Tuberculosis最新文献_第4页

Diagnosis of extrapulmonary tuberculosis by Truenat® MTB/MTB Plus assay 应用Truenat®MTB/MTB Plus检测诊断肺外结核

IF 2.9 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-12-01 Epub Date: 2025-09-05 DOI: 10.1016/j.tube.2025.102688

Promod K. Mehta, Jefry Sebastian

Diagnosis of extrapulmonary tuberculosis (EPTB) is challenging. During the last two decades, several nucleic acid amplification tests have been deliberated to diagnose TB (including EPTB) and drug resistance (DR), i.e. in-house PCR/multiplex-PCR, commercial real-time PCR (e.g. Cobas TaqMan/LightCycler), line probe assay (e.g. GenoType MTBDRplus), GeneXpert®/GeneXpert® Ultra and Truenat®MTB/MTB Plus (TruPlus). However, we still need a simple and reliable diagnostic test especially for remote areas. Markedly, both GeneXpert/Xpert Ultra require a constant power supply and their high cost is a major hindrance in resource-limited settings. To overcome this, Molbio Diagnostics, India, introduced a Truenat/TruPlus assay (the WHO endorsed), which is chip-based micro real-time PCR system that targets nrdB, while TruPlus targets IS6110+nrdZ for the identification of Mtb within 1 h. After a positive result, an ‘add-on’ chip, i.e. Truenat® MTB-RIF Dx (TruRif) is utilized to detect rifampicin-resistance (RIF-R) that takes another 1 h. Although there is adequate literature on the diagnosis of pulmonary TB by Truenat/TruPlus, limited information is available on EPTB diagnosis. In this review, we assessed the performance of Truenat/TruPlus in different EPTB types, i.e. TB lymphadenitis, TB pleuritis, TB meningitis, osteoarticular TB, etc. that exhibits moderate to good sensitivity/specificity. Meanwhile, few false negative/positive RIF-R results are obtained by TruRif. Since Truenat/TruPlus is portable, battery-operated and relatively cost-effective as compared to GeneXpert/Xpert Ultra, it can be utilized for preliminary screening of EPTB specimens in peripheral settings, which may be further confirmed by other tests.

肺外结核（EPTB）的诊断具有挑战性。在过去的二十年中，已经考虑了几种核酸扩增检测来诊断结核病（包括EPTB）和耐药（DR），即内部PCR/多重PCR，商业实时PCR（例如Cobas TaqMan/LightCycler），线探针检测（例如基因型MTBDRplus）， GeneXpert®/GeneXpert®Ultra和Truenat®MTB/MTB Plus （TruPlus）。然而，我们仍然需要一种简单可靠的诊断测试，特别是对于偏远地区。显然，GeneXpert/Xpert Ultra都需要恒定的电源，它们的高成本是资源有限环境下的主要障碍。为了克服这一问题，印度Molbio Diagnostics公司推出了Truenat/TruPlus检测（世卫组织认可），这是一种基于芯片的微实时PCR系统，以nrdB为目标，而TruPlus以IS6110+nrdZ为目标，在1小时内识别结核分枝杆菌。在结果呈阳性后，使用“附加”芯片，即Truenat®Mtb - rif Dx （TruRif）检测利福平耐药性（RIF-R），需要另外1小时。关于EPTB诊断的信息有限。在这篇综述中，我们评估了Truenat/TruPlus在不同类型EPTB中的表现，即结核淋巴结炎、结核胸膜炎、结核脑膜炎、骨关节结核等，表现出中等至良好的敏感性/特异性。同时，TruRif得到的假阴性/阳性RIF-R结果很少。由于与GeneXpert/Xpert Ultra相比，Truenat/TruPlus是便携式的、电池供电的，并且相对具有成本效益，因此它可用于在外围环境中对EPTB标本进行初步筛选，这可能会通过其他测试进一步证实。

{"title":"Diagnosis of extrapulmonary tuberculosis by Truenat® MTB/MTB Plus assay","authors":"Promod K. Mehta, Jefry Sebastian","doi":"10.1016/j.tube.2025.102688","DOIUrl":"10.1016/j.tube.2025.102688","url":null,"abstract":"<div><div>Diagnosis of extrapulmonary tuberculosis (EPTB) is challenging. During the last two decades, several nucleic acid amplification tests have been deliberated to diagnose TB (including EPTB) and drug resistance (DR), <em>i.e</em>. in-house PCR/multiplex-PCR, commercial real-time PCR (<em>e.g.</em> Cobas TaqMan/LightCycler), line probe assay (<em>e.g.</em> GenoType MTBDRplus), GeneXpert®/GeneXpert® Ultra and Truenat®MTB/MTB Plus (TruPlus). However, we still need a simple and reliable diagnostic test especially for remote areas. Markedly, both GeneXpert/Xpert Ultra require a constant power supply and their high cost is a major hindrance in resource-limited settings. To overcome this, Molbio Diagnostics, India, introduced a Truenat/TruPlus assay (the WHO endorsed), which is chip-based micro real-time PCR system that targets <em>nrdB</em>, while TruPlus targets IS<em>6110</em>+<em>nrdZ</em> for the identification of <em>Mtb</em> within 1 h. After a positive result, an ‘add-on’ chip, <em>i.e</em>. Truenat® MTB-RIF Dx (TruRif) is utilized to detect rifampicin-resistance (RIF-R) that takes another 1 h. Although there is adequate literature on the diagnosis of pulmonary TB by Truenat/TruPlus, limited information is available on EPTB diagnosis. In this review, we assessed the performance of Truenat/TruPlus in different EPTB types, <em>i.e</em>. TB lymphadenitis, TB pleuritis, TB meningitis, osteoarticular TB, etc. that exhibits moderate to good sensitivity/specificity. Meanwhile, few false negative/positive RIF-R results are obtained by TruRif. Since Truenat/TruPlus is portable, battery-operated and relatively cost-effective as compared to GeneXpert/Xpert Ultra, it can be utilized for preliminary screening of EPTB specimens in peripheral settings, which may be further confirmed by other tests.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102688"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145158213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Analysis of tuberculosis infection dynamics using Caputo fractional-order models with diagnosis and treatment interventions 用Caputo分数阶模型分析结核感染动态与诊断和治疗干预。

IF 2.9 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-12-01 Epub Date: 2025-09-27 DOI: 10.1016/j.tube.2025.102694

Oluwafemi Ezekiel Abiodun , Morufu Oyedunsi Olayiwola

This paper develops and analyzes a Caputo fractional-order mathematical model for tuberculosis (TB) transmission that incorporates testing, therapy, isolation, and treatment interventions. The model divides the population into five compartments—susceptible, exposed, infectious, isolated, and recovered—and its qualitative properties, including positivity, boundedness, existence, and uniqueness of solutions, are established. The basic reproduction number R₀ is derived, and sensitivity analysis identifies transmission, progression, testing, and treatment rates as critical drivers of TB dynamics. Using the Laplace–Adomian decomposition method (LADM), numerical simulations are performed to assess the impact of fractional-order derivatives on disease spread and control. The results show that increasing the order of the fractional derivative enhances the accuracy of the model and reveals memory effects in TB dynamics. Moreover, early diagnosis, therapy, and isolation significantly reduce infection levels and improve recovery outcomes. These findings highlight the advantages of fractional-order models over classical approaches and provide valuable insights for designing effective TB control strategies.

本文开发并分析了结核病（TB）传播的Caputo分数阶数学模型，该模型包括检测、治疗、隔离和治疗干预措施。该模型将种群划分为易感、暴露、感染、隔离和恢复5个分区，并建立了其定性性质，包括解的正性、有界性、存在性和唯一性。推导出基本繁殖数R0，敏感性分析确定传播、进展、检测和治疗率是结核病动态的关键驱动因素。利用Laplace-Adomian分解方法（LADM）进行数值模拟，评估分数阶导数对疾病传播和控制的影响。结果表明，增加分数阶导数的阶数可以提高模型的精度，并显示出TB动力学中的记忆效应。此外，早期诊断、治疗和隔离可显著降低感染水平并改善康复结果。这些发现突出了分数阶模型相对于经典方法的优势，并为设计有效的结核病控制策略提供了有价值的见解。

{"title":"Analysis of tuberculosis infection dynamics using Caputo fractional-order models with diagnosis and treatment interventions","authors":"Oluwafemi Ezekiel Abiodun , Morufu Oyedunsi Olayiwola","doi":"10.1016/j.tube.2025.102694","DOIUrl":"10.1016/j.tube.2025.102694","url":null,"abstract":"<div><div>This paper develops and analyzes a Caputo fractional-order mathematical model for tuberculosis (TB) transmission that incorporates testing, therapy, isolation, and treatment interventions. The model divides the population into five compartments—susceptible, exposed, infectious, isolated, and recovered—and its qualitative properties, including positivity, boundedness, existence, and uniqueness of solutions, are established. The basic reproduction number R<sub>0</sub> is derived, and sensitivity analysis identifies transmission, progression, testing, and treatment rates as critical drivers of TB dynamics. Using the Laplace–Adomian decomposition method (LADM), numerical simulations are performed to assess the impact of fractional-order derivatives on disease spread and control. The results show that increasing the order of the fractional derivative enhances the accuracy of the model and reveals memory effects in TB dynamics. Moreover, early diagnosis, therapy, and isolation significantly reduce infection levels and improve recovery outcomes. These findings highlight the advantages of fractional-order models over classical approaches and provide valuable insights for designing effective TB control strategies.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102694"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

“The cytokine profiles of the inflammatory response in chronic granulomatous encephalitis caused by Mycobacterium tuberculosis do not influence the patient's clinical presentation" 由结核分枝杆菌引起的慢性肉芽肿性脑炎炎症反应的细胞因子谱不影响患者的临床表现。

IF 2.9 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-12-01 Epub Date: 2025-10-23 DOI: 10.1016/j.tube.2025.102700

Alejandro Rivas-Castro , Itzel Rocío Manzano Espinosa , Diana Villa Sepúlveda , Eduardo Pablo Sánchez Martínez , José Alberto Choreño-Parra , Yaser Sánchez Gama , Ana Sofía Alonso Villaseñor , Fernando Daniel Argueta Muñoz , Erick Gómez Apo , Citlaltepetl Salinas-Lara , Carlos Sánchez-Garibay , Martha Lilia Tena Suck

Introduction

Central nervous system tuberculosis (CNS-TB) is the most lethal form of tuberculosis, characterized by severe clinical manifestations and distinctive histopathological changes. Although several cytokines are implicated in the immune response to Mycobacterium tuberculosis, their relationship with disease severity and histological alterations remains unclear. This study aimed to evaluate the associations between cytokine expression, histopathological changes, and clinical features in patients with CNS-TB.

Methods

We conducted a retrospective, observational, cross-sectional, descriptive study of 25 biopsies that fulfilled criteria for CNS-TB at the National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez.” Cases were classified according to the Suzaan Marais criteria. Immunohistochemistry was performed to assess IL-1β, IL-4, IL-10, IL-17, IL-23, TNF-α, and IFN-γ expression in meningeal and parenchymal tissues.

Results

Strong expression of IL-1β, IL-17, IL-23, and TNF-α was observed in glial cells, vascular endothelial cells, and macrophages, particularly within inflammatory and vascular lesions.

Conclusions

Although no direct correlation was found between cytokine expression and clinical severity, the findings support a predominant pro-inflammatory response mediated by IL-1β, IL-17, IL-23, and TNF-α, associated with tissue and vascular damage. The elevated cytokine expression in foam cells suggests a potential role in local immune regulation in CNS-TB.

简介：中枢神经系统结核（CNS-TB）是最致命的结核形式，具有严重的临床表现和独特的组织病理学改变。尽管几种细胞因子与结核分枝杆菌的免疫应答有关，但它们与疾病严重程度和组织学改变的关系尚不清楚。本研究旨在评估CNS-TB患者细胞因子表达、组织病理学改变和临床特征之间的关系。方法：我们在国家神经病学和神经外科研究所“Manuel Velasco Suárez”对25例符合CNS-TB标准的活检进行了回顾性、观察性、横断面、描述性研究。根据Suzaan Marais标准对病例进行分类。采用免疫组化方法检测脑膜和实质组织中IL-1β、IL-4、IL-10、IL-17、IL-23、TNF-α和IFN-γ的表达。结果：IL-1β、IL-17、IL-23和TNF-α在神经胶质细胞、血管内皮细胞和巨噬细胞中表达强烈，尤其是在炎症和血管病变中。结论：虽然没有发现细胞因子表达与临床严重程度之间的直接相关性，但研究结果支持IL-1β， IL-17， IL-23和TNF-α介导的主要促炎反应与组织和血管损伤相关。泡沫细胞中细胞因子表达的升高提示CNS-TB局部免疫调节的潜在作用。

{"title":"“The cytokine profiles of the inflammatory response in chronic granulomatous encephalitis caused by Mycobacterium tuberculosis do not influence the patient's clinical presentation\"","authors":"Alejandro Rivas-Castro , Itzel Rocío Manzano Espinosa , Diana Villa Sepúlveda , Eduardo Pablo Sánchez Martínez , José Alberto Choreño-Parra , Yaser Sánchez Gama , Ana Sofía Alonso Villaseñor , Fernando Daniel Argueta Muñoz , Erick Gómez Apo , Citlaltepetl Salinas-Lara , Carlos Sánchez-Garibay , Martha Lilia Tena Suck","doi":"10.1016/j.tube.2025.102700","DOIUrl":"10.1016/j.tube.2025.102700","url":null,"abstract":"<div><h3>Introduction</h3><div>Central nervous system tuberculosis (CNS-TB) is the most lethal form of tuberculosis, characterized by severe clinical manifestations and distinctive histopathological changes. Although several cytokines are implicated in the immune response to <em>Mycobacterium tuberculosis</em>, their relationship with disease severity and histological alterations remains unclear. This study aimed to evaluate the associations between cytokine expression, histopathological changes, and clinical features in patients with CNS-TB.</div></div><div><h3>Methods</h3><div>We conducted a retrospective, observational, cross-sectional, descriptive study of 25 biopsies that fulfilled criteria for CNS-TB at the National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez.” Cases were classified according to the Suzaan Marais criteria. Immunohistochemistry was performed to assess IL-1β, IL-4, IL-10, IL-17, IL-23, TNF-α, and IFN-γ expression in meningeal and parenchymal tissues.</div></div><div><h3>Results</h3><div>Strong expression of IL-1β, IL-17, IL-23, and TNF-α was observed in glial cells, vascular endothelial cells, and macrophages, particularly within inflammatory and vascular lesions.</div></div><div><h3>Conclusions</h3><div>Although no direct correlation was found between cytokine expression and clinical severity, the findings support a predominant pro-inflammatory response mediated by IL-1β, IL-17, IL-23, and TNF-α, associated with tissue and vascular damage. The elevated cytokine expression in foam cells suggests a potential role in local immune regulation in CNS-TB.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102700"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145393303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of mycobacteria proliferation in macrophages by diaryl ether derivatives of Dehydrozingerone compound and repurposed drugs (Rebamipide, Sofalcone) via NF-κB pathway inhibition Dehydrozingerone化合物二芳基醚衍生物和Rebamipide、Sofalcone通过抑制NF-κB通路抑制巨噬细胞分枝杆菌增殖

IF 2.9 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-12-01 Epub Date: 2025-11-21 DOI: 10.1016/j.tube.2025.102706

Safiya Mehraj , Shazia Ali , Chetan Kumar , Asif Ali , Zahoor Ahmad

Background

Chronic inflammation fuels tissue damage and morbidity in numerous diseases, including Tuberculosis, underscoring the vital need for Host-Directed Therapies to safely modulate the exaggerated host response. We investigated the immunomodulatory potential of Sofalcone and Rebamipide alongside a novel Diaryl Ether derivative of Dehydrozingerone DHZ (6), hypothesizing that they exert therapeutic effects by targeting the central inflammatory driver, the NF-κB pathway.

Methods

We evaluated the safety and efficacy of the compounds in THP-1 macrophages infected with M. smegmatis. Mechanistic studies utilized Western blotting, immunofluorescence, and ELISA to track NF-κB activation. MMP activity was assessed by gelatin zymography, and ROS production was quantified using the DCFH-DA assay.

Results

All compounds exhibited low cytotoxicity and significantly reduced intracellular bacterial survival. Agents potently and consistently inhibited the NF-κB cascade, evidenced by ≈ 83 % suppression of upstream P-IKKα/IKKβ and up to ≈89 % reduction in p65 phosphorylation. This molecular blockade prevented p65 nuclear translocation and resulted in a downstream functional benefit: near total abolition of MMP-2/9 activity and ≈71 % mitigation of ROS production.

Conclusion

Our results unequivocally validate NF-κB inhibition by DHZ (6), Sofalcone, and Rebamipide as a powerful strategy for HDT. These compounds are promising adjunct therapies to suppress host inflammation and limit tissue damage.

慢性炎症会导致包括结核病在内的许多疾病的组织损伤和发病率，这强调了对宿主导向疗法的迫切需要，以安全地调节过度的宿主反应。我们研究了Sofalcone和Rebamipide以及Dehydrozingerone DHZ的新型二芳基醚衍生物的免疫调节潜力(6)，假设它们通过靶向中枢炎症驱动因子NF-κB途径发挥治疗作用。方法评价化合物对耻垢分枝杆菌感染的THP-1巨噬细胞的安全性和有效性。机制研究采用Western blotting、免疫荧光和ELISA追踪NF-κB活化。明胶酶谱法测定MMP活性，DCFH-DA法测定ROS产量。结果所有化合物均表现出较低的细胞毒性，并显著降低细胞内细菌存活率。药物有效且持续地抑制NF-κB级联，上游P-IKKα/IKKβ抑制约83%，p65磷酸化降低约89%。这种分子阻断阻止了p65核易位，并导致下游功能获益：MMP-2/9活性几乎完全消除，ROS产生减少约71%。结论：我们的研究结果明确证实了DHZ(6)、Sofalcone和Rebamipide对NF-κB的抑制是治疗HDT的有效策略。这些化合物是抑制宿主炎症和限制组织损伤的有希望的辅助疗法。

{"title":"Inhibition of mycobacteria proliferation in macrophages by diaryl ether derivatives of Dehydrozingerone compound and repurposed drugs (Rebamipide, Sofalcone) via NF-κB pathway inhibition","authors":"Safiya Mehraj , Shazia Ali , Chetan Kumar , Asif Ali , Zahoor Ahmad","doi":"10.1016/j.tube.2025.102706","DOIUrl":"10.1016/j.tube.2025.102706","url":null,"abstract":"<div><h3>Background</h3><div>Chronic inflammation fuels tissue damage and morbidity in numerous diseases, including Tuberculosis, underscoring the vital need for Host-Directed Therapies to safely modulate the exaggerated host response. We investigated the immunomodulatory potential of Sofalcone and Rebamipide alongside a novel Diaryl Ether derivative of Dehydrozingerone DHZ (6), hypothesizing that they exert therapeutic effects by targeting the central inflammatory driver, the NF-κB pathway.</div></div><div><h3>Methods</h3><div>We evaluated the safety and efficacy of the compounds in THP-1 macrophages infected with <em>M. smegmatis.</em> Mechanistic studies utilized Western blotting, immunofluorescence, and ELISA to track NF-κB activation. MMP activity was assessed by gelatin zymography, and ROS production was quantified using the DCFH-DA assay.</div></div><div><h3>Results</h3><div>All compounds exhibited low cytotoxicity and significantly reduced intracellular bacterial survival. Agents potently and consistently inhibited the NF-κB cascade, evidenced by ≈ 83 % suppression of upstream P-IKKα/IKKβ and up to ≈89 % reduction in p65 phosphorylation. This molecular blockade prevented p65 nuclear translocation and resulted in a downstream functional benefit: near total abolition of MMP-2/9 activity and ≈71 % mitigation of ROS production.</div></div><div><h3>Conclusion</h3><div>Our results unequivocally validate NF-κB inhibition by DHZ (6), Sofalcone, and Rebamipide as a powerful strategy for HDT. These compounds are promising adjunct therapies to suppress host inflammation and limit tissue damage.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102706"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145623326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Letter to Editor: manuscript entitled “Utility of pleural fluid-derived extracellular vesicles as a source of Mycobacterium tuberculosis antigens MPT51 and MPT64 for pleural TB diagnosis: a proof-of-concept study” by Jindal et al. published in Tuberculosis150 (2025) 102578 致编辑的信：由Jindal等人撰写的题为“胸膜液来源的细胞外囊泡作为结核分枝杆菌抗原MPT51和MPT64用于胸膜结核诊断的效用：一项概念验证研究”的手稿，发表在结核菌150(2025)102578上。

IF 2.9 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-12-01 Epub Date: 2025-10-14 DOI: 10.1016/j.tube.2025.102695

Promod K. Mehta

引用次数: 0

ESAT-6 of Mycobacterium tuberculosis downregulates cofilin1, leads to filamentous actin enrichment and reduces the phagosome acidification in infected macrophages, which are partially reversed by a single methionine mutation 结核分枝杆菌的ESAT-6下调cofilin1，导致丝状肌动蛋白富集并减少感染巨噬细胞的吞噬体酸化，这一过程可通过单个蛋氨酸突变部分逆转

IF 2.9 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-12-01 Epub Date: 2025-08-28 DOI: 10.1016/j.tube.2025.102680

P.P. Mahesh , R.J. Retnakumar , K.C. Sivakumar , Sathish Mundayoor

Mycobacterium tuberculosis (M. tuberculosis) persists within macrophages by evading phagosome maturation. In this study, we considered the role of actin dynamics in this process. Macrophages infected with virulent M. tuberculosis showed high F-actin/G-actin ratio, accompanied by reduced expression of the actin-depolymerizing protein cofilin1 and increased levels of its inactive phosphorylated form. Overexpression of a constitutively active cofilin1 variant reduced F-actin accumulation and enhanced phagosome acidification. Similar effects were observed with sorafenib, a PI3K-dependent activator of cofilin1, which decreased F-actin levels and promoted phagosome acidification in infected macrophages. Ectopic expression of the mycobacterial virulence factor ESAT-6 in macrophages led to cofilin1 downregulation. ESAT-6 also increased F-actin, altered cell morphology and impaired phagosome acidification in infections with avirulent M. tuberculosis strain. As cofilin1 is positively regulated by reactive oxygen species (ROS), we examined the role of methionine in ESAT-6-mediated ROS suppression. Mutation of methionine 93 in ESAT-6 increased intracellular ROS, enhanced phagosome acidification, and decreased F-actin levels. These findings reveal that M. tuberculosis impairs phagosome acidification by modulating host actin dynamics at least partially through ESAT-6–mediated suppression of cofilin1 and ROS. Enhancing cofilin1 activity may represent a potential therapeutic strategy to restore phagosome function and improve bacterial clearance, more specifically during the initial establishment of infection.

结核分枝杆菌（M. tuberculosis）通过逃避吞噬体成熟而持续存在于巨噬细胞内。在这项研究中，我们考虑了肌动蛋白动力学在这一过程中的作用。感染致病性结核分枝杆菌的巨噬细胞表现出高的F-actin/G-actin比值，同时肌动蛋白解聚蛋白cofilin1的表达减少，其无活性磷酸化形式的表达增加。过表达一个组成活性cofilin1变体减少了f -肌动蛋白的积累和增强了吞噬体的酸化。sorafenib（一种依赖pi3k的cofilin1激活剂）也有类似的效果，可降低感染巨噬细胞的F-actin水平，促进吞噬体酸化。巨噬细胞中分枝杆菌毒力因子ESAT-6的异位表达导致cofilin1下调。ESAT-6也增加了f -肌动蛋白，改变了细胞形态，破坏了吞噬体酸化感染的无毒性结核分枝杆菌菌株。由于cofilin1受到活性氧（ROS）的正调控，我们研究了蛋氨酸在esat -6介导的ROS抑制中的作用。ESAT-6中蛋氨酸93的突变增加了细胞内ROS，增强了吞噬体酸化，降低了f -肌动蛋白水平。这些发现表明，结核分枝杆菌通过esat -6介导的cofilin1和ROS的抑制，至少部分地通过调节宿主肌动蛋白动力学来损害吞噬体酸化。增强cofilin1活性可能是恢复吞噬体功能和提高细菌清除的潜在治疗策略，更具体地说，是在感染的初始阶段。

{"title":"ESAT-6 of Mycobacterium tuberculosis downregulates cofilin1, leads to filamentous actin enrichment and reduces the phagosome acidification in infected macrophages, which are partially reversed by a single methionine mutation","authors":"P.P. Mahesh , R.J. Retnakumar , K.C. Sivakumar , Sathish Mundayoor","doi":"10.1016/j.tube.2025.102680","DOIUrl":"10.1016/j.tube.2025.102680","url":null,"abstract":"<div><div><em>Mycobacterium tuberculosis</em> (<em>M. tuberculosis</em>) persists within macrophages by evading phagosome maturation. In this study, we considered the role of actin dynamics in this process. Macrophages infected with virulent <em>M. tuberculosis</em> showed high F-actin/G-actin ratio, accompanied by reduced expression of the actin-depolymerizing protein cofilin1 and increased levels of its inactive phosphorylated form. Overexpression of a constitutively active cofilin1 variant reduced F-actin accumulation and enhanced phagosome acidification. Similar effects were observed with sorafenib, a PI3K-dependent activator of cofilin1, which decreased F-actin levels and promoted phagosome acidification in infected macrophages. Ectopic expression of the mycobacterial virulence factor ESAT-6 in macrophages led to cofilin1 downregulation. ESAT-6 also increased F-actin, altered cell morphology and impaired phagosome acidification in infections with avirulent <em>M. tuberculosis</em> strain. As cofilin1 is positively regulated by reactive oxygen species (ROS), we examined the role of methionine in ESAT-6-mediated ROS suppression. Mutation of methionine 93 in ESAT-6 increased intracellular ROS, enhanced phagosome acidification, and decreased F-actin levels. These findings reveal that <em>M. tuberculosis</em> impairs phagosome acidification by modulating host actin dynamics at least partially through ESAT-6–mediated suppression of cofilin1 and ROS. Enhancing cofilin1 activity may represent a potential therapeutic strategy to restore phagosome function and improve bacterial clearance, more specifically during the initial establishment of infection.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102680"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144926761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Minimal immune cell subset differences in a cohort of close contacts of tuberculosis index cases 结核病指数病例密切接触者队列中最小免疫细胞亚群差异

IF 2.9 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-12-01 Epub Date: 2025-11-15 DOI: 10.1016/j.tube.2025.102707

Sudhasini Panda , Catherine Cheng , Naomi Hillery , Donald G. Catanzaro , Nelly Ciobanu , Valeriu Crudu , Timothy Rodwell , Antonino Catanzaro , Julie G. Burel , Bjoern Peters , Cecilia S. Lindestam Arlehamn

Understanding the perturbations in immune response across the spectrum of TB infection is still unclear. Here, we followed close contacts of pulmonary TB patients with serial QFT testing at 0, 3, 6, and 12 months, and stratified them into six subgroups: QFT-increasing (low/high), QFT-converters (QFT-to QFT+), QFT + stable, and QFT-individuals. Despite these distinct QFT trajectories, we observed minimal differences in immune cell frequencies, activation profiles, and T-helper subset distributions among QFT subgroups, suggesting limited immunological stratification based on QFT dynamics. Ex vivo immune phenotyping, including CD4, CD8, NKT cell frequencies, memory T-cell subsets, and activated T-cells (HLA-DR⁺CD38⁺), failed to distinguish between QFT subgroups, suggesting blood-based immune profiling may not capture subtle immunological transitions among different QFT subgroups. Active TB (ATB) patients showed marked immune alterations, with elevated antigen-specific CD4 T-cells, activated T cells, intermediate monocytes, NK cells at-diagnosis, which declined following treatment, indicating immune recovery. This suggest, while ex vivo immune profiling effectively distinguishes ATB from non-diseased states, it lacks the sensitivity to resolve QFT-based subgroups. Findings suggest either immune similarity among close contacts regardless of QFT status or limits of blood-based profiling in detecting early changes, underscoring the difficulty of distinguishing QFT subgroups with conventional ex vivo approaches.

了解免疫反应的扰动在整个结核病感染谱仍不清楚。在这里，我们对肺结核患者的密切接触者进行了0、3、6和12个月的连续QFT检测，并将他们分为六个亚组：QFT增加（低/高）、QFT转换（从QFT转为QFT+）、QFT稳定和QFT个体。尽管有这些不同的QFT轨迹，我们观察到免疫细胞频率、激活谱和辅助性t细胞亚群分布在QFT亚组之间的差异很小，这表明基于QFT动力学的免疫分层有限。体外免疫表型，包括CD4、CD8、NKT细胞频率、记忆t细胞亚群和活化t细胞（HLA-DR+CD38+），无法区分QFT亚群，这表明基于血液的免疫谱可能无法捕捉不同QFT亚群之间微妙的免疫转变。活动性结核（ATB）患者表现出明显的免疫改变，诊断时抗原特异性CD4 T细胞、活化T细胞、中间单核细胞、NK细胞升高，治疗后下降，表明免疫恢复。这表明，虽然体外免疫谱分析可以有效区分ATB和非病变状态，但它缺乏分辨基于qft的亚群的敏感性。研究结果表明，无论QFT状态如何，密切接触者之间的免疫相似性或基于血液的谱分析在检测早期变化方面的局限性，都强调了用传统的离体方法区分QFT亚群的困难。

{"title":"Minimal immune cell subset differences in a cohort of close contacts of tuberculosis index cases","authors":"Sudhasini Panda , Catherine Cheng , Naomi Hillery , Donald G. Catanzaro , Nelly Ciobanu , Valeriu Crudu , Timothy Rodwell , Antonino Catanzaro , Julie G. Burel , Bjoern Peters , Cecilia S. Lindestam Arlehamn","doi":"10.1016/j.tube.2025.102707","DOIUrl":"10.1016/j.tube.2025.102707","url":null,"abstract":"<div><div>Understanding the perturbations in immune response across the spectrum of TB infection is still unclear. Here, we followed close contacts of pulmonary TB patients with serial QFT testing at 0, 3, 6, and 12 months, and stratified them into six subgroups: QFT-increasing (low/high), QFT-converters (QFT-to QFT+), QFT + stable, and QFT-individuals. Despite these distinct QFT trajectories, we observed <strong>minimal differences in immune cell frequencies, activation profiles, and T-helper subset distributions among QFT subgroups,</strong> suggesting limited immunological stratification based on QFT dynamics. Ex vivo immune phenotyping, including CD4, CD8, NKT cell frequencies, memory T-cell subsets, and activated T-cells (HLA-DR<sup>+</sup>CD38<sup>+</sup>), failed to distinguish between QFT subgroups, suggesting blood-based immune profiling may not capture subtle immunological transitions among different QFT subgroups. Active TB (ATB) patients showed marked immune alterations, with elevated antigen-specific CD4 T-cells, activated T cells, intermediate monocytes, NK cells at-diagnosis, which declined following treatment, indicating immune recovery. This suggest, while ex vivo immune profiling effectively distinguishes ATB from non-diseased states, it lacks the sensitivity to resolve QFT-based subgroups. Findings suggest either immune similarity among close contacts regardless of QFT status or limits of blood-based profiling in detecting early changes, underscoring the difficulty of distinguishing QFT subgroups with conventional ex vivo approaches.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102707"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145550934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Understanding the role of PezAT and MbcTA toxin-antitoxin systems in the pathophysiology of Mycobacterium tuberculosis 了解PezAT和MbcTA毒素-抗毒素系统在结核分枝杆菌病理生理中的作用

IF 2.9 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-12-01 Epub Date: 2025-10-23 DOI: 10.1016/j.tube.2025.102703

Manisha Singh , Deepika Chaudhary , Arun Sharma, Sonu Kumar Gupta, Imran Ahmad, Yashwant Kumar, Ramandeep Singh

Toxin antitoxin (TA) systems are bicistronic genetic elements encoding for a stable toxin and its cognate labile antitoxin. The genome of Mycobacterium tuberculosis (M. tuberculosis) encodes a large repertoire of TA systems and these are highly conserved in members of the M. tuberculosis complex. In the present study, we have characterised PezAT and MbcTA TA systems from M. tuberculosis. We show that the transcript levels of toxins and antitoxins belonging to PezAT and MbcTA were increased in M. tuberculosis exposed to oxidative stress, nitrosative stress and rifampicin. We also show that the relative levels of precursors for the peptidoglycan biosynthesis were increased in the PezT overexpression strain of M. smegmatis relative to uninduced cultures. Here, we have used temperature-sensitive mycobacteriophages to generate ΔpezAT and ΔmbcT mutant strains of M. tuberculosis. We demonstrate that the deletion of pezAT reduced the growth of M. tuberculosis upon exposure to detergent stress or rifampicin. However, the deletion of mbcT does not affect M. tuberculosis growth in various stress conditions. We also report that both PezAT and MbcT are dispensable for M. tuberculosis growth in macrophages and guinea pigs. Overall, these findings suggest that functional redundancy exists between TA systems.

毒素抗毒素（TA）系统是编码稳定毒素及其同源不稳定抗毒素的双链遗传元件。结核分枝杆菌（M. tuberculosis）的基因组编码大量的TA系统，这些系统在结核分枝杆菌复合体成员中高度保守。在本研究中，我们对结核分枝杆菌的PezAT和MbcTA TA系统进行了表征。我们发现，在暴露于氧化应激、亚硝化应激和利福平的结核分枝杆菌中，属于PezAT和MbcTA的毒素和抗毒素的转录水平增加。我们还发现，相对于未诱导的培养物，耻垢分枝杆菌PezT过表达菌株中肽聚糖生物合成的前体的相对水平有所增加。在这里，我们使用温度敏感的分枝杆菌噬菌体产生ΔpezAT和ΔmbcT结核分枝杆菌突变株。我们证明pezAT的缺失在暴露于洗涤剂胁迫或利福平时减少了结核分枝杆菌的生长。然而，在各种应激条件下，mbcT的缺失并不影响结核分枝杆菌的生长。我们还报道了PezAT和MbcT对于巨噬细胞和豚鼠的结核分枝杆菌生长都是不可缺少的。总的来说，这些发现表明TA系统之间存在功能冗余。

{"title":"Understanding the role of PezAT and MbcTA toxin-antitoxin systems in the pathophysiology of Mycobacterium tuberculosis","authors":"Manisha Singh , Deepika Chaudhary , Arun Sharma, Sonu Kumar Gupta, Imran Ahmad, Yashwant Kumar, Ramandeep Singh","doi":"10.1016/j.tube.2025.102703","DOIUrl":"10.1016/j.tube.2025.102703","url":null,"abstract":"<div><div>Toxin antitoxin (TA) systems are bicistronic genetic elements encoding for a stable toxin and its cognate labile antitoxin. The genome of <em>Mycobacterium tuberculosis</em> (<em>M. tuberculosis</em>) encodes a large repertoire of TA systems and these are highly conserved in members of the <em>M. tuberculosis</em> complex. In the present study, we have characterised PezAT and MbcTA TA systems from <em>M. tuberculosis.</em> We show that the transcript levels of toxins and antitoxins belonging to PezAT and MbcTA were increased in <em>M. tuberculosis</em> exposed to oxidative stress, nitrosative stress and rifampicin. We also show that the relative levels of precursors for the peptidoglycan biosynthesis were increased in the PezT overexpression strain of <em>M. smegmatis</em> relative to uninduced cultures. Here, we have used temperature-sensitive mycobacteriophages to generate Δ<em>pezAT</em> and Δ<em>mbcT</em> mutant strains of <em>M. tuberculosis</em>. We demonstrate that the deletion of <em>pezAT</em> reduced the growth of <em>M. tuberculosi</em>s upon exposure to detergent stress or rifampicin. However, the deletion of <em>mbcT</em> does not affect <em>M. tuberculosis</em> growth in various stress conditions. We also report that both PezAT and MbcT are dispensable for <em>M. tuberculosis</em> growth in macrophages and guinea pigs. Overall, these findings suggest that functional redundancy exists between TA systems.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102703"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

M. bovis FadR mutant exhibits an altered colony morphotype and increased virulence 牛分枝杆菌FadR突变体表现出改变的菌落形态和增加的毒力

IF 2.9 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-12-01 Epub Date: 2025-09-06 DOI: 10.1016/j.tube.2025.102689

Vandana Singh , Mohd Mustkim Ansari , Debashis Dutta , R.S. Rajmani , Amit Singh , Bhupendra N. Singh

FadR, a GntR family transcriptional regulator, is known to maintain fatty acid homeostasis in prokaryotes. In this study, a fadR deletion mutant was generated in Mycobacterium bovis, which exhibited distinct morphological changes, along with enhanced permeability and increased antibiotic susceptibility. Interrupted cell-wall homeostasis often leads to such collateral phenotype. To gain insight into the lipid profile, we conducted lipidomics analysis, which revealed that the levels of DAT and PAT were higher in the mutant, while keto-mycolate methyl esters were lower. Further, key proteins responsible for altered phenotypes and lipid profiles were identified using a comparative proteomics approach between M. bovis and the ΔfadR mutant. In addition to lipid metabolism, several intermediary metabolic and stress response proteins predicted to have roles in the growth, survival, and pathogenicity of mycobacteria were also altered in the mutant. Notably, deletion of fadR led to hypervirulence in the animal model. Taken together, this study establishes a crucial role of FadR in the survival of mycobacteria by regulating lipid metabolism, providing insights into its potential as a target for therapeutic strategies against slow-growing mycobacteria.

FadR是一种GntR家族转录调节因子，已知在原核生物中维持脂肪酸稳态。在这项研究中，牛分枝杆菌产生了一个fadR缺失突变体，该突变体表现出明显的形态变化，同时通透性增强，抗生素敏感性增加。细胞壁稳态的中断常常导致这种侧枝表型。为了深入了解脂质谱，我们进行了脂质组学分析，结果显示突变体中DAT和PAT的水平较高，而酮-真菌酸甲酯的水平较低。此外，使用比较蛋白质组学方法鉴定了牛分枝杆菌和ΔfadR突变体之间表型和脂质谱改变的关键蛋白。除了脂质代谢外，在分枝杆菌的生长、存活和致病性中起作用的几种中间代谢和应激反应蛋白也在突变体中发生了改变。值得注意的是，在动物模型中，fadR的缺失导致了高毒力。综上所述，本研究确定了FadR通过调节脂质代谢在分枝杆菌存活中的关键作用，为其作为治疗缓慢生长的分枝杆菌的治疗策略提供了潜在的见解。

{"title":"M. bovis FadR mutant exhibits an altered colony morphotype and increased virulence","authors":"Vandana Singh , Mohd Mustkim Ansari , Debashis Dutta , R.S. Rajmani , Amit Singh , Bhupendra N. Singh","doi":"10.1016/j.tube.2025.102689","DOIUrl":"10.1016/j.tube.2025.102689","url":null,"abstract":"<div><div>FadR, a GntR family transcriptional regulator, is known to maintain fatty acid homeostasis in prokaryotes. In this study, a <em>fadR</em> deletion mutant was generated in <em>Mycobacterium bovis</em>, which exhibited distinct morphological changes, along with enhanced permeability and increased antibiotic susceptibility. Interrupted cell-wall homeostasis often leads to such collateral phenotype. To gain insight into the lipid profile, we conducted lipidomics analysis, which revealed that the levels of DAT and PAT were higher in the mutant, while keto-mycolate methyl esters were lower. Further, key proteins responsible for altered phenotypes and lipid profiles were identified using a comparative proteomics approach between <em>M. bovis</em> and the Δ<em>fadR</em> mutant. In addition to lipid metabolism, several intermediary metabolic and stress response proteins predicted to have roles in the growth, survival, and pathogenicity of mycobacteria were also altered in the mutant. Notably, deletion of <em>fadR</em> led to hypervirulence in the animal model. Taken together, this study establishes a crucial role of FadR in the survival of mycobacteria by regulating lipid metabolism, providing insights into its potential as a target for therapeutic strategies against slow-growing mycobacteria.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102689"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145046233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluating selection at intermediate scales within genes provides robust identification of genes under positive selection in M. tuberculosis clinical isolates 在中间尺度评估基因内的选择为结核分枝杆菌临床分离株的阳性选择提供了强有力的基因鉴定。

IF 2.9 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-12-01 Epub Date: 2025-09-11 DOI: 10.1016/j.tube.2025.102690

Thomas R. Ioerger, Anthony Shatby

Multiple studies have reported genes in the M. tuberculosis (Mtb) genome that are under diversifying selection, based on genetic variants among Mtb clinical isolates. These might reflect adaptions to selection pressures associated with modern clinical treatment of TB. Many, but not all, of these genes under selection are related to drug resistance. Most of these studies have evaluated selection at the gene-level. However, positive selection can be evaluated on different scales, including individual sites (codons) and local regions within an ORF. In this paper, we use GenomegaMap, a Bayesian method for calculating selection, to evaluate selection of genes in the Mtb genome at all three levels. We present evidence that the intermediate analysis (windows of codons) yields the most credible list of candidate genes under selection (excluding PPE and PE_PGRS genes, which are predicted less reliably due to frequent sequencing errors). A further advantage of this approach is that it identifies specific regions within proteins that are under selective pressure, which is useful for structural and functional interpretation. In an analysis of two separate collections of Mtb clinical isolates (from Moldova; and a globally-representative set), we observed 53 and 173 significant genes under selection, with 36 % overlap. The lists of genes under selection include many drug-resistance genes, as well as other genes that have previously been reported to be under selection (resR, phoR). The specific regions under selection identified within drug-resistance genes are shown to correspond to protein structural features known to be involved in resistance, supporting accuracy of the method. Positive selection in several ESX-1-related genes was also observed, suggesting adaptation to immune pressure.

多项研究报告了结核分枝杆菌（Mtb）基因组中的基因正在进行多样化选择，这是基于结核分枝杆菌临床分离株的遗传变异。这些可能反映了对与现代结核病临床治疗相关的选择压力的适应。在这些被选择的基因中，有许多（但不是全部）与耐药性有关。这些研究大多在基因水平上评估选择。然而，正选择可以在不同的尺度上进行评估，包括ORF内的单个位点（密码子）和局部区域。在本文中，我们使用GenomegaMap（一种计算选择的贝叶斯方法）来评估结核分枝杆菌基因组中所有三个水平的基因选择。我们提供的证据表明，中间分析（密码子窗口）产生了最可信的候选基因选择列表（不包括PPE和PE_PGRS基因，由于频繁的测序错误，它们的预测可靠性较低）。这种方法的另一个优点是，它可以识别蛋白质中处于选择压力下的特定区域，这对结构和功能解释很有用。在对两组单独收集的结核分枝杆菌临床分离株（来自摩尔多瓦和一组具有全球代表性的菌株）进行分析时，我们观察到53和173个重要基因在选择中，重叠率为36%。正在选择的基因清单包括许多耐药基因，以及以前报道的正在选择的其他基因（resR, phoR）。在耐药基因中鉴定的特定选择区域显示与已知参与耐药的蛋白质结构特征相对应，支持该方法的准确性。在一些esx -1相关基因中也观察到正选择，提示对免疫压力的适应。

{"title":"Evaluating selection at intermediate scales within genes provides robust identification of genes under positive selection in M. tuberculosis clinical isolates","authors":"Thomas R. Ioerger, Anthony Shatby","doi":"10.1016/j.tube.2025.102690","DOIUrl":"10.1016/j.tube.2025.102690","url":null,"abstract":"<div><div>Multiple studies have reported genes in the <em>M. tuberculosis</em> (Mtb) genome that are under diversifying selection, based on genetic variants among Mtb clinical isolates. These might reflect adaptions to selection pressures associated with modern clinical treatment of TB. Many, but not all, of these genes under selection are related to drug resistance. Most of these studies have evaluated selection at the gene-level. However, positive selection can be evaluated on different scales, including individual sites (codons) and local regions within an ORF. In this paper, we use GenomegaMap, a Bayesian method for calculating selection, to evaluate selection of genes in the Mtb genome at all three levels. We present evidence that the intermediate analysis (windows of codons) yields the most credible list of candidate genes under selection (excluding PPE and PE_PGRS genes, which are predicted less reliably due to frequent sequencing errors). A further advantage of this approach is that it identifies specific regions within proteins that are under selective pressure, which is useful for structural and functional interpretation. In an analysis of two separate collections of Mtb clinical isolates (from Moldova; and a globally-representative set), we observed 53 and 173 significant genes under selection, with 36 % overlap. The lists of genes under selection include many drug-resistance genes, as well as other genes that have previously been reported to be under selection (<em>resR, phoR</em>). The specific regions under selection identified within drug-resistance genes are shown to correspond to protein structural features known to be involved in resistance, supporting accuracy of the method. Positive selection in several ESX-1-related genes was also observed, suggesting adaptation to immune pressure.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102690"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0