Pub Date : 2025-10-23DOI: 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.
{"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":"2025-10-23","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}
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.
{"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":"2025-10-23","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}
Pub Date : 2025-10-22DOI: 10.1016/j.tube.2025.102702
Angela Hidalgo-Gajardo , Bryan Mangui , Carla Villavicencio , Jorge R. Toledo , Frank Camacho
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB), Bacille Calmette-Guérin (BCG) is the only licensed vaccine for tuberculosis, but it provides limited and inconsistent protection against pulmonary TB in adults. Furthermore, current diagnostic methods show low sensitivity in latent stages, and the standard treatment is long, complex, and conducive to the emergence of drug-resistant strains.
In this context, heat shock protein X (HspX), also known as Rv2031c or α-crystallin, has emerged as a potential biomarker and vaccine candidate. This 16-kDa protein is predominantly expressed under stressful conditions such as hypoxia and nitric oxide exposure, which are characteristic of the granulomatous microenvironment where MTB persists. Its expression during latency and high immunogenicity has been demonstrated in individuals with latent tuberculosis infection and those vaccinated with BCG.
Preclinical studies have shown that recombinant HspX potentiates the host immune response used as a component in subunit vaccines, either alone or in combination with other antigens. Incorporating this protein into new diagnostic, therapeutic, and vaccine strategies could optimize disease control. This review explores HspX's multifaceted role and potential applications in tuberculosis diagnosis, treatment, and vaccine development.
{"title":"Targeting HspX of Mycobacterium tuberculosis: Advances in diagnostics, treatment, and vaccine development","authors":"Angela Hidalgo-Gajardo , Bryan Mangui , Carla Villavicencio , Jorge R. Toledo , Frank Camacho","doi":"10.1016/j.tube.2025.102702","DOIUrl":"10.1016/j.tube.2025.102702","url":null,"abstract":"<div><div>Tuberculosis (TB) is an infectious disease caused by <em>Mycobacterium tuberculosis</em> (MTB), Bacille Calmette-Guérin (BCG) is the only licensed vaccine for tuberculosis, but it provides limited and inconsistent protection against pulmonary TB in adults. Furthermore, current diagnostic methods show low sensitivity in latent stages, and the standard treatment is long, complex, and conducive to the emergence of drug-resistant strains.</div><div>In this context, heat shock protein X (HspX), also known as Rv2031c or α-crystallin, has emerged as a potential biomarker and vaccine candidate. This 16-kDa protein is predominantly expressed under stressful conditions such as hypoxia and nitric oxide exposure, which are characteristic of the granulomatous microenvironment where MTB persists. Its expression during latency and high immunogenicity has been demonstrated in individuals with latent tuberculosis infection and those vaccinated with BCG.</div><div>Preclinical studies have shown that recombinant HspX potentiates the host immune response used as a component in subunit vaccines, either alone or in combination with other antigens. Incorporating this protein into new diagnostic, therapeutic, and vaccine strategies could optimize disease control. This review explores HspX's multifaceted role and potential applications in tuberculosis diagnosis, treatment, and vaccine development.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102702"},"PeriodicalIF":2.9,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145423010","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 : 2025-10-14DOI: 10.1016/j.tube.2025.102698
Qiangsen Zhong , Xiaochun Wang , Yun Xu , Runlin Wang , Mingming Zhou , Xinkuang Liu
Tuberculosis (TB) is the leading cause of death in global infectious diseases, and precise diagnosis and preventive intervention of latent tuberculosis infection (LTBI) are important to end the TB epidemic. In this study, we explored the diagnostic value of five Mycobacterium tuberculosis (MTB) dormant highly expressed antigens (Rv0470c, Rv2026c, Rv2466c, Rv3334, and Rv3406) in LTBI and evaluated the immunologic efficacy of a novel subunit vaccine, PB2-DIMQ (antigen PB2:Rv0470c-Rv1846c; adjuvant DIMQ: liposome dimethyl dioctadecylammonium bromide [DDA] + imiquimod [IMQ]). It was found that all five antigens were generally capable of eliciting immune responses among patients with LTBI and those with active tuberculosis (ATB). Although differences in the intensity of responses were present for some antigens between the two groups, their discriminatory power in differentiating LTBI from ATB was limited (AUC = 0.6622–0.7473). Nevertheless, these antigens still hold promising potential for application in the diagnosis of MTB infection (AUC = 0.7415–0.9556). On the other hand, under the prime-boost strategy, the PB2-DIMQ vaccine induced a significantly stronger Th1-type immune response than BCG in a mouse model, promoting the expansion of multifunctional T cells (CD4+/CD8+ IFN-γ+ IL-2+), and enhanced in vitro bacterial inhibition. This study provides new targets and strategies (fusion antigen PB2 + adjuvant DIMQ) for the development of novel TB diagnostic tools and next-generation TB vaccines with important clinical translational prospects.
{"title":"Diagnostic value of five Mycobacterium tuberculosis dormant highly expressed antigens in latent infections and immunogenicity assessment of a novel subunit vaccine PB2-DIMQ","authors":"Qiangsen Zhong , Xiaochun Wang , Yun Xu , Runlin Wang , Mingming Zhou , Xinkuang Liu","doi":"10.1016/j.tube.2025.102698","DOIUrl":"10.1016/j.tube.2025.102698","url":null,"abstract":"<div><div>Tuberculosis (TB) is the leading cause of death in global infectious diseases, and precise diagnosis and preventive intervention of latent tuberculosis infection (LTBI) are important to end the TB epidemic. In this study, we explored the diagnostic value of five <em>Mycobacterium tuberculosis</em> (MTB) dormant highly expressed antigens (Rv0470c, Rv2026c, Rv2466c, Rv3334, and Rv3406) in LTBI and evaluated the immunologic efficacy of a novel subunit vaccine, PB2-DIMQ (antigen PB2:Rv0470c-Rv1846c; adjuvant DIMQ: liposome dimethyl dioctadecylammonium bromide [DDA] + imiquimod [IMQ]). It was found that all five antigens were generally capable of eliciting immune responses among patients with LTBI and those with active tuberculosis (ATB). Although differences in the intensity of responses were present for some antigens between the two groups, their discriminatory power in differentiating LTBI from ATB was limited (AUC = 0.6622–0.7473). Nevertheless, these antigens still hold promising potential for application in the diagnosis of MTB infection (AUC = 0.7415–0.9556). On the other hand, under the prime-boost strategy, the PB2-DIMQ vaccine induced a significantly stronger Th1-type immune response than BCG in a mouse model, promoting the expansion of multifunctional T cells (CD4<sup>+</sup>/CD8<sup>+</sup> IFN-γ<sup>+</sup> IL-2<sup>+</sup>), and enhanced in vitro bacterial inhibition. This study provides new targets and strategies (fusion antigen PB2 + adjuvant DIMQ) for the development of novel TB diagnostic tools and next-generation TB vaccines with important clinical translational prospects.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102698"},"PeriodicalIF":2.9,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318633","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 : 2025-10-10DOI: 10.1016/j.tube.2025.102697
Eamonn Gormley , David E. MacHugh , Kieran G. Meade
As a zoonotic disease, with a global impact on animal health, welfare and trade, bovine tuberculosis (bTB), caused by infection with Mycobacterium bovis, has been subject to strict control measures in many countries to reduce the impact of the disease on cattle and their handlers. However, eradication efforts have been constrained in some countries for several reasons, including limitations in diagnostic test sensitivity. As a result, a proportion of M. bovis-infected cattle are being misdiagnosed, which then become reservoirs of infection contributing to further spread of disease. A significant amount of research effort has focused on understanding the immune responses to M. bovis infection in cattle and on investigating how these can be leveraged to improve diagnostic performance. More recently, and predominantly in human and murine models of Mycobacterium tuberculosis infection, there has been a growing recognition that chemical modifications to DNA and proteins (referred collectively to as epigenetic mechanisms), which spatially govern gene activity across host chromosomes, can directly regulate the immune responses. However, knowledge of epigenetic changes in response to M. bovis infection in cattle is still in its infancy. Epigenetic “marks” (e.g., DNA methylation and histone modifications) are dynamic, and alterations induced by the infecting pathogen lead to a complex biochemical interplay that can ultimately determine the infection outcome. Drawing on the extensive wealth of epigenetic findings from studies on M. tuberculosis infection, this review explores the evidence for epigenetic control of the immune response to M. bovis and bTB disease by methylation and acetylation of host chromosomes. Understanding the extent and nature of epigenetic control may reveal how M. bovis coevolution with the bovine host shapes both immune outcomes and diagnostic test sensitivity.
{"title":"Epigenetic regulation of the immune response to Mycobacterium bovis infection in cattle: potential implications for diagnostic test sensitivity","authors":"Eamonn Gormley , David E. MacHugh , Kieran G. Meade","doi":"10.1016/j.tube.2025.102697","DOIUrl":"10.1016/j.tube.2025.102697","url":null,"abstract":"<div><div>As a zoonotic disease, with a global impact on animal health, welfare and trade, bovine tuberculosis (bTB), caused by infection with <em>Mycobacterium bovis</em>, has been subject to strict control measures in many countries to reduce the impact of the disease on cattle and their handlers. However, eradication efforts have been constrained in some countries for several reasons, including limitations in diagnostic test sensitivity. As a result, a proportion of <em>M. bovis</em>-infected cattle are being misdiagnosed, which then become reservoirs of infection contributing to further spread of disease. A significant amount of research effort has focused on understanding the immune responses to <em>M. bovis</em> infection in cattle and on investigating how these can be leveraged to improve diagnostic performance. More recently, and predominantly in human and murine models of <em>Mycobacterium tuberculosis</em> infection, there has been a growing recognition that chemical modifications to DNA and proteins (referred collectively to as epigenetic mechanisms), which spatially govern gene activity across host chromosomes, can directly regulate the immune responses. However, knowledge of epigenetic changes in response to <em>M. bovis</em> infection in cattle is still in its infancy. Epigenetic “marks” (e.g., DNA methylation and histone modifications) are dynamic, and alterations induced by the infecting pathogen lead to a complex biochemical interplay that can ultimately determine the infection outcome. Drawing on the extensive wealth of epigenetic findings from studies on <em>M. tuberculosis</em> infection, this review explores the evidence for epigenetic control of the immune response to <em>M. bovis</em> and bTB disease by methylation and acetylation of host chromosomes. Understanding the extent and nature of epigenetic control may reveal how <em>M. bovis</em> coevolution with the bovine host shapes both immune outcomes and diagnostic test sensitivity.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102697"},"PeriodicalIF":2.9,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145303558","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 : 2025-10-04DOI: 10.1016/j.tube.2025.102696
Lei Wang , Li-ping Cheng , Xiao-na Shen , Yuanyuan Yu , Jie Cao , Zhi-bin Liu , Qingrong Qu , Xiao-cui Wu , Wei Sha , Qin Sun
Objective
This study aimed to analyze the differences in lymphocyte subsets and immune function between tuberculosis (TB) and nontuberculous mycobacterial pulmonary disease (NTM-PD), thereby deepening the understanding of the pathogenesis of these diseases and providing important insights for clinical diagnosis, treatment, and prognosis evaluation.
Methods
Patients with pulmonary imaging abnormalities admitted to the Tuberculosis Department of Shanghai Pulmonary Hospital from January 2023 to December 2023 were included. Based on diagnostic assessments, they were categorized into active tuberculosis (ATB), NTM-PD, and other pulmonary diseases (including inflammatory and neoplastic lung diseases). Flow cytometry was used to detect lymphocyte subset counts.
Results
(1) There were no significant differences in lymphocyte subset counts between the ATB and NTM groups; however, both groups showed marked differences when compared with the group of patients with other respiratory diseases. Specifically, the percentages and absolute counts of CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD19+ B cells were significantly lower in the ATB and NTM groups, whereas the levels of CD16+56+ natural killer (NK) cells were higher compared to those with other respiratory diseases.(2) Patients in the non-severe ATB (nSATB) group exhibited higher levels of CD3+ T cells and CD19+ B cells compared to those in the severe ATB (SATB) group.(3) Among patients with ATB, those with concomitant diabetes had lower CD8+ T cell counts and percentages, as well as a higher CD4/CD8 ratio, compared to those without diabetes.(4) In patients with NTM-PD, those with severe disease had lower percentages of CD16+56+ NK cells than those with non-severe NTM-PD.(5) No significant differences in lymphocyte subset parameters were observed between drug-resistant and drug-sensitive ATB patients, or between patients with rapidly growing and slowly growing NTM species.
Conclusion
This study revealed the lymphocyte subset characteristics of patients with TB and NTM infections and identified potential associations between disease severity, diabetes comorbidities, and immune cell subsets with disease status. These findings provide a basis for further research on the immune mechanisms of infectious pulmonary diseases and contribute to the development of precision medicine strategies.
{"title":"Comparative analysis of lymphocyte subsets in tuberculosis, NTM infections, and other respiratory diseases","authors":"Lei Wang , Li-ping Cheng , Xiao-na Shen , Yuanyuan Yu , Jie Cao , Zhi-bin Liu , Qingrong Qu , Xiao-cui Wu , Wei Sha , Qin Sun","doi":"10.1016/j.tube.2025.102696","DOIUrl":"10.1016/j.tube.2025.102696","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to analyze the differences in lymphocyte subsets and immune function between tuberculosis (TB) and nontuberculous mycobacterial pulmonary disease (NTM-PD), thereby deepening the understanding of the pathogenesis of these diseases and providing important insights for clinical diagnosis, treatment, and prognosis evaluation.</div></div><div><h3>Methods</h3><div>Patients with pulmonary imaging abnormalities admitted to the Tuberculosis Department of Shanghai Pulmonary Hospital from January 2023 to December 2023 were included. Based on diagnostic assessments, they were categorized into active tuberculosis (ATB), NTM-PD, and other pulmonary diseases (including inflammatory and neoplastic lung diseases). Flow cytometry was used to detect lymphocyte subset counts.</div></div><div><h3>Results</h3><div>(1) There were no significant differences in lymphocyte subset counts between the ATB and NTM groups; however, both groups showed marked differences when compared with the group of patients with other respiratory diseases. Specifically, the percentages and absolute counts of CD3<sup>+</sup> T cells, CD4<sup>+</sup> T cells, CD8<sup>+</sup> T cells, and CD19<sup>+</sup> B cells were significantly lower in the ATB and NTM groups, whereas the levels of CD16<sup>+</sup>56<sup>+</sup> natural killer (NK) cells were higher compared to those with other respiratory diseases.(2) Patients in the non-severe ATB (nSATB) group exhibited higher levels of CD3<sup>+</sup> T cells and CD19<sup>+</sup> B cells compared to those in the severe ATB (SATB) group.(3) Among patients with ATB, those with concomitant diabetes had lower CD8<sup>+</sup> T cell counts and percentages, as well as a higher CD4/CD8 ratio, compared to those without diabetes.(4) In patients with NTM-PD, those with severe disease had lower percentages of CD16<sup>+</sup>56<sup>+</sup> NK cells than those with non-severe NTM-PD.(5) No significant differences in lymphocyte subset parameters were observed between drug-resistant and drug-sensitive ATB patients, or between patients with rapidly growing and slowly growing NTM species.</div></div><div><h3>Conclusion</h3><div>This study revealed the lymphocyte subset characteristics of patients with TB and NTM infections and identified potential associations between disease severity, diabetes comorbidities, and immune cell subsets with disease status. These findings provide a basis for further research on the immune mechanisms of infectious pulmonary diseases and contribute to the development of precision medicine strategies.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102696"},"PeriodicalIF":2.9,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145293821","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}
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.
{"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":"2025-09-27","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}
Pub Date : 2025-09-19DOI: 10.1016/j.tube.2025.102693
Yufan Xu , Longlong Wang , Jijie Jiang , Guocheng Zhao , Zhe Wang
The rising prevalence of drug-resistant tuberculosis (DR-TB), coupled with stagnation in the development of novel therapeutics, underscores the urgent need for new drug targets and innovative anti-tuberculosis agents. In this study, we demonstrate that CRISPR interference-mediated knockdown of argH, a nitrogen metabolism-associated gene encoding argininosuccinate lyase, significantly impairs the growth of Mycolicibacterium smegmatis (formerly Mycobacterium smegmatis). This growth defect was alleviated in a concentration-dependent manner by arginine supplementation. In a goldfish infection model, argH knockdown led to a marked reduction in bacterial burden within both liver and kidney tissues. Notably, bacitracin and 5-fluorouracil exhibited synergistic effects when combined with argH knockdown. Metabolomic profiling revealed significant perturbations in multiple amino acids, as well as in succinyl-CoA and lactate levels, suggesting that suppression of argH impairs M. smegmatis proliferation by disrupting amino acid homeostasis and interfering with aerobic respiration.
{"title":"Knockdown of argininosuccinate lyase influences the growth of Mycolicibacterium smegmatis in vitro and in vivo","authors":"Yufan Xu , Longlong Wang , Jijie Jiang , Guocheng Zhao , Zhe Wang","doi":"10.1016/j.tube.2025.102693","DOIUrl":"10.1016/j.tube.2025.102693","url":null,"abstract":"<div><div>The rising prevalence of drug-resistant tuberculosis (DR-TB), coupled with stagnation in the development of novel therapeutics, underscores the urgent need for new drug targets and innovative anti-tuberculosis agents. In this study, we demonstrate that CRISPR interference-mediated knockdown of argH, a nitrogen metabolism-associated gene encoding argininosuccinate lyase, significantly impairs the growth of <em>Mycolicibacterium smegmatis</em> (formerly <em>Mycobacterium smegmatis</em>). This growth defect was alleviated in a concentration-dependent manner by arginine supplementation. In a goldfish infection model, argH knockdown led to a marked reduction in bacterial burden within both liver and kidney tissues. Notably, bacitracin and 5-fluorouracil exhibited synergistic effects when combined with argH knockdown. Metabolomic profiling revealed significant perturbations in multiple amino acids, as well as in succinyl-CoA and lactate levels, suggesting that suppression of argH impairs <em>M. smegmatis</em> proliferation by disrupting amino acid homeostasis and interfering with aerobic respiration.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102693"},"PeriodicalIF":2.9,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119026","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 : 2025-09-19DOI: 10.1016/j.tube.2025.102692
Natalia Przysucha , Magdalena Paplińska-Goryca , Katarzyna Górska , Paulina Misiukiewicz-Stępień , Michał Mlącki , Agata Cyran , Rafal Krenke
Background
Chitinases and chitinase-like proteins are implicated in the pathophysiology of lung diseases. This study aimed to evaluate the significance of chitotriosidase (CHIT1) and YKL-40 in tuberculous pleural effusion (TPE), identify their cellular sources, and assess their diagnostic potential as TPE biomarkers.
Methods
This observational, retrospective study included 66 patients with pleural effusion of different origins: malignant (MPE), tuberculous (TPE), parapneumonic (PPE), and transudative (TE). Pleural fluid levels of YKL-40 and CHIT1 were measured. Expressions of YKL-40 and CHIT1 in tuberculous pleural granulomas were also assessed using immunohistochemical staining.
Results
We found the highest median CHIT1 and YKL-40 levels for TPE: 70.51 (interquartile range [IQR] 49.65–136.98) ng/mL and 569.84 (IQR 530.32–706.01) ng/mL, respectively. YKL-40 was significantly higher in TPE than in PPE (387.98 [IQR 262.94–539.09] ng/mL, p < 0.01)] and TE (254.95 [IQR 188.93–334.1 ng/ml] ng/mL, p < 0.001). There was a strong positive correlation between the YKL-40 level in TPE and the percentage of macrophages (r = 0.73, p = 0.003) and the adenosine deaminase activity (r = 0.82, p < 0.001). We revealed strong YKL-40 expression in tuberculoid pleural granulomas.
Conclusion
YKL-40, but not CHIT-1, may contribute to the pleural inflammatory response associated with tuberculosis.
几丁质酶和几丁质酶样蛋白参与肺部疾病的病理生理。本研究旨在评估壳三醇苷酶（CHIT1）和YKL-40在结核性胸腔积液（TPE）中的意义，确定它们的细胞来源，并评估它们作为TPE生物标志物的诊断潜力。方法回顾性观察66例不同来源的胸腔积液：恶性（MPE）、结核性（TPE）、肺副性（PPE）和肺泡性（TE）。测定胸膜液中YKL-40和CHIT1水平。免疫组化染色法检测结核性胸膜肉芽肿组织中YKL-40和CHIT1的表达。结果TPE患者的CHIT1和YKL-40水平中位数最高，分别为70.51（四分位间距[IQR] 49.65 ~ 136.98） ng/mL和569.84 (IQR 530.32 ~ 706.01) ng/mL。TPE中YKL-40含量显著高于PPE （387.98 [IQR 262.94-539.09] ng/mL, p < 0.01）和TE （254.95 [IQR 188.93-334.1] ng/mL, p < 0.001）。TPE中YKL-40水平与巨噬细胞百分比（r = 0.73, p = 0.003）和腺苷脱氨酶活性（r = 0.82, p < 0.001）呈极显著正相关。我们发现YKL-40在结核样胸膜肉芽肿中表达强烈。结论ykl -40可能参与结核相关胸膜炎症反应，而CHIT-1不参与。
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Pub Date : 2025-09-12DOI: 10.1016/j.tube.2025.102691
Miguel Pinto , Rita Macedo
To improve TB surveillance and diagnosis, the Portuguese National Reference Laboratory (NRL) began implementing whole-genome sequencing (WGS) for all RR/MDR-TB cases in 2019. Since 2020, this approach has been expanded to indiscriminately include all received isolates. We describe the current WGS-based surveillance system in Portugal, framed in prospective and retrospective data (n = 1171), upgraded for antimicrobial resistance (AMR) prediction and epidemiological analysis. This system relies on three main steps: QC/QA and contamination assessment, with a novel data filtering step; genotyping and AMR prediction; and dynamic SNP-based approach, maximizing variable sites under analysis. While lineage 4 was the most prevalent (84.3 %) followed by lineage 2 (9.1 %), less common EU/EEA sub-lineages (e.g., lineages 3 and 6) showcased cross-border transmissions. Molecular clusters (n = 157) displayed distinct AMR profiles and diverse possible epidemiological contexts. Among the pipeline upgrades, we highlight: i) the novel filtering step that allowed the improvement of 123 out of 128 contaminated samples; ii) tolerating missing data per site more than doubled core variable site resolution; iii) automatic maximization of shared variable sites for in-depth cluster analysis, key for consolidating genetic links in epidemiological investigation. This study highlights the importance of sustained prospective genomic surveillance towards strengthening TB management and diagnosis in Portugal.
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