天津市耐药结核病危险因素及结核分枝杆菌耐药分子机制研究
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摘要
目的：了解天津市耐药结核病的流行现状及其危险因素,北京基因型结核分枝杆菌在人群中的流行现状及其在耐药结核病传播中的作用,揭示天津地区耐药结核分枝杆菌四种一线抗结核药物耐药相关基因的突变类型、突变频率及其与耐药表型和北京基因型的关系,结核分枝杆菌药物外排泵基因的表达与耐药表型、耐药相关基因突变型的关系。
对象和方法：
1.耐药结核病流行情况：研究对象为2008年1月至2009年6月,在天津市结核病控制中心、天津市10个区县结防机构就诊的结核分枝杆菌分离培养阳性肺结核患者。采用“世界卫生组织/国际防痨与肺部疾病联合会”推荐的比例法,对研究对象初次分离培养获得的菌株进行利福平、异烟肼、链霉素和乙胺丁醇的药物敏感实验。运用横断面调查的方法描述耐药结核病的流行情况。
2耐药结核病危险因素分析：对以上研究对象,采用单因素非条件和多因素非条件logistic回归分析从社会人口学、菌株相关实验室信息、临床信息和结核病管理信息四个方面分析耐多药结核病和其他耐药结核病的危险因素。
3北京基因型菌株的流行情况：对从以上研究对象初次分离的结核分枝杆菌菌株,采用多重PCR方法鉴定北京基因型菌株,并分析北京基因型菌株的分布特征及其与耐药表型的关系。
4耐药相关基因突变的研究：对从以上研究对象初次分离的全部耐药结核分枝杆菌菌株采用直接测序法检测以下耐药相关基因的突变情况并分析耐药相关基因突变型与耐药表型和北京基因型的关系：异烟肼耐药株：katG、inhA、 oxyR-ahpC、ndh;利福平耐药株：rpoB;链霉素耐药株：rpsL和rrs;乙胺丁醇耐药株：embB、embC和embA。
5药物外排泵表达量的研究：研究对象为2007年天津市结核病控制中心参比室库存的71株菌株。采用real-time RT-PCR方法检测药物外排泵基因Rv1258c、 Rv1410c、Rv2136c、Rv0783c和Rv1819c的表达与耐药表型、耐药相关基因突变型的关系。
结果：
1.耐药结核病流行现状：共纳入肺结核患者656例,其中初治568例,复治88例。药物敏感试验结果显示：总耐药率为26.98%(177/656),初治病人耐药率为24.47%(139/568),复治病人耐药率为43.18%(38/88)；总耐多药率为6.25%(41/656),初治病人耐多药率为3.70%(21/568),复治病人耐多药率为22.73%(20/88)。
2耐药结核病危险因素分析：耐多药结核病与以下因素有关：年龄组(30-49岁/≥50岁,OR=3.000,95%CI:1.121-8.024)、胸片受累肺野数(6个/1-5个,OR=3.153,95%CI：1.187-8.378)、结核病治疗史(复治/初治,OR=6.984,95%CI:3.250-15.009)和督导员(其他督导员/医务人员,OR=2.935,95%CI：1.204-7.152)。未发现有关因素与其他耐药结核病有关。
3北京基因型菌株的流行情况：分离到的656株结核分枝杆菌中,北京基因型菌株占91.46%(600/656),其分布与天津市户籍(χ2=4.26,p=0.039)和年龄≥55岁(χ2=4.03,p=0.045)有关,未发现北京基因型菌株的特殊耐药型。
4耐药相关基因突变的研究：异烟肼耐药株katG突变率为49.09%(54/110),其中47株(42.73%)为katG315ACC(Thr), inhA-15C→T突变率为24.55%(27/110), oxyR-ahpC突变率为11.82%(13/110),未检测到ndh突变,异烟肼耐药株总突变率为85.45%(94/110),katG315位突变与异烟肼耐药株同时对其他药物耐药有关。利福平耐药株rpoB基因突变率为88.46%(46/52),以利福平耐药决定区内突变为主,531、526和516位密码子的突变率分别为50.00%(26/52)、23.08%(12/52)和5.77%(3/52),rpoB突变与利福平耐药株联合链霉素、链霉素和异烟肼有关。链霉素耐药株rpsL突变率为73.27%(85/116),rrs突变率为14.66%(17/116),总突变率为87.07%(102/116),rpsL基因突变与北京基因型菌株有关。乙胺丁醇耐药株embB基因突变率为27.27%(9/33),embC突变率为3.03%(1/33),未见embA突变。embB突变与多药耐药有关。
5.药物外排泵基因表达量的研究：Rv1258c表达阴性。与全敏菌株相比,Rv1410c表达量在以下耐药菌株中表达量升高：链霉素(t=2.18,p=0.034),异烟肼(t=2.20,p=0.032),异烟肼+链霉素(t=2.43,p=0.021),≥2种抗结核药(F=3.60,p=0.018)；Rv2136c：异烟肼(t=2.03,p=0.047),耐多药(t=2.22,p=0.037),异烟肼+链霉素(t=2.28,p=0.029)。Rv0783c的表达量：利福平耐药株rpoB531位密码子突变菌株高于该位点未突变的利福平耐药株(t=2.84,p=0.016)。
结论：
1年龄在30-49岁、胸片受累6个肺野、结核病治疗史、受非医务人员及非家庭成员(其他督导员)督导,是耐多药结核病的危险因素。因此在结核病防控工作中应对肺结核病人群的此类特征加以关注并采取相应措施。
2未发现北京基因菌株具有特殊的耐药型。北京基因型菌株是天津市的主要流行株,在年龄≥55岁的人群中传播较广。
3耐药相关基因突变是天津市结核分枝杆菌耐药的主要分子机制,rpsL基因突变与北京基因型有关。本研究结果将为研发结核分枝杆菌药物敏感性检测的新方法提供依据。
4Rv0783c的高表达与利福平耐药株rpoB531位密码子突变有关。Rv1410c和Rv2136c表达量可做为鉴定结核分枝杆菌多药耐药性的指标。
To investigate the prevalence and the risk factors of drug-resistant tuberculosis in Tianjin; to identify the Beijing genotype Mycobacterium tuberculosis and describe the association of Beijing genotype Mycobacterium tuberculosis and drug resistance and other characters; to research the drug-resistance genotype of four anti-tuberculosis drugs and the mutated codons and their association with the corresponding drug resistance phenotype, drug resistance level and Beijing genotype; to detect the expression of drug efflux pump genes and analyze their association with drug resistant phenotype and drug resistance related mutated patterns.
Methods:
1A cross-sectional study was conducted to describe the drug-resistant tuberculosis prevalence in Tianjin:The subjects were all culture-positive pulmonary tuberculosis patients newly diagnosed or retreated in Tianjin Tuberculosis Control Center and10districs or county tuberculosis dispensaries from January2008to June2009. The proportion method recommended by WHO/IUATLD was used for testing the strains' susceptibility to rifampicin, isoniazid, streptomicin and ethambutol.
2Bivariate and multiple unconditional logistic regression were performed to identified factors associated with multidrug-resistant tuberculosis and other drug-resistant tuberculosis.
3Multiplex PCR was performed to identify Beijing genotype of the above subjects' first isolated strains.
4DNA sequencing the genes of the above subjects'first isolated strains was applied to investigate the drug-resistance genotype, the most common mutated codons and their association with the corresponding drug resistance phenotype, drug resistance level and Beijing genotype. The genes sequenced were katG, inhA, oxyR-ahpC and ndh associated with isoniazid resistance, rpoB associated with rifampicin resistance, rpsL and rrs associated with streptomycin resistance, embB, embC and embA associated with ethambutol resistance.
5Real-time RT-PCR was used to assess the expressions of putative drug efflux pump genes Rv1258c, Rv1410c, Rv2136c, Rv0783c and Rv2136c in71mycobacterium tuberculosis strains from Tianjin Tuberculosis Control center in2007.
Results:
1656subjects were included,568were new tuberculosis cases and88were previously treated. The prevalence of overall resistance among all cases was26.98%(177),24.47%(139) among new cases,43.18%(38) among previously treated cases. The prevalence of MDR-TB among all cases was6.25%(41),3.70%(21) in new cases,22.73%(20) among previously treated cases.
2The independent predictors of multidrug-resistant tuberculosis were age group (30-49years old/≥50years old, OR=3.000,95%CI:1.121-8.024), the numbers of abnormal lung fields (6/1-5, OR=3.153,95%CI:1.187-8.378), previous treatment history (OR=6.984,95%CI:3.250-15.009), supervisors except doctors and family members (OR=2.787,95%CI:1.152-6.741). No associations were found between any factors and the other drug-resistant tuberculosis.
3Six hundreds of656strains were Beijing genotype, and Beijing genotype strains were more prevalent in population from Tianjin (χ2=4.26, p=0.039) and age≤55years old (χ=4.03,p=0.045). No association was found between Beijing genotype and drug resistance.
4Of110isoniazid resistant isolates,54(49.09%) had mutations in the katG with315ACC(Thr) for responsible for42.73%of isoniazid resistance,27(24.55%) had mutation of inhA-15C→T, and13(11.82%) had mutations in the oxyR-ahpC, no mutation was found in ndh. In all,94of110isoniazid resistant isolates carried mutations. Mutations in katG315were related to combination resistance of isoniazid and other drugs. Forty six out of51rifampicin resistant isolates carried the mutations within the81-bp rifampicin resistance determining region (RRDR) of the rpoB gene, and the most frequent mutations were at codon531(50.00%),526(23.08%), and516(5.77%), respectively. Mutations of rpoB were related to combination resistance of rifampicin and streptomycin and/or isoniazid. Of116streptomycin resistant isolates,85(73.27%) had mutations in rpsL,17(14.66%) had mutations in rrs. Mutations in rpsL were related to Beijing genotype. Of33ethambutol resistant isolates,9(27.27%) had mutations in embB,1(3.03%) had mutations in embC, no mutations was found in embA.
5The expression of drug efflux pump gene Rv1258c of all isolates was negative. Compared to pan-sensitive isolates, Rv1410c showed higher expression in streptomycin (t=2.18, p=0.034), isoniazid (t=2.20,p=0.032), isoniazid+streptomycin (t=2.43, p=0.021),≥2any of four drugs (F=3.60,p=0.018) resistant isolates; Rv2136c showed higher expression in isoniazid resistant isolates (t=2.03,p=0.047) and multidrug-resistant isolates (t=2.22, p=0.037). The expression of Rv0783c in rifampicin resistant isolates with rpoB531mutations was higher than those with wild type of rpoB531(t=2.84,p=0.016).
Conclusions:
1Age and clinic characters (abnormal lung fields, previous treatment history) and supervisors were related to drug resistance, more interventions should be taken on such characters of tuberculosis patients.
2Beijing genotype mycobacterium tuberculosis was prevalent in Tianjin China and population with age≥55years old. No association was found between Beijing genotype and drug resistance.
3Mutations in drug related genes were the major mechanism leading to drug resistance. And this study will provide clues for choosing a suitable molecular biology method based on gene mutations testing for diagnosing drug susceptibility of mycobacterium tuberculosis strains in Tianjin, China. Mutations in rpsL were more frequent in Beijing genotype stains.
4It was concluded that the expressions of Rv1410c and Rv2136c could be targets of molecular methods for diagnosing drug resistance. The expression of Rv0783c in rifampicin resistant isolates was associated with mutation rpoB531.
对象和方法：
1.耐药结核病流行情况：研究对象为2008年1月至2009年6月,在天津市结核病控制中心、天津市10个区县结防机构就诊的结核分枝杆菌分离培养阳性肺结核患者。采用“世界卫生组织/国际防痨与肺部疾病联合会”推荐的比例法,对研究对象初次分离培养获得的菌株进行利福平、异烟肼、链霉素和乙胺丁醇的药物敏感实验。运用横断面调查的方法描述耐药结核病的流行情况。
2耐药结核病危险因素分析：对以上研究对象,采用单因素非条件和多因素非条件logistic回归分析从社会人口学、菌株相关实验室信息、临床信息和结核病管理信息四个方面分析耐多药结核病和其他耐药结核病的危险因素。
3北京基因型菌株的流行情况：对从以上研究对象初次分离的结核分枝杆菌菌株,采用多重PCR方法鉴定北京基因型菌株,并分析北京基因型菌株的分布特征及其与耐药表型的关系。
4耐药相关基因突变的研究：对从以上研究对象初次分离的全部耐药结核分枝杆菌菌株采用直接测序法检测以下耐药相关基因的突变情况并分析耐药相关基因突变型与耐药表型和北京基因型的关系：异烟肼耐药株：katG、inhA、 oxyR-ahpC、ndh;利福平耐药株：rpoB;链霉素耐药株：rpsL和rrs;乙胺丁醇耐药株：embB、embC和embA。
5药物外排泵表达量的研究：研究对象为2007年天津市结核病控制中心参比室库存的71株菌株。采用real-time RT-PCR方法检测药物外排泵基因Rv1258c、 Rv1410c、Rv2136c、Rv0783c和Rv1819c的表达与耐药表型、耐药相关基因突变型的关系。
结果：
1.耐药结核病流行现状：共纳入肺结核患者656例,其中初治568例,复治88例。药物敏感试验结果显示：总耐药率为26.98%(177/656),初治病人耐药率为24.47%(139/568),复治病人耐药率为43.18%(38/88)；总耐多药率为6.25%(41/656),初治病人耐多药率为3.70%(21/568),复治病人耐多药率为22.73%(20/88)。
2耐药结核病危险因素分析：耐多药结核病与以下因素有关：年龄组(30-49岁/≥50岁,OR=3.000,95%CI:1.121-8.024)、胸片受累肺野数(6个/1-5个,OR=3.153,95%CI：1.187-8.378)、结核病治疗史(复治/初治,OR=6.984,95%CI:3.250-15.009)和督导员(其他督导员/医务人员,OR=2.935,95%CI：1.204-7.152)。未发现有关因素与其他耐药结核病有关。
3北京基因型菌株的流行情况：分离到的656株结核分枝杆菌中,北京基因型菌株占91.46%(600/656),其分布与天津市户籍(χ2=4.26,p=0.039)和年龄≥55岁(χ2=4.03,p=0.045)有关,未发现北京基因型菌株的特殊耐药型。
4耐药相关基因突变的研究：异烟肼耐药株katG突变率为49.09%(54/110),其中47株(42.73%)为katG315ACC(Thr), inhA-15C→T突变率为24.55%(27/110), oxyR-ahpC突变率为11.82%(13/110),未检测到ndh突变,异烟肼耐药株总突变率为85.45%(94/110),katG315位突变与异烟肼耐药株同时对其他药物耐药有关。利福平耐药株rpoB基因突变率为88.46%(46/52),以利福平耐药决定区内突变为主,531、526和516位密码子的突变率分别为50.00%(26/52)、23.08%(12/52)和5.77%(3/52),rpoB突变与利福平耐药株联合链霉素、链霉素和异烟肼有关。链霉素耐药株rpsL突变率为73.27%(85/116),rrs突变率为14.66%(17/116),总突变率为87.07%(102/116),rpsL基因突变与北京基因型菌株有关。乙胺丁醇耐药株embB基因突变率为27.27%(9/33),embC突变率为3.03%(1/33),未见embA突变。embB突变与多药耐药有关。
5.药物外排泵基因表达量的研究：Rv1258c表达阴性。与全敏菌株相比,Rv1410c表达量在以下耐药菌株中表达量升高：链霉素(t=2.18,p=0.034),异烟肼(t=2.20,p=0.032),异烟肼+链霉素(t=2.43,p=0.021),≥2种抗结核药(F=3.60,p=0.018)；Rv2136c：异烟肼(t=2.03,p=0.047),耐多药(t=2.22,p=0.037),异烟肼+链霉素(t=2.28,p=0.029)。Rv0783c的表达量：利福平耐药株rpoB531位密码子突变菌株高于该位点未突变的利福平耐药株(t=2.84,p=0.016)。
结论：
1年龄在30-49岁、胸片受累6个肺野、结核病治疗史、受非医务人员及非家庭成员(其他督导员)督导,是耐多药结核病的危险因素。因此在结核病防控工作中应对肺结核病人群的此类特征加以关注并采取相应措施。
2未发现北京基因菌株具有特殊的耐药型。北京基因型菌株是天津市的主要流行株,在年龄≥55岁的人群中传播较广。
3耐药相关基因突变是天津市结核分枝杆菌耐药的主要分子机制,rpsL基因突变与北京基因型有关。本研究结果将为研发结核分枝杆菌药物敏感性检测的新方法提供依据。
4Rv0783c的高表达与利福平耐药株rpoB531位密码子突变有关。Rv1410c和Rv2136c表达量可做为鉴定结核分枝杆菌多药耐药性的指标。
To investigate the prevalence and the risk factors of drug-resistant tuberculosis in Tianjin; to identify the Beijing genotype Mycobacterium tuberculosis and describe the association of Beijing genotype Mycobacterium tuberculosis and drug resistance and other characters; to research the drug-resistance genotype of four anti-tuberculosis drugs and the mutated codons and their association with the corresponding drug resistance phenotype, drug resistance level and Beijing genotype; to detect the expression of drug efflux pump genes and analyze their association with drug resistant phenotype and drug resistance related mutated patterns.
Methods:
1A cross-sectional study was conducted to describe the drug-resistant tuberculosis prevalence in Tianjin:The subjects were all culture-positive pulmonary tuberculosis patients newly diagnosed or retreated in Tianjin Tuberculosis Control Center and10districs or county tuberculosis dispensaries from January2008to June2009. The proportion method recommended by WHO/IUATLD was used for testing the strains' susceptibility to rifampicin, isoniazid, streptomicin and ethambutol.
2Bivariate and multiple unconditional logistic regression were performed to identified factors associated with multidrug-resistant tuberculosis and other drug-resistant tuberculosis.
3Multiplex PCR was performed to identify Beijing genotype of the above subjects' first isolated strains.
4DNA sequencing the genes of the above subjects'first isolated strains was applied to investigate the drug-resistance genotype, the most common mutated codons and their association with the corresponding drug resistance phenotype, drug resistance level and Beijing genotype. The genes sequenced were katG, inhA, oxyR-ahpC and ndh associated with isoniazid resistance, rpoB associated with rifampicin resistance, rpsL and rrs associated with streptomycin resistance, embB, embC and embA associated with ethambutol resistance.
5Real-time RT-PCR was used to assess the expressions of putative drug efflux pump genes Rv1258c, Rv1410c, Rv2136c, Rv0783c and Rv2136c in71mycobacterium tuberculosis strains from Tianjin Tuberculosis Control center in2007.
Results:
1656subjects were included,568were new tuberculosis cases and88were previously treated. The prevalence of overall resistance among all cases was26.98%(177),24.47%(139) among new cases,43.18%(38) among previously treated cases. The prevalence of MDR-TB among all cases was6.25%(41),3.70%(21) in new cases,22.73%(20) among previously treated cases.
2The independent predictors of multidrug-resistant tuberculosis were age group (30-49years old/≥50years old, OR=3.000,95%CI:1.121-8.024), the numbers of abnormal lung fields (6/1-5, OR=3.153,95%CI:1.187-8.378), previous treatment history (OR=6.984,95%CI:3.250-15.009), supervisors except doctors and family members (OR=2.787,95%CI:1.152-6.741). No associations were found between any factors and the other drug-resistant tuberculosis.
3Six hundreds of656strains were Beijing genotype, and Beijing genotype strains were more prevalent in population from Tianjin (χ2=4.26, p=0.039) and age≤55years old (χ=4.03,p=0.045). No association was found between Beijing genotype and drug resistance.
4Of110isoniazid resistant isolates,54(49.09%) had mutations in the katG with315ACC(Thr) for responsible for42.73%of isoniazid resistance,27(24.55%) had mutation of inhA-15C→T, and13(11.82%) had mutations in the oxyR-ahpC, no mutation was found in ndh. In all,94of110isoniazid resistant isolates carried mutations. Mutations in katG315were related to combination resistance of isoniazid and other drugs. Forty six out of51rifampicin resistant isolates carried the mutations within the81-bp rifampicin resistance determining region (RRDR) of the rpoB gene, and the most frequent mutations were at codon531(50.00%),526(23.08%), and516(5.77%), respectively. Mutations of rpoB were related to combination resistance of rifampicin and streptomycin and/or isoniazid. Of116streptomycin resistant isolates,85(73.27%) had mutations in rpsL,17(14.66%) had mutations in rrs. Mutations in rpsL were related to Beijing genotype. Of33ethambutol resistant isolates,9(27.27%) had mutations in embB,1(3.03%) had mutations in embC, no mutations was found in embA.
5The expression of drug efflux pump gene Rv1258c of all isolates was negative. Compared to pan-sensitive isolates, Rv1410c showed higher expression in streptomycin (t=2.18, p=0.034), isoniazid (t=2.20,p=0.032), isoniazid+streptomycin (t=2.43, p=0.021),≥2any of four drugs (F=3.60,p=0.018) resistant isolates; Rv2136c showed higher expression in isoniazid resistant isolates (t=2.03,p=0.047) and multidrug-resistant isolates (t=2.22, p=0.037). The expression of Rv0783c in rifampicin resistant isolates with rpoB531mutations was higher than those with wild type of rpoB531(t=2.84,p=0.016).
Conclusions:
1Age and clinic characters (abnormal lung fields, previous treatment history) and supervisors were related to drug resistance, more interventions should be taken on such characters of tuberculosis patients.
2Beijing genotype mycobacterium tuberculosis was prevalent in Tianjin China and population with age≥55years old. No association was found between Beijing genotype and drug resistance.
3Mutations in drug related genes were the major mechanism leading to drug resistance. And this study will provide clues for choosing a suitable molecular biology method based on gene mutations testing for diagnosing drug susceptibility of mycobacterium tuberculosis strains in Tianjin, China. Mutations in rpsL were more frequent in Beijing genotype stains.
4It was concluded that the expressions of Rv1410c and Rv2136c could be targets of molecular methods for diagnosing drug resistance. The expression of Rv0783c in rifampicin resistant isolates was associated with mutation rpoB531.
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