Pub Date : 2026-03-01Epub Date: 2026-02-05DOI: 10.1016/j.tube.2026.102745
Quan Ma , Jian Zeng , Jinyun Chen , Mingwen Bao , Weijian Liu , Huan Huang , Zhaohua Xia , Yuxiang Wang , Xin Lu , Xuelin Li , Yatian Li , Huazhen Liu , Shuihua Lu , Jianfeng Zeng
Background/objectives
Tuberculous pleuritis (TP), a common manifestation of Mycobacterium tuberculosis infection, poses challenges in differentiating microbiologically positive (PEMP-MT) from negative (PEMN-MT) pleural effusions due to the limited sensitivity of traditional diagnostic methods.
Methods
Proteomics analysis using iTRAQ, non-targeted metabolomics, parallel reaction monitoring (PRM), and machine learning were employed to diagnose PEMN-MT or PEMP-MT. A validation cohort of 63 PEMN-MT and 28 PEMP-MT patients underwent ELISA experiments. Receiver operating characteristic (ROC) curves evaluated the predictive value of LDH and LV218 individually and in combination.
Results
Differentially expressed proteins (DEPs) and metabolites (DEMs) were identified using bioinformatics tools and pathway enrichment analyses. A machine learning model utilizing six biomarkers (LV218, F13A, RET4, LV321, TBA1C, and LDH) demonstrated excellent diagnostic performance with an AUROC of 0.987 and an AUPR of 0.974, distinguishing PEMP-MT from PEMN-MT. ROC curve analysis showed that both LDH and LV218, alone and in combination, provided strong predictive value for distinguishing the two groups.
Conclusion
LDH and LV218 are promising biomarkers for differentiating microbiologically positive and negative pleural effusions in tuberculous pleuritis. These biomarkers, particularly when combined, could improve diagnostic accuracy and clinical management.
{"title":"LDH and LV218 as biomarkers for diagnosing microbiologically positive tuberculous pleural effusions","authors":"Quan Ma , Jian Zeng , Jinyun Chen , Mingwen Bao , Weijian Liu , Huan Huang , Zhaohua Xia , Yuxiang Wang , Xin Lu , Xuelin Li , Yatian Li , Huazhen Liu , Shuihua Lu , Jianfeng Zeng","doi":"10.1016/j.tube.2026.102745","DOIUrl":"10.1016/j.tube.2026.102745","url":null,"abstract":"<div><h3>Background/objectives</h3><div>Tuberculous pleuritis (TP), a common manifestation of <em>Mycobacterium tuberculosis</em> infection, poses challenges in differentiating microbiologically positive (PEMP-MT) from negative (PEMN-MT) pleural effusions due to the limited sensitivity of traditional diagnostic methods.</div></div><div><h3>Methods</h3><div>Proteomics analysis using iTRAQ, non-targeted metabolomics, parallel reaction monitoring (PRM), and machine learning were employed to diagnose PEMN-MT or PEMP-MT. A validation cohort of 63 PEMN-MT and 28 PEMP-MT patients underwent ELISA experiments. Receiver operating characteristic (ROC) curves evaluated the predictive value of LDH and LV218 individually and in combination.</div></div><div><h3>Results</h3><div>Differentially expressed proteins (DEPs) and metabolites (DEMs) were identified using bioinformatics tools and pathway enrichment analyses. A machine learning model utilizing six biomarkers (LV218, F13A, RET4, LV321, TBA1C, and LDH) demonstrated excellent diagnostic performance with an AUROC of 0.987 and an AUPR of 0.974, distinguishing PEMP-MT from PEMN-MT. ROC curve analysis showed that both LDH and LV218, alone and in combination, provided strong predictive value for distinguishing the two groups.</div></div><div><h3>Conclusion</h3><div>LDH and LV218 are promising biomarkers for differentiating microbiologically positive and negative pleural effusions in tuberculous pleuritis. These biomarkers, particularly when combined, could improve diagnostic accuracy and clinical management.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"157 ","pages":"Article 102745"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158436","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}
Pub Date : 2026-03-01Epub Date: 2026-01-05DOI: 10.1016/j.tube.2026.102736
Risha Hazarika , Sanjukta Patra
Introduction
One of the biggest challenges associated with tuberculosis is the emerging drug resistance which emphasizes the need of alternative therapeutic approaches. In recent years, multitargeting approach for TB therapy has garnered considerable attention. The Antigen85 complex of proteins represent key enzymes which are involved in Mtb cell wall biosynthesis. This study aims at investigating the antimycobacterial effects of Centella asiatica and its two compounds - asiatic acid and quercetin against these three proteins and validate them as multi targets for drug targeting.
Methods
Three-fold validation approach included in-silico studies, in-vitro inhibitory studies against MtbH37Ra strain and inhibition studies against recombinant enzymes.
Results
Displaying good bioavailability, asiatic acid and quercetin exhibited favorable binding affinities. Disruption of the integrity of the cell membrane of MtbH37Ra was observed through electron microscopy and flow cytometry. Both compounds and extract showed inhibitory activity against the enzymes and microorganism and were found to act synergistically in conjunction with isoniazid. Asiatic acid demonstrated bactericidal activity. The reduced reaction rate of the recombinant enzymes implied their function and activity were hampered, which was confirmed through a fluorometric assay.
Conclusion
These results highlight the potential of asiatic acid and quercetin as multitarget inhibitors of the Mtb Antigen85 complex.
{"title":"Targeting the antigen 85 complex of Mycobacterium tuberculosis: A three-fold validation of antimycobacterial activity of Centella asiatica","authors":"Risha Hazarika , Sanjukta Patra","doi":"10.1016/j.tube.2026.102736","DOIUrl":"10.1016/j.tube.2026.102736","url":null,"abstract":"<div><h3>Introduction</h3><div>One of the biggest challenges associated with tuberculosis is the emerging drug resistance which emphasizes the need of alternative therapeutic approaches. In recent years, multitargeting approach for TB therapy has garnered considerable attention. The Antigen85 complex of proteins represent key enzymes which are involved in <em>Mtb</em> cell wall biosynthesis. This study aims at investigating the antimycobacterial effects of <em>Centella asiatica</em> and its two compounds - asiatic acid and quercetin against these three proteins and validate them as multi targets for drug targeting.</div></div><div><h3>Methods</h3><div>Three-fold validation approach included <em>in-silico</em> studies, <em>in-vitro</em> inhibitory studies against <em>Mtb</em>H37Ra strain and inhibition studies against recombinant enzymes.</div></div><div><h3>Results</h3><div>Displaying good bioavailability, asiatic acid and quercetin exhibited favorable binding affinities. Disruption of the integrity of the cell membrane of <em>Mtb</em>H37Ra was observed through electron microscopy and flow cytometry. Both compounds and extract showed inhibitory activity against the enzymes and microorganism and were found to act synergistically in conjunction with isoniazid. Asiatic acid demonstrated bactericidal activity. The reduced reaction rate of the recombinant enzymes implied their function and activity were hampered, which was confirmed through a fluorometric assay.</div></div><div><h3>Conclusion</h3><div>These results highlight the potential of asiatic acid and quercetin as multitarget inhibitors of the <em>Mtb</em> Antigen85 complex.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"157 ","pages":"Article 102736"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146038669","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}
Tuberculosis (TB) remains the world's deadliest infectious disease, with treatment increasingly complicated by the emergence of multidrug-resistant strains (MDR-TB). This study conducted structure-based drug screening targeting Mycobacterium tuberculosis protein kinase B (MtPknB), a serine/threonine kinase essential for M. tuberculosis survival and proliferation, to identify novel anti-TB drug candidates. From the ChemBridge library, a hierarchical screening pipeline integrating docking and molecular dynamics simulations identified candidate compounds. Among these, a quinoline-pyridine hybrid chemical demonstrated antibacterial activity against Mycobacterium smegmatis (IC50 = 31.8 μM) without toxicity to Escherichia coli or mammalian cells. MM-PBSA and ab initio fragment molecular orbital (FMO) analyses revealed LEU17, VAL25, and MET155 as key stabilizing residues in the MtPknB active site. ProLIF interaction fingerprinting confirmed stable hydrophobic and van der Waals interactions formed by the quinoline-pyridine hybrid chemical. SwissADME and ProTox-3.0 predictions indicated favorable drug-like properties for the quinoline-pyridine hybrid chemical, despite potential toxicity risks. Structure-activity relationship analysis of the quinoline-pyridine hybrid chemical analogs demonstrated that subtle variations in hydrophobic interactions and substituent positioning significantly influence antibacterial potency. These findings position these chemicals as promising lead compounds for MtPknB-targeted anti-TB drug development.
{"title":"In silico identification of quinoline-pyridine hybrids binding to Mycobacterium protein kinase B, assessment by molecular dynamics simulation and quantum mechanics calculation, and in vitro validation of antimicrobial activity","authors":"Kotomi Saiki, Mikuri Yokota, Soichiro Yamamura, Kousuke Moriyama, Seiya Morita, Shunsuke Aoki","doi":"10.1016/j.tube.2026.102742","DOIUrl":"10.1016/j.tube.2026.102742","url":null,"abstract":"<div><div>Tuberculosis (TB) remains the world's deadliest infectious disease, with treatment increasingly complicated by the emergence of multidrug-resistant strains (MDR-TB). This study conducted structure-based drug screening targeting <em>Mycobacterium tuberculosis</em> protein kinase B (<em>Mt</em>PknB), a serine/threonine kinase essential for <em>M. tuberculosis</em> survival and proliferation, to identify novel anti-TB drug candidates. From the ChemBridge library, a hierarchical screening pipeline integrating docking and molecular dynamics simulations identified candidate compounds. Among these, a quinoline-pyridine hybrid chemical demonstrated antibacterial activity against <em>Mycobacterium smegmatis</em> (IC<sub>50</sub> = 31.8 μM) without toxicity to <em>Escherichia coli</em> or mammalian cells. MM-PBSA and ab initio fragment molecular orbital (FMO) analyses revealed LEU17, VAL25, and MET155 as key stabilizing residues in the <em>Mt</em>PknB active site. ProLIF interaction fingerprinting confirmed stable hydrophobic and van der Waals interactions formed by the quinoline-pyridine hybrid chemical. SwissADME and ProTox-3.0 predictions indicated favorable drug-like properties for the quinoline-pyridine hybrid chemical, despite potential toxicity risks. Structure-activity relationship analysis of the quinoline-pyridine hybrid chemical analogs demonstrated that subtle variations in hydrophobic interactions and substituent positioning significantly influence antibacterial potency. These findings position these chemicals as promising lead compounds for <em>Mt</em>PknB-targeted anti-TB drug development.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"157 ","pages":"Article 102742"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146120437","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}
Pub Date : 2026-03-01Epub Date: 2026-01-08DOI: 10.1016/j.tube.2026.102735
Deepak Devadiga , T.N. Ahipa , S. Umamaheshwari , Chinmay Bhat , S.K. Keerthi , D. Deepika , Santosh L. Gaonkar
In the present study, a series of new pyridine-embedded 1,3,4-oxadiazole derivatives (OXn series) bearing terminal long-chain alkoxy groups like decyloxy, dodecyloxy, tetra decyloxy, and hexadecyloxy groups have been systematically synthesized. Further, the presence of these long-chain alkoxy groups in the OXn series would help to improve the overall molecular lipophilicity and ability to penetrate the lipid-rich mycobacterial cell membrane. Molecular docking has been performed against the mycobacterial InhA enzyme to gain an insight into the possible interactions with the protein, which could pave the way for our endeavor to identify potent antitubercular candidates. Also, these compounds were evaluated for their in vitro antitubercular activities. Among the screened compounds of OXn series, the compound (OX-14) have exhibited potent antitubercular activity against Mycobacterium tuberculosis H37Rv strain with MIC value 32.0 μg/mL and IC50 value of 10.4 μg/mL. We believe that further optimization of this molecule may lead to potent antitubercular agents.
{"title":"Pyridine embedded 1,3,4-oxadiazole derivatives: Design, synthesis, molecular docking and antitubercular activity evaluation","authors":"Deepak Devadiga , T.N. Ahipa , S. Umamaheshwari , Chinmay Bhat , S.K. Keerthi , D. Deepika , Santosh L. Gaonkar","doi":"10.1016/j.tube.2026.102735","DOIUrl":"10.1016/j.tube.2026.102735","url":null,"abstract":"<div><div>In the present study, a series of new pyridine-embedded 1,3,4-oxadiazole derivatives (<strong>OXn</strong> series) bearing terminal long-chain alkoxy groups like decyloxy, dodecyloxy, tetra decyloxy, and hexadecyloxy groups have been systematically synthesized. Further, the presence of these long-chain alkoxy groups in the <strong>OXn</strong> series would help to improve the overall molecular lipophilicity and ability to penetrate the lipid-rich mycobacterial cell membrane. Molecular docking has been performed against the mycobacterial InhA enzyme to gain an insight into the possible interactions with the protein, which could pave the way for our endeavor to identify potent antitubercular candidates. Also, these compounds were evaluated for their <em>in vitro</em> antitubercular activities. Among the screened compounds of <strong>OXn</strong> series, the compound <strong>(OX-14)</strong> have exhibited potent antitubercular activity against <em>Mycobacterium tuberculosis</em> H37Rv strain with MIC value 32.0 μg/mL and IC<sub>50</sub> value of 10.4 μg/mL. We believe that further optimization of this molecule may lead to potent antitubercular agents.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"157 ","pages":"Article 102735"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980510","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}
Pub Date : 2026-03-01Epub Date: 2026-01-31DOI: 10.1016/j.tube.2026.102744
Emily Behrens , Niklas Köhler , Max Münchow , Nika Zielinski , Christoph Pfaffendorf , Hans-Peter Grobbel , Dagmar Schaub , Maja Reimann , Patricia Maria Sánchez Carballo , Barbara Kalsdorf , Doris Hillemann , Martin Kuhns , Sabine Hofmann-Thiel , Harald Hoffmann , Laurent A. Decosterd , Eva Choong , Rob Aarnoutse , Christoph Lange , Sebastian G. Wicha
Clofazimine, moxifloxacin and terizidone/cycloserine play an important role in the treatment of drug-resistant tuberculosis (DR-TB). Personalized therapy guided by model-informed precision dosing (MIPD) can be a powerful tool to improve treatment outcomes, minimize adverse effects and combat the emergence of resistance. To set up an MIPD workflow, a population pharmacokinetic model (popPK model) is required. In this study, an external evaluation of popPK models of the three aforementioned drugs was carried out, using pharmacokinetic data from a cohort of patients with DR-TB, in order to identify the model with the best predictive performance. The best performing models (Abdelwahab et al. for clofazimine, Chirehwa et al. for moxifloxacin and Mulubwa and Mugabo for terizidone/cycloserine) were selected to calculate the area under the concentration-time curve (AUC, total exposure). An interoccasion variability (IOV, variability across dosing occasions) of AUC was quantified (13.4%CV (clofazimine), 16.1%CV (moxifloxacin), 14.5%CV (cycloserine)) indicating that using samples from one dosing occasion for AUC calculations may be sufficient to guide potential dose adjustment. Various single sampling schemes to estimate AUC were evaluated, but a unified timepoint for all drugs could not be determined. Known pharmacodynamic targets (AUC0–24h/MIC, or T>MIC) were attained in almost all patients and dosing occasions.
{"title":"Towards model-informed precision dosing of clofazimine, moxifloxacin, and terizidone/cycloserine in the treatment of drug-resistant tuberculosis: An external model evaluation study","authors":"Emily Behrens , Niklas Köhler , Max Münchow , Nika Zielinski , Christoph Pfaffendorf , Hans-Peter Grobbel , Dagmar Schaub , Maja Reimann , Patricia Maria Sánchez Carballo , Barbara Kalsdorf , Doris Hillemann , Martin Kuhns , Sabine Hofmann-Thiel , Harald Hoffmann , Laurent A. Decosterd , Eva Choong , Rob Aarnoutse , Christoph Lange , Sebastian G. Wicha","doi":"10.1016/j.tube.2026.102744","DOIUrl":"10.1016/j.tube.2026.102744","url":null,"abstract":"<div><div>Clofazimine, moxifloxacin and terizidone/cycloserine play an important role in the treatment of drug-resistant tuberculosis (DR-TB). Personalized therapy guided by model-informed precision dosing (MIPD) can be a powerful tool to improve treatment outcomes, minimize adverse effects and combat the emergence of resistance. To set up an MIPD workflow, a population pharmacokinetic model (popPK model) is required. In this study, an external evaluation of popPK models of the three aforementioned drugs was carried out, using pharmacokinetic data from a cohort of patients with DR-TB, in order to identify the model with the best predictive performance. The best performing models (Abdelwahab et al. for clofazimine, Chirehwa et al. for moxifloxacin and Mulubwa and Mugabo for terizidone/cycloserine) were selected to calculate the area under the concentration-time curve (AUC, total exposure). An interoccasion variability (IOV, variability across dosing occasions) of AUC was quantified (13.4%CV (clofazimine), 16.1%CV (moxifloxacin), 14.5%CV (cycloserine)) indicating that using samples from one dosing occasion for AUC calculations may be sufficient to guide potential dose adjustment. Various single sampling schemes to estimate AUC were evaluated, but a unified timepoint for all drugs could not be determined. Known pharmacodynamic targets (AUC<sub>0–24h</sub>/MIC, or T>MIC) were attained in almost all patients and dosing occasions.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"157 ","pages":"Article 102744"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195672","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}
Pub Date : 2026-03-01Epub Date: 2026-01-29DOI: 10.1016/j.tube.2026.102743
B.C. Mann , J. Loubser , S. Omar , C. Glanz , Y. Ektefaie , K.R. Jacobson , R.M. Warren , M.R. Farhat
Direct sputum whole genome sequencing (dsWGS) can revolutionize Mycobacterium tuberculosis (Mtb) diagnosis by enabling rapid detection clinically relevant resistance mutations and strain diversity without the biohazard of culture. We searched PubMed, Web of Science, and Google Scholar, identifying 8 studies meeting inclusion criteria for testing protocols for dsWGS. Utilising meta-regression, we identified factors positively associated with dsWGS success, including higher Mtb bacillary load, mechanical disruption, enzymatic/chemical lysis and sequencing volume. Decontamination with sodium hydroxide (NaOH) was negatively associated with dsWGS success (OR = 0.00032, 95 % CI: 1.33 × 10ˆ-6–0.077; p = 0.004), likely due to its harsh effects on Mtb cells. Mechanical lysis (OR = 6120, 95 % CI: 7.23–5.18 × 10ˆ6; p = 0.011) and enzymatic/chemical lysis (OR = 131, 95 % CI: 1.68–1.03 × 10ˆ4; p = 0.028) were positively associated with sequencing success, as was heat inactivation (OR = 4.66, 95 % CI: 1.24–17.5; p = 0.023). Total sequencing volume was also strongly associated with dsWGS success (OR = 10.35, 95 % CI: 4.43–24.2; p = 6.53 × 10ˆ-8). In addition to these effects, we also observed high variability in pre-processing approaches, highlighting the need for standardized practices and identified pre-processing steps including decontamination and DNA extraction as priorities for further optimization. Considering the strong association between Mtb load and successful dsWGS, protocols for optimal sputum sample collection, handling, and storage could also further enhance the success rate of dsWGS.
{"title":"Systematic review and meta-analysis of protocols and sequencing yield for whole genome sequencing of Mycobacterium tuberculosis directly from sputum samples","authors":"B.C. Mann , J. Loubser , S. Omar , C. Glanz , Y. Ektefaie , K.R. Jacobson , R.M. Warren , M.R. Farhat","doi":"10.1016/j.tube.2026.102743","DOIUrl":"10.1016/j.tube.2026.102743","url":null,"abstract":"<div><div>Direct sputum whole genome sequencing (dsWGS) can revolutionize <em>Mycobacterium tuberculosis</em> (Mtb) diagnosis by enabling rapid detection clinically relevant resistance mutations and strain diversity without the biohazard of culture. We searched PubMed, Web of Science, and Google Scholar, identifying 8 studies meeting inclusion criteria for testing protocols for dsWGS. Utilising meta-regression, we identified factors positively associated with dsWGS success, including higher Mtb bacillary load, mechanical disruption, enzymatic/chemical lysis and sequencing volume. Decontamination with sodium hydroxide (NaOH) was negatively associated with dsWGS success (OR = 0.00032, 95 % CI: 1.33 × 10ˆ-6–0.077; p = 0.004), likely due to its harsh effects on Mtb cells. Mechanical lysis (OR = 6120, 95 % CI: 7.23–5.18 × 10ˆ6; p = 0.011) and enzymatic/chemical lysis (OR = 131, 95 % CI: 1.68–1.03 × 10ˆ4; p = 0.028) were positively associated with sequencing success, as was heat inactivation (OR = 4.66, 95 % CI: 1.24–17.5; p = 0.023). Total sequencing volume was also strongly associated with dsWGS success (OR = 10.35, 95 % CI: 4.43–24.2; p = 6.53 × 10ˆ-8). In addition to these effects, we also observed high variability in pre-processing approaches, highlighting the need for standardized practices and identified pre-processing steps including decontamination and DNA extraction as priorities for further optimization. Considering the strong association between <em>Mtb</em> load and successful dsWGS, protocols for optimal sputum sample collection, handling, and storage could also further enhance the success rate of dsWGS.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"157 ","pages":"Article 102743"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146114415","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}
Tuberculosis (TB), caused by Mycobacterium tuberculosis, exhibits pronounced sex differences in incidence and disease progression, with adult males disproportionately affected. Increasing evidence indicates that sex steroid hormones estrogen, progesterone, and testosterone modulate immune responses critical for MTB control. This narrative review synthesizes findings from both human and animal studies using PubMed, ScienceDirect, and Google Scholar.
Effective host defense against MTB relies on pro-inflammatory cytokines, including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, whereas anti-inflammatory cytokines such as IL-4, IL-5, and IL-10 are associated with reduced bacterial control and disease progression. Sex steroid hormones regulate both the magnitude and balance of these immune responses in a dose, stag-, and context-dependent manner. Estrogen enhances Th1-mediated immunity at physiological concentrations but may favor Th2-biased responses at supraphysiologic levels, such as during pregnancy. Progesterone contributes to immune homeostasis at basal concentrations but suppresses dendritic cell function and Th1 immunity at elevated levels. Testosterone consistently attenuates Th1 immunity and enhances anti-inflammatory pathways.
Human epidemiologic and clinical studies support these trends, showing adult males are more susceptible to active TB, while women experience increased risk during pregnancy. However, circulating hormone data in TB patients are inconsistent, highlighting the need for longitudinal, hormone-aware studies. Overall, sex hormone mediated immune modulation influences TB susceptibility and pathogenesis, and future research should adopt sex and hormone-dose-aware designs to optimize host-directed therapies.
{"title":"Sex hormones and tuberculosis: Implications for immune regulation, susceptibility, and disease pathogenesis","authors":"Eshet Gebrie , Habtamu Wondifraw Baynes , Birhan Mulugeta , Henok Worku , Berihun Agegn Mengistie , Amanuale Zayede , Elias Chane","doi":"10.1016/j.tube.2026.102740","DOIUrl":"10.1016/j.tube.2026.102740","url":null,"abstract":"<div><div>Tuberculosis (TB), caused by <em>Mycobacterium tuberculosis</em>, exhibits pronounced sex differences in incidence and disease progression, with adult males disproportionately affected. Increasing evidence indicates that sex steroid hormones estrogen, progesterone, and testosterone modulate immune responses critical for MTB control. This narrative review synthesizes findings from both human and animal studies using PubMed, ScienceDirect, and Google Scholar.</div><div>Effective host defense against MTB relies on pro-inflammatory cytokines, including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, whereas anti-inflammatory cytokines such as IL-4, IL-5, and IL-10 are associated with reduced bacterial control and disease progression. Sex steroid hormones regulate both the magnitude and balance of these immune responses in a dose, stag-, and context-dependent manner. Estrogen enhances Th1-mediated immunity at physiological concentrations but may favor Th2-biased responses at supraphysiologic levels, such as during pregnancy. Progesterone contributes to immune homeostasis at basal concentrations but suppresses dendritic cell function and Th1 immunity at elevated levels. Testosterone consistently attenuates Th1 immunity and enhances anti-inflammatory pathways.</div><div>Human epidemiologic and clinical studies support these trends, showing adult males are more susceptible to active TB, while women experience increased risk during pregnancy. However, circulating hormone data in TB patients are inconsistent, highlighting the need for longitudinal, hormone-aware studies. Overall, sex hormone mediated immune modulation influences TB susceptibility and pathogenesis, and future research should adopt sex and hormone-dose-aware designs to optimize host-directed therapies.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"157 ","pages":"Article 102740"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146038655","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}
Pub Date : 2026-01-01Epub Date: 2025-11-21DOI: 10.1016/j.tube.2025.102710
Eileen M. Murphy , G. Michael Taylor , Tom A. Mendum , Graham R. Stewart
Eight burials from the multi-period rural settlement site of Ranelagh near Roscommon town, Ireland, with palaeopathological lesions suggestive of skeletal tuberculosis or brucellosis were examined by ancient DNA (aDNA) testing. Tuberculosis infection (MTB complex DNA) was confirmed in five individuals – an 11th-13th CE adolescent female (14.5–17.5 years), two young adults females (18–35 years, 7th-10th CE), one adolescent of unknown sex and one middle-aged adult (35–50 years, medieval in date). In the latter case, the differential diagnosis included brucellosis due to the presence of small multifocal lytic lesions in the lower spinal vertebrae. However, this individual and all cases tested negative for Brucella species DNA. In two positive cases, lineage 4 (Euro-American) Mycobacterium tuberculosis DNA was identified in extracts obtained from tooth pulp cavities. These are the first archaeological individuals from Ireland to have had tuberculosis infection confirmed through aDNA analysis.
{"title":"First confirmation of Mycobacterium tuberculosis complex from medieval Ireland by aDNA analysis – palaeopathological and microbial findings","authors":"Eileen M. Murphy , G. Michael Taylor , Tom A. Mendum , Graham R. Stewart","doi":"10.1016/j.tube.2025.102710","DOIUrl":"10.1016/j.tube.2025.102710","url":null,"abstract":"<div><div>Eight burials from the multi-period rural settlement site of Ranelagh near Roscommon town, Ireland, with palaeopathological lesions suggestive of skeletal tuberculosis or brucellosis were examined by ancient DNA (aDNA) testing. Tuberculosis infection (MTB complex DNA) was confirmed in five individuals – an 11th-13th CE adolescent female (14.5–17.5 years), two young adults females (18–35 years, 7th-10th CE), one adolescent of unknown sex and one middle-aged adult (35–50 years, medieval in date). In the latter case, the differential diagnosis included brucellosis due to the presence of small multifocal lytic lesions in the lower spinal vertebrae. However, this individual and all cases tested negative for <em>Brucella</em> species DNA. In two positive cases, lineage 4 (Euro-American) <em>Mycobacterium tuberculosis</em> DNA was identified in extracts obtained from tooth pulp cavities. These are the first archaeological individuals from Ireland to have had tuberculosis infection confirmed through aDNA analysis.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"156 ","pages":"Article 102710"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145795039","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}
Pub Date : 2026-01-01Epub Date: 2025-12-11DOI: 10.1016/j.tube.2025.102720
Anuradha Rajamanickam , Evangeline Ann Daniel , Nikhil Gupte , Kannan Thiruvengadam , Padmapriyadarsini Chandrasekaran , Sathyamurthi Pattabiraman , Brindha Bhanu , Amsaveni Sivaprakasam , Mandar Paradkar , Vandana Kulkarni , Rajesh Karyakarte , Vidya Mave , Amita Gupta , Luke Elizabeth Hanna , Subash Babu
Background
Identifying host biomarkers associated with progression from Mycobacterium tuberculosis infection to active tuberculosis (TB) could support early risk stratification in household contacts (HHCs). This exploratory study evaluated baseline plasma immune biomarkers in HHCs of pulmonary TB (PTB) patients to assess their association with subsequent disease development.
Methods
We analyzed baseline plasma samples from 15 progressors and 29 non-progressors enrolled from PTB-affected households. Acute-phase proteins (α-2-macroglobulin (α-2-M), C-reactive protein [CRP], haptoglobin (Hp), serum amyloid P (SAP)) and microbial translocation markers (lipopolysaccharide, lipid-binding protein, endotoxin core antibodies IgG, intestinal fatty acid-binding protein [iFABP], sCD14, and zonulin) were measured using Luminex and ELISA. Logistic regression and ROC analyses were performed as exploratory assessments of biomarker associations.
Results
Higher baseline levels of CRP, iFABP, and zonulin were observed among progressors compared with non-progressors. In univariable analyses, these biomarkers showed strong discriminatory ability (AUC ≥0.90), although estimates should be interpreted cautiously given the small sample size. A combined model including CRP, iFABP, and zonulin demonstrated high discriminatory performance (AUC 0.99 [95 % CI: 0.97–1.00]), but confidence intervals reflect the imprecision inherent to the limited dataset.
Conclusions
In this exploratory cohort, elevated CRP, iFABP, and zonulin were associated with progression to active TB among household contacts. These preliminary findings suggest potential involvement of inflammatory and gut-barrier pathways in TB progression and warrant validation in larger, independent cohorts to define their translational utility.
{"title":"Plasma biomarkers CRP, iFABP, and zonulin as predictors of tuberculosis progression in household contacts of pulmonary TB patients","authors":"Anuradha Rajamanickam , Evangeline Ann Daniel , Nikhil Gupte , Kannan Thiruvengadam , Padmapriyadarsini Chandrasekaran , Sathyamurthi Pattabiraman , Brindha Bhanu , Amsaveni Sivaprakasam , Mandar Paradkar , Vandana Kulkarni , Rajesh Karyakarte , Vidya Mave , Amita Gupta , Luke Elizabeth Hanna , Subash Babu","doi":"10.1016/j.tube.2025.102720","DOIUrl":"10.1016/j.tube.2025.102720","url":null,"abstract":"<div><h3>Background</h3><div>Identifying host biomarkers associated with progression from <em>Mycobacterium tuberculosis</em> infection to active tuberculosis (TB) could support early risk stratification in household contacts (HHCs). This exploratory study evaluated baseline plasma immune biomarkers in HHCs of pulmonary TB (PTB) patients to assess their association with subsequent disease development.</div></div><div><h3>Methods</h3><div>We analyzed baseline plasma samples from 15 progressors and 29 non-progressors enrolled from PTB-affected households. Acute-phase proteins (α-2-macroglobulin (α-2-M), C-reactive protein [CRP], haptoglobin (Hp), serum amyloid P (SAP)) and microbial translocation markers (lipopolysaccharide, lipid-binding protein, endotoxin core antibodies IgG, intestinal fatty acid-binding protein [iFABP], sCD14, and zonulin) were measured using Luminex and ELISA. Logistic regression and ROC analyses were performed as exploratory assessments of biomarker associations.</div></div><div><h3>Results</h3><div>Higher baseline levels of CRP, iFABP, and zonulin were observed among progressors compared with non-progressors. In univariable analyses, these biomarkers showed strong discriminatory ability (AUC ≥0.90), although estimates should be interpreted cautiously given the small sample size. A combined model including CRP, iFABP, and zonulin demonstrated high discriminatory performance (AUC 0.99 [95 % CI: 0.97–1.00]), but confidence intervals reflect the imprecision inherent to the limited dataset.</div></div><div><h3>Conclusions</h3><div>In this exploratory cohort, elevated CRP, iFABP, and zonulin were associated with progression to active TB among household contacts. These preliminary findings suggest potential involvement of inflammatory and gut-barrier pathways in TB progression and warrant validation in larger, independent cohorts to define their translational utility.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"156 ","pages":"Article 102720"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145782650","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}
Pub Date : 2026-01-01Epub Date: 2025-12-19DOI: 10.1016/j.tube.2025.102722
Safiya Mehraj , Shazia Ali , Chetan Kumar , Asif Ali , Zahoor Ahmad
{"title":"Corrigendum to “Inhibition of mycobacteria proliferation in macrophages by diaryl ether derivatives of Dehydrozingerone compound and repurposed drugs (Rebamipide, Sofalcone) via NF-κB pathway inhibition” [Tuberculosis, 155(2025), 102706]","authors":"Safiya Mehraj , Shazia Ali , Chetan Kumar , Asif Ali , Zahoor Ahmad","doi":"10.1016/j.tube.2025.102722","DOIUrl":"10.1016/j.tube.2025.102722","url":null,"abstract":"","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"156 ","pages":"Article 102722"},"PeriodicalIF":2.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145791078","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}
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