CN110499353B - 一种用于结核耐药诊断的微生物标志物及其应用 - Google Patents
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Abstract
本发明公开了一种用于结核耐药诊断的微生物标志物,所述微生物标志物为痰液微生物标志物,包括纤毛菌属(Leptotrichia)、颗粒链菌属(Granulicatella)、弯曲菌属(Campylobacter)、代尔夫特菌(Delftia)、金氏菌属(Kingella)、罗尔斯通菌属(Ralstonia)、嗜衣原体属(Chlamydophila)、博代氏杆菌属(Bordetella)中的至少一种。本发明提供了一种快速诊断结核耐药类型的生物标志物。根据不同结核耐药类型个体的痰液微生态进行分析,从平衡上呼吸道微生物的角度为结核耐药的治疗提供新的思路。
Description
技术领域
本发明涉及微生物医学领域,特别涉及一种用于结核耐药诊断的微生物标志物及其应用。
背景技术
随着耐药结核菌株的流行使得疾病的控制变得更复杂,有研究估计原发耐药结核是获得性耐药结核的3倍。耐药结核的流行与肺结核发病率和死亡率密切相关,是导致结核病患者死亡的最主要原因。早期发现和及时规范治疗是当前耐药结核防控的关键。
目前耐药结核的诊断主要包括表型检测和分子基因型检测。传统药物敏感性检测(drug susceptibility testing, DST)是耐药结核检测的金标准,但总体而言,基于结核菌培养的表型检测技术检测周期长、操作复杂、不易标准化,不能充分满足临床快速诊断的需要。此外,部分标本因结核菌含量低、培养阴性,无法进行耐药性检测。分子药敏检测技术近年来进展迅速,是WHO重点推荐的结核病快速药敏检测方法,与培养法相比,分子基因型检测迅速,周期短至1-2 d,甚至数小时。分子基因型检测具有检测迅速、特异性和灵敏度高的特点,但它无法鉴定未知的耐药突变和部分一二线药物耐药突变,且对异质性耐药标本检测敏感性低,因此临床上不能完全取代表型检测技术。总之,随着对耐药结核快速检测的深入研究,新的诊断技术和产品不断涌向临床,但耐药结核的变异多样化,各实验室受到不同条件的限制,均不能充分满足临床检测需求,因此探究新的检测方法和筛选新的诊断标志物显得尤为重要。
近年来随着测序技术的发展,和对人体微生态的不断深入研究,发现我们人体内定植的微生物在人生理过程中扮演着重要角色,TB可能是复杂的微生物群落相互作用,而不是传统上认为的单一病原体导致的结果。在健康个体中微生态组成和丰度的动态平衡被打破,将导致菌群紊乱,致病菌的增殖,生物体相关的病理免疫应答和疾病产生。有研究发现结核患者肺部微生态环境可能更容易受到外来微生物定植,结核患者痰液中致病菌存在更高的多样性和复杂性。因此通过对痰液样本微生物组成的研究和筛选出与结核耐药类型相关性高的生物标志物有重要意义。一方面,利用结核病有关的生物标志物可以为结核药敏诊断提供新的方法,缩短诊断周期。另一方面,对不同耐药类型结核患者的治疗具有一定的临床指导意义。
发明内容
本发明的目的在于提供一种用于结核耐药诊断的微生物标志物及其应用。
本发明所采取的技术方案是:
痰液微生物作为结核耐药诊断标志物的应用,其中,痰液微生物为纤毛菌属(Leptotrichia)、颗粒链菌属(Granulicatella)、弯曲菌属(Campylobacter)、代尔夫特菌(Delftia)、金氏菌属(Kingella)、罗尔斯通菌属(Ralstonia)、嗜衣原体属(Chlamydophila)、博代氏杆菌属(Bordetella)中的至少一种。
定量痰液微生物含量的试剂在制备结核耐药诊断试剂中的应用,其中,痰液微生物为纤毛菌属(Leptotrichia)、颗粒链菌属(Granulicatella)、弯曲菌属(Campylobacter)、代尔夫特菌(Delftia)、金氏菌属(Kingella)、罗尔斯通菌属(Ralstonia)、嗜衣原体属(Chlamydophila)、博代氏杆菌属(Bordetella)中的至少一种。
作为上述应用的进一步改进,纤毛菌属(Leptotrichia)、颗粒链菌属(Granulicatella)和弯曲菌属(Campylobacter)可用于预测结核耐异烟肼药物风险。
作为上述应用的进一步改进,纤毛菌属(Leptotrichia)、颗粒链菌属(Granulicatella)和弯曲菌属(Campylobacter)相对于结核药敏患者痰液中微生物丰度上调标志着结核耐异烟肼药物风险高。
作为上述应用的进一步改进,代尔夫特菌(Delftia)可用于预测结核耐利福平药物风险。
作为上述应用的进一步改进,代尔夫特菌(Delftia)相对于结核药敏患者痰液中微生物丰度上调标志着结核耐利福平药物风险高。
作为上述应用的进一步改进,代尔夫特菌(Delftia)、金氏菌属(Kingella)、罗尔斯通菌属(Ralstonia)和嗜衣原体属(Chlamydophila)可用于预测结核耐多药风险。
作为上述应用的进一步改进,代尔夫特菌(Delftia)、金氏菌属(Kingella)、罗尔斯通菌属(Ralstonia)和嗜衣原体属(Chlamydophila)相对于结核药敏患者痰液中微生物丰度上调标志着结核耐多药风险高。
作为上述应用的进一步改进,代尔夫特菌(Delftia)、罗尔斯通菌属(Ralstonia)、博代氏杆菌属(Bordetella)可用于预测结核多耐药风险。
作为上述应用的进一步改进,代尔夫特菌(Delftia)、罗尔斯通菌属(Ralstonia)和博代氏杆菌属(Bordetella)相对于结核药敏患者痰液中微生物丰度上调标志着结核多耐药风险高。
本发明的有益效果是:
本发明提供了一种快速诊断结核耐药类型的生物标志物。根据不同结核耐药类型个体的痰液微生态进行分析,从平衡上呼吸道微生物的角度为结核耐药的治疗提供新的思路。
具体实施方式
发明人基于测定的总计55例结核药敏(drug sensitivity, DS)和66例结核耐药(drug resistant, DR)患者的痰液样本测序结果的分析,鉴别出其中的微生物标志物。在66例耐药患者中,异烟肼耐药患者23例、利福平耐药患者3例,耐多药患者11例,多耐药患者29例。
微生物在人群中的分布情况如表1~4所示:
表1耐异烟肼(MR-INH)和药敏组(DS)差异菌属的相对丰度
通过对结核异烟肼耐药个体和结核药敏个体的痰液样本的微生物丰度进行差异比较分析,纤毛菌属(Leptotrichia)、颗粒链菌属(Granulicatella)、弯曲菌属(Campylobacter)在结核异烟肼耐药个体的痰液样本含量显著高于结核药敏个体的含量,且具有统计学意义,因此纤毛菌属(Leptotrichia)、颗粒链菌属(Granulicatella)和弯曲菌属(Campylobacter)可作为结核耐异烟肼的潜在标志物,三种微生物的丰度上调标志着结核耐异烟肼风险高。
表2耐利福平(MR-RFP)和药敏组(DS)差异菌属的相对丰度
通过对耐利福平个体和结核药敏个体的痰液样本的微生物丰度进行差异比较分析,代尔夫特菌(Delftia)在结核利福平耐药个体的痰液样本含量显著高于结核药敏个体的含量,且具有统计学意义,因此代尔夫特菌(Delftia)可作为结核耐利福平的潜在标志物,其丰度的上调标志着结核耐利福平风险高。
表3耐多药(MDR)和药敏组(DS)差异菌属的相对丰度
通过对耐多药个体和结核药敏个体的痰液样本的微生物丰度进行差异比较分析,代尔夫特菌(Delftia)、金氏菌属(Kingella)、罗尔斯通菌属(Ralstonia)、嗜衣原体属(Chlamydophila)在结核耐多药个体的痰液样本含量显著高于结核药敏个体的含量,且具有统计学意义,因此代尔夫特菌(Delftia)、金氏菌属(Kingella)、罗尔斯通菌属(Ralstonia)和嗜衣原体属(Chlamydophila)可作为结核耐多药的潜在标志物,四种微生物的丰度上调标志着结核耐多药风险高。
表4多耐药(PR)和药敏组(DS)差异菌属的相对丰度
通过对结核多耐药个体和结核药敏个体的痰液样本的微生物丰度进行差异比较分析,代尔夫特菌(Delftia)、罗尔斯通菌属(Ralstonia)、博代氏杆菌属(Bordetella)在结核多耐药个体的痰液样本含量显著高于结核药敏个体的含量,且具有统计学意义,因此代尔夫特菌(Delftia)、罗尔斯通菌属(Ralstonia)和博代氏杆菌属(Bordetella)可作为结核多耐药的潜在标志物,三种微生物的丰度上调标志着结核多耐药风险高。
利用上述差异菌群为标志物,预测个体耐药类型。
标志物及预测模型效果验证
我们另外收集了共60个样品作为测试集,其中耐异烟肼21人,耐利福平5人,耐多药10人,多耐药26人。所述的微生物标志物在人群中的丰度情况如表5~8所示:
表5耐异烟肼(MR-INH)和药敏组(DS)差异菌属的相对丰度
表6耐利福平(MR-RFP)和药敏组(DS)差异菌属的相对丰度
表7耐多药(MDR)和药敏组(DS)差异菌属的相对丰度
表8多耐药(PR)和药敏组(DS)差异菌属的相对丰度
预测结果如表9~11所示,发现本发明中的标志物及预测模型表现良好。对于耐异烟肼分类模型,模型预测了21个阳性结果,通过混淆矩阵评估,其中18个真阳性,3个假阳性,2个假阴性,准确度达到了91.6%(表9)。对于耐利福平,模型预测了5个阳性结果,其中3个真阳性,2两个假阳性,并未出现假阴性结果。对于耐多药结果,模型预测了10个阳性结果,其中有7个真阳性,2个假阳性和1个假阴性,测试集准确度达到了95%(表10)。对于多耐药的结果,模型预测了26个阳性结果,其中22个真阳性,4个假阳性,3个假阴性,通过混淆矩阵评估准确度达到了88.3%(表11)。
表9 耐异烟肼分类模型评估混淆矩阵
表10 耐多药分类模型评估混淆矩阵
表11 多耐药分类模型评估混淆矩阵
Claims (2)
1.定量检测痰液微生物含量的测序试剂在制备结核耐异烟肼诊断试剂中的应用,其中,所述痰液微生物为纤毛菌属、颗粒链菌属和弯曲菌属;所述纤毛菌属、颗粒链菌属和弯曲菌属相对于结核药敏患者痰液中微生物丰度上调标志着结核耐异烟肼药物风险高。
2.根据权利要求1所述的应用,其特征在于,所述纤毛菌属、颗粒链菌属和弯曲菌属可用于预测结核耐异烟肼药物风险。
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