40
1455199537618298200447334551545593408
2508276590671375253501385604598646462
3561353643724452306555436657651699516
4614430696777529359609487710704752570
5667507749830606412663538763757805624
6720584802883683465717589816810858678
7773661855936760518771640869863911732
8826738908989837571825691922916964786
98798159611 0429146248797429759691 017840
109328921 0141 0959916779337931 0281 0221 070894
), ArticleFig(id=1240748859907961818, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=CN, label=表2, caption=

不同位点重复次数产物长度对照表（bp）

, figureFileSmall=null, figureFileBig=null, tableContent=
重复次数MIRU2MIRU4MIRU10MIRU16MIRU20MIRU23MIRU24MIRU26MIRU27MIRU31MIRU39MIRU40
1455199537618298200447334551545593408
2508276590671375253501385604598646462
3561353643724452306555436657651699516
4614430696777529359609487710704752570
5667507749830606412663538763757805624
6720584802883683465717589816810858678
7773661855936760518771640869863911732
8826738908989837571825691922916964786
98798159611 0429146248797429759691 017840
109328921 0141 0959916779337931 0281 0221 070894
), ArticleFig(id=1240748860029596639, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=EN, label=Table 3, caption=

SITVIT2 website analysis results

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菌株编号MIRU-VNTR 12位点法12MIT相同型别分布a相同型别基因家族相同型别耐药类型b
ZG079242 325 152 322106AUS、CHN、GBR、SGP、USA、ZAFT1、T20.1.2.3
ZG051232 325 153 323109CHN、CAN、SGPT3、H30.3
ZG100、ZG116、ZG057232 325 153 3241 109CAN、CHN、COL、ESP、GBRS、T1、T20.1.2.3
ZG088233 325 173 5321 137JPN、SGPBeijing0.1
ZG091232 325 153 3221 161COLT1、H30.1.2.3
ZG007233 325 172 4331 421CHNBeijing、MANU22
ZG052233 325 173 4331 423CHNBeijing2.3
ZG101、ZG005233 225 173 4331 433CHNBeijing1.2.3
ZG094233 325 173 5231 468CHNBeijing1
ZG111233 225 173 5331 492CHNBeijing、MANU21
ZG093233 325 153 323311BGR、DOM、GBR、GUF、PAN、USA、ZAFS、T1、H10.1.2
ZG019、ZG022、ZG023、ZG027、ZG028、ZG036、ZG059、ZG060、ZG069、ZG071、ZG074、ZG075、ZG076、ZG083、ZG084、ZG113、ZG118、ZG119233 325 173 533570ESP、JPN、PAN、USABeijing0.1
), ArticleFig(id=1240748860121871333, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=CN, label=表3, caption=

SITVIT2网站分析结果

, figureFileSmall=null, figureFileBig=null, tableContent=
菌株编号MIRU-VNTR 12位点法12MIT相同型别分布a相同型别基因家族相同型别耐药类型b
ZG079242 325 152 322106AUS、CHN、GBR、SGP、USA、ZAFT1、T20.1.2.3
ZG051232 325 153 323109CHN、CAN、SGPT3、H30.3
ZG100、ZG116、ZG057232 325 153 3241 109CAN、CHN、COL、ESP、GBRS、T1、T20.1.2.3
ZG088233 325 173 5321 137JPN、SGPBeijing0.1
ZG091232 325 153 3221 161COLT1、H30.1.2.3
ZG007233 325 172 4331 421CHNBeijing、MANU22
ZG052233 325 173 4331 423CHNBeijing2.3
ZG101、ZG005233 225 173 4331 433CHNBeijing1.2.3
ZG094233 325 173 5231 468CHNBeijing1
ZG111233 225 173 5331 492CHNBeijing、MANU21
ZG093233 325 153 323311BGR、DOM、GBR、GUF、PAN、USA、ZAFS、T1、H10.1.2
ZG019、ZG022、ZG023、ZG027、ZG028、ZG036、ZG059、ZG060、ZG069、ZG071、ZG074、ZG075、ZG076、ZG083、ZG084、ZG113、ZG118、ZG119233 325 173 533570ESP、JPN、PAN、USABeijing0.1
), ArticleFig(id=1240748860218340334, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=EN, label=Table 4, caption=

HGI values at different sites

, figureFileSmall=null, figureFileBig=null, tableContent=
位点名称MIRU2MIRU4MIRU10MIRU16MIRU20MIRU23MIRU24MIRU26MIRU27MIRU31MIRU39MIRU40
HGI0.0000.2160.4890.3570.0650.0970.0170.6790.2530.7030.5350.405
), ArticleFig(id=1240748860314809334, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240375271828811791, language=CN, label=表4, caption=

不同位点的HGI值

, figureFileSmall=null, figureFileBig=null, tableContent=
位点名称MIRU2MIRU4MIRU10MIRU16MIRU20MIRU23MIRU24MIRU26MIRU27MIRU31MIRU39MIRU40
HGI0.0000.2160.4890.3570.0650.0970.0170.6790.2530.7030.5350.405
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2018—2020年四川省自贡市耐药结核分枝杆菌分子流行病学分析
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唐静 1 , 王斌 2 , 龙莹 1 , 汪川 1 , 罗睿心 2 , 邓建平 2
现代预防医学 | 实验技术及其应用 2024,51(8): 1493-1498
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现代预防医学 | 实验技术及其应用 2024, 51(8): 1493-1498
2018—2020年四川省自贡市耐药结核分枝杆菌分子流行病学分析
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唐静1, 王斌2, 龙莹1, 汪川1 , 罗睿心2, 邓建平2
作者信息
  • 1.四川大学华西公共卫生学院（华西第四医院），四川 成都 610041
  • 2.自贡市疾病预防控制中心

    • 唐静（2000—），女，硕士在读，研究方向：疾病防控实验技术与应用

通讯作者:

汪川，E-mail：
Molecular epidemiological analyses of drug-resistant Mycobacterium tuberculosis in Zigong City, 2018-2020
Jing TANG1, Bin WANG2, Ying LONG1, Chuan WANG1 , Rui-xin LUO2, Jian-ping DENG2
Affiliations
  • West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan 610041, China
出版时间: 2024-04-25 doi: 10.20043/j.cnki.MPM.202311202
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摘要
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目的

探究2018—2020年自贡市耐药结核分枝杆菌的聚类情况，分析菌株之间的亲缘关系，推测不同病人中分离的耐药菌株之间是否存在潜在的相关性，为自贡市耐药结核病的防治提供参考依据。

方法

以2018—2020年自贡市结核病定点医院分离得到的120株耐药结核分枝杆菌菌株为研究对象，采用标准MIRU-VNTR 12位点法进行分型研究。用PCR和琼脂糖凝胶电泳对扩增产物的条带大小进行分析，获得菌株不同位点的重复次数；将数据导入到MIRU-VNTRplus数据库和SITVIT2网站，构建系统发育树图和最小生成树，并对分离得到的菌株进行全球来源分析；通过位点多态性分析，评价12位点法的分辨能力；通过计算成簇率和近期传播率，分析当地耐药结核病的流行和传播情况。

结果

MIRU-VNTR标准12位点分型的总体分辨力HGI指数为0.974，MIRU26和MIRU31呈现高多态性，MIRU10、MIRU16、MIRU39和MIRU40呈现中等多态性，其余位点呈现低多态性。重复次数最集中的位点是MIRU2，最为分散的位点是MIRU26。120株耐药菌株包含77个基因型，成簇率为46.67%，近期传播率为34.17%。最小生成树显示120株耐药菌株根据VNTR分型结果可以分成三个克隆复合体CC1、CC2和CC3。120份菌株中有32株菌的12个基因型可以在SITVIT2网站中找到相应的12MIT编号，12个基因型分布于全球五个洲14个国家。

结论

标准VNTR-12位点法对于耐药结核菌株有较好的分辨力，自贡市的耐药结核病存在一定的传播范围，近期传播率较高，针对性的监测有助于结核病的防治。

自贡市  /  耐药结核分枝杆菌  /  分子流行病学
Objective

To explore the clustering of drug-resistant Mycobacterium tuberculosis (MTB) in Zigong from 2018 to 2020, analyze the genetic relationship between strains, and speculate whether there is a potential correlation between drug-resistant strains isolated from different patients, so as to provide a reference for the prevention and treatment of drug-resistant tuberculosis in Zigong.

Methods

The drug-resistant MTB strains isolated from Zigong from 2018 to 2020 were used as the research objects and the standard MIRU-VNTR 12-loci method was used for typing study. The band sizes of the amplified products were analyzed by PCR and agarose gel electrophoresis to obtain the number of replicates of different loci of the strains. The data were imported into the MIRU-VNTRplus database and the SITVIT2 website to construct the phylogenetic tree diagrams and the minimum spanning trees, and the global source analysis of the isolated strains was performed. The discriminatory ability of the 12-locus method was evaluated by locus polymorphism analysis, and the local prevalence and transmission of drug-resistant TB were analyzed by calculating the cluster formation rate and recent transmission rate.

Results

The overall resolution HGI index of MIRU-VNTR standard 12-loci typing was 0.974. MIRU26 and MIRU31 showed high polymorphism; MIRU10, MIRU16, MIRU39, and MIRU40 showed moderate polymorphism, and the remaining loci showed low polymorphism. The most concentrated locus was MIRU2, and the most dispersed locus was MIRU26. The 120 drug-resistant strains contained 77 genotypes, with a clustering rate of 46.67 % and a recent transmission rate of 34.17 %. The minimum spanning tree showed that 120 drug-resistant strains could be divided into three clonal complexes, CC1, CC2, and CC3, according to the VNTR typing results. Among the 120 valid strains, 12 genotypes of 32 strains could be found on the SITVIT2 website, and the corresponding 12 MIT numbers were distributed in 14 countries on five continents worldwide.

Conclusion

The standard VNTR-12 locus method resolves drug-resistant tuberculosis strains well. There is a certain range of transmission of drug-resistant TB in Zigong, and the recent transmission rate is high, targeted surveillance is helpful in the prevention and control of tuberculosis.

Zigong City  /  Drug-resistant Mycobacterium tuberculosis  /  Molecular epidemiology
唐静, 王斌, 龙莹, 汪川, 罗睿心, 邓建平. 2018—2020年四川省自贡市耐药结核分枝杆菌分子流行病学分析. 现代预防医学, 2024 , 51 (8) : 1493 -1498 . DOI: 10.20043/j.cnki.MPM.202311202
Jing TANG, Bin WANG, Ying LONG, Chuan WANG, Rui-xin LUO, Jian-ping DENG. Molecular epidemiological analyses of drug-resistant Mycobacterium tuberculosis in Zigong City, 2018-2020[J]. Modern Preventive Medicine, 2024 , 51 (8) : 1493 -1498 . DOI: 10.20043/j.cnki.MPM.202311202
正文
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结核病（tuberculosis, TB）是由结核分枝杆菌（Mycobacterium Tuberculosis, MTB）引起的慢性呼吸道传染病，是全球和我国公共卫生面临的重大挑战之一。根据世界卫生组织（World Health Organization, WHO）发布的《2022年全球结核病报告》，我国2021年估算的结核病新发患者数在30个结核病高负担国家中排第3位[1]。WHO提出的终止结核病战略的愿景是在2015年的基础上，到2035年实现结核病死亡率下降95%，发病率下降90%，不再因结核病对家庭造成灾难性支出[2]，但是耐药结核病，特别是耐多药结核病和广泛耐药结核病的出现和广泛传播，成为了实现这一目标的主要障碍[3]。
结核分枝杆菌基因分型在确定患者感染类型和追踪结核传播方面具有重要作用，有助于对结核传播进行分类、治疗和控制[4]。目前，多种分子分型方法被用于MTB分型，IS6110限制性片段长度多态性（Insertion Sequences 6110-Restricted Fragment Length Polymorphism, IS6110-RFLP）分析被公认为确定MTB亚种最可靠的结核病流行病学分析方法[5]。然而，IS6110-RFLP技术有一些局限性，例如需要大量的高质量DNA、步骤繁琐、技术要求高等。串联重复序列可变数目分型（Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeat Typing, MIRU-VNTR）是一种新的基于PCR的分型方法，通过扩增结核分枝杆菌基因组中的插入重复序列来确定每个基因座的大小和重复数。其操作简单、成本经济、结果可重复和鉴别力高，因而近年来广泛应用于结核菌基因分型[6]，并且该方法得到的数字结果可以在实验室之间直接和可靠地进行比较，从而可基于互联网构建用于大规模流行病学和群体遗传研究的全球数据库[7]。
四川省近几年肺结核报告发病率位于我国前列[8]，结核病防控问题十分严峻。自贡市地处成渝地区双城经济圈建设南翼、川南城市群中心，截至2022年末，全市常住人口245.2万人。同时，自贡市近5年的结核病报告发病率均处于全省的中间水平，选择自贡市作为研究对象可以较好地反映四川省结核病整体情况。本研究以自贡市2018—2020年临床分离得到的耐药结核分枝杆菌菌株为研究对象，对其进行VNTR-12位点分型，通过基因型探究菌株的聚类情况，分析菌株之间的亲缘关系，推测不同病人来源的耐药菌株之间是否存在潜在的相关性，为自贡市耐药结核病的防治提供参考依据。
1 材料与方法
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1.1 菌株标准
菌株H37Rv来源于四川省疾病预防控制中心。120株耐药结核分枝杆菌临床分离株来源于自贡市各区县定点医院（自贡市第一人民医院、自贡市第三人民医院、荣县人民医院和富顺县人民医院），从病人的痰液中分离培养得到，保存于自贡市疾病预防控制中心。
1.2 主要试剂与仪器
NaCl、Tris、EDTA、绿色荧光核酸染料（北京索莱宝科技有限公司）；冰乙酸（重庆川东化工集团有限公司）；琼脂糖（BIOWEST）；2x Taq PCR mix、100 bp marker、Marker I（康为世纪生物科技股份有限公司）；药敏罗氏培养基（珠海贝索生物技术有限公司）；普通PCR仪（SENSO）；电泳仪、凝胶成像仪（BIO-RAD）；超声破碎仪（Elmasonic S 30）；离心机（eppendorf）。
1.3 方法
1.3.1 耐药菌株鉴定
对临床分离菌株进行比例法药敏试验判定为耐药的菌株，即计算耐药百分比（含药培养基上生长的菌落数/对照培养基上生长的菌落数×100%），结果>1%就认为该菌对于该种药物耐药。
1.3.2 DNA提取
采用金属浴和超声破碎的方法，提取菌株的基因组DNA。吸取500 μl的超纯水于EP管中，然后用接种环刮取培养基上的耐药结核分枝杆菌菌落2~3环于EP管中，置于金属浴中于98 ℃反应30 min，结束后将EP管放入超声破碎仪中超声15 min，最后将EP管转至离心机中13 400 g离心3 min，吸取上清液400 μl作为样本DNA于-20 ℃保存。
1.3.3 PCR扩增
配制PCR反应体系，PCR扩增条件为94 ℃预变性3 min；94 ℃变性1 min，58 ℃退火1 min，72 ℃延伸1 min，30个循环；72 ℃延伸5 min。将PCR产物在250 V电泳30 min，电泳结束后进行紫外成像。MIRU-VNTR 12位点引物序列见表1。
1.3.4 条带分析
根据marker对应的条带大小和产物长度对照表（表2）判读并记录每个位点的重复单元数。
1.3.5 遗传多样性和亲缘性分析
将所有菌株VNTR位点的重复次数导入到MIRU-VNTRplus数据库（https://www.miru-vntrplus.org/MIRU/index），采用非加权配对算术平均法（Unweighted Pair Group Method with Arithmetic Mean, UPMGA）进行聚类分析获得系统发育树图，运用iTOL（http://itol.embl.de/）对树状图进行美化。以categorical法计算相似性系数，构建最小生成树。同时将MIRU-VNTR结果上传至SITVIT2网站（http://www.pasteur-guadeloupe.fr:8081/SITVIT2），对分离得到的菌株进行全球来源分析。
1.3.6 成簇性分析
两个或两个以上菌株具有完全相同的MIRU-VNTR图谱，即被认为是成簇菌株，成簇率=成簇菌株数/总菌株数。近期传播率=（成簇菌株总数-成簇基因型数）/菌株总数×100%。
1.3.7 位点分辨力和分辨力指数（Hunter-Gaston Index, HGI）
根据Hunter 和Gaston用于描述分型方法分辨指数的公式[9]计算不同MIRU位点的HGI值。各VNTR位点的分辨率和总分辨率用Hunter-Gaston指数表示。
1.3.8 位点多态性分析
对于MIRU-VNTR位点：HGI>0.6认为其具有高多态性，0.3≤HGI≤0.6呈中等程度的多态性，HGI<0.3为低多态性。
2 结果
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2.1 一般情况
本研究共获得120株耐药结核分枝杆菌临床分离株，包括6株单耐利福平菌株、35株单耐异烟肼菌株和79株耐多药菌株，120株样本均成功进行了VNTR-12位点分型。
2.2 菌株不同位点的重复次数分析
部分菌株的MIRU26位点重复次数琼脂糖凝胶电泳结果见图1，不同MIRU位点不同重复次数的菌株数量分布见图2。MIRU2是重复次数集中的位点，120株耐药菌株中仅有一个单元重复次数“2”；MIRU26是重复次数最为分散的位点，120株耐药菌株中有11个重复单元次数。
2.3 遗传多样性和亲缘性分析
在SITVIT2网站对这120株菌株的MIRU-VNTR结果进行查询，其中有32株菌的12个基因型可以在网站中找到相应的12MIT编号，见下表3。其余88株菌的基因型尚未在数据库中被定义，为新的基因型。在MIRU-VNTR plus进行相应的聚类分析和最小生成树分析分别形成如图3和图4所示的系统发育树图和最小生成树。在最小生成树中，一个圈代表一个序列类型（Sequence Typing, ST），圈的颜色深浅代表菌株数量的多少，圈之间连线上的数字代表两个ST之间相同等位基因的数量，相同阴影下的圈属于同一个ST群。最小生成树显示120株菌根据MIRU-VNTR分型结果可以分成三个克隆复合体CC1、CC3和CC3，其中C1复合体中包含的菌株数量最多（共包含74株菌），成簇号为13的菌株被认为是进化的起始菌株，位于复合体的中心。
2.4 成簇率分析
120株耐药菌株的MIRU分型结果包含77个基因型（13个基因簇和64个独立基因型），成簇率为46.67%（56/120）。13个成簇的基因簇中，含菌株数最多的一簇有18株菌。根据传播率计算公式计算出近期传播率为34.17%（41/120）。分析成簇菌株的耐药表型，有些成簇的菌株其药敏谱即耐药表型也是相似的，如簇号1、3所包含菌株的耐药表型均为异烟肼（isoniazid, INH），簇号5所包含菌株的耐药表型均为INH、利福平（rifampicin, RIF）、链霉素（streptomycin, SM）、阿米卡星（amikacin, AMK）；但簇号2、4、6、7、8、11、13所包含的菌株的耐药表型不完全相同，说明MIRU-VNTR基因型别的相似并不代表耐药表型也相似。
2.5 位点分辨力HGI值和多态性分析
MIRU-VNTR 12位点法对菌株总的分辨力HGI值为0.974。VNTR-12各个位点的分辨力HGI指数见表4。其中MIRU26和MIRU31呈现高多态性，MIRU10、MIRU16、MIRU39和MIRU40呈现中等多态性，其余位点即MIRU2 、MIRU4、MIRU20、MIRU23、MIRU24和MIRU27呈现低多态性，其中，MIRU2位点的重复单元次数均为2，未表现出多态性。
3 讨论
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耐药结核病的治疗由于药物毒副作用大、疗程长、不良反应发生率高、治疗费用高，是结核病控制的沉重负担，可能导致患者治疗效果差或死亡，对患者身心健康及其家庭造成巨大损害。分子分型方法是监测控制结核病传播以及检测确认结核病暴发的有力辅助手段，对制定有效的感染控制政策具有重要价值。MIRU-VNTR12位点法是一种基于重复序列的分子生物学技术，用于结核分枝杆菌分离株的不同MIRU-VNTR位点分型方法中，MIRU -VNTR 12位点法是目前使用最广泛的方法，并且已在美国等国家范围内被整合到结核病控制系统中[10]。MIRU-VNTR基于结核分枝杆菌基因组中的短串联重复序列，这些序列在不同的菌株间会有不同的复制数目，因此可以用来区分不同的菌株。这种方法的优点在于，可以在许多不同的菌株中进行大规模和快速的分型，而且分辨率较高，MIRU -VNTR 12位点法分型鉴别力接近 IS6110-RFLP 分型的鉴别力。因此，MIRU-VNTR被广泛应用于结核病的流行病学研究和监测，以了解疾病的传播模式和菌株的遗传变异。
本研究选择了自贡市2018至2020年的120株耐药菌株进行分析，MIRU-VNTR 12位点法分辨力HGI值为0.974，与印度[11]、伊朗[12]、北京[13]等研究的分辨力结果相符合。除了MIRU02外，其余11个位点均呈现出一定的多态性。其中，MIRU26和MIRU31的HGI指数大于0.6，呈现高多态性，而在自贡市对2010年菌株的分型研究中仅MIRU26呈现高多态性，但MIRU31的HGI为0.592也呈现较高的多态性位居第二[14]，提示近5年自贡市流行的结核分枝杆菌从基因型方面来说可能变化较小。
对这些菌株聚类分析可以发现，这120株耐药菌株的成簇率高达45.83%，远高于同类型的其他研究，如宜昌（12.15%）[15]、新疆（7.93%）[16]。成簇率高反映了这些菌株存在一定的亲缘关系，可能是近期感染导致的。在本研究中近期传播率为35%，高于同类型的其他研究[17]，反映自贡市的耐药菌株存在一定的传播范围，这些菌株来源的患者可能存在一定的空间交集，成簇菌株间是否存在流行病学关联还需进一步验证。
SITVIT2分析结果显示，本次纳入的菌株中有26.7%的菌株可以在网站上找到相同型别的菌株数据，这些相同型别的菌株来自全球14个国家五个洲，包括12个型别，12个型别中有5个型别只在中国被发现，有4个型别只在国外有所报道。由于这些数据的上传时间都在2012年以前，因此可以看出在最近10年的时间里，由于与欧美国家的贸易旅游往来增加，一些欧美国家的流行株也被引入国内[18]。同时，从从成簇菌株的耐药表型结果可见，同型别不同菌株的耐药情况是多样化的，说明MIRU-VNTR型别与耐药的关系不大，仅靠分型结果还无法预测菌株的耐药类型。
本研究结果证实MIRU-VNTR分型是研究区域环境中耐药MTB遗传多样性的有效工具，发现自贡市的耐药结核病存在一定的传播范围，近期传播率较高，提示在之后的耐药病人管理上还需要采取进一步的措施。然而，这项研究样本量相对较小，今后的研究可以扩大样本量，将MIRU-VNTR 分型方法与其他分型方法（如spoligotype和 IS6110 RFLP）相结合，有助于对正在研究的分离株进行更广泛的区分。综上，本研究对自贡市近年来耐药结核分枝杆菌的基因构成和流行情况进行了描述，VNTR-12“233325173533”型别为自贡市近年耐药菌株中为最主要的流行类型，同时也存在个别独立型的流行。建议在自贡市范围内加强对耐药结核菌株的监测和筛查工作，特别是针对VNTR-12“233325173533”型别的菌株进行重点监测，与此同时积极共享关于耐药结核菌株的信息，加强地区间的卫生监测与防控合作。
基金
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  • 成都市科技局重大应用示范项目(2022-YF09-00011-SN)
文献
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2024年第51卷第8期
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doi: 10.20043/j.cnki.MPM.202311202
  • 接收时间：2023-11-09
  • 首发时间：2026-03-16
  • 出版时间：2024-04-25
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  • 收稿日期：2023-11-09
基金
成都市科技局重大应用示范项目(2022-YF09-00011-SN)
作者信息
    1.四川大学华西公共卫生学院（华西第四医院），四川 成都 610041
    2.自贡市疾病预防控制中心

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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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