Pub Date : 2025-10-29DOI: 10.1016/j.tube.2025.102704
Valnês da Silva Rodrigues-Junior , Maria Eugênia.G. de Freitas , Maria Gabriella S. Sidrônio , Daniel.W.A. Magalhães , Gisela C. Paulino , Francisco Jaime B. Mendonça-Junior , Sandra Rodrigues-Mascarenhas , Maria Martha Campos
Inhibition of PI3Kγ is an attractive therapeutic target for the development of novel host-directed modulating strategies for the treatment of infectious diseases. This work investigated the antimicrobial potential of AS605240, a selective inhibitor of PI3Kγ, in pre-clinical models of mycobacterial infections. Of note, we observed that treatment with AS605240 effectively reduced both intracellular M. smegmatis and M. tuberculosis counts in RAW 264.7 cells. Moreover, treatment of M. tuberculosis-infected cells with AS605240 increased TNF-α and decreased IL-1β levels compared to the infected group. Importantly, we found that AS605240 is bacteriostatic in the lungs and bactericidal in spleens from M. tuberculosis-infected mice. Our data provide novel evidence on the relevance of PI3Kγ as a novel molecular target for new anti-tubercular drugs.
{"title":"In vitro and in vivo efficacy of PI3Kγ inhibitor AS605240 in controlling mycobacterial infections","authors":"Valnês da Silva Rodrigues-Junior , Maria Eugênia.G. de Freitas , Maria Gabriella S. Sidrônio , Daniel.W.A. Magalhães , Gisela C. Paulino , Francisco Jaime B. Mendonça-Junior , Sandra Rodrigues-Mascarenhas , Maria Martha Campos","doi":"10.1016/j.tube.2025.102704","DOIUrl":"10.1016/j.tube.2025.102704","url":null,"abstract":"<div><div>Inhibition of PI3Kγ is an attractive therapeutic target for the development of novel host-directed modulating strategies for the treatment of infectious diseases. This work investigated the antimicrobial potential of AS605240, a selective inhibitor of PI3Kγ, in pre-clinical models of mycobacterial infections. Of note, we observed that treatment with AS605240 effectively reduced both intracellular <em>M. smegmatis</em> and <em>M. tuberculosis</em> counts in RAW 264.7 cells. Moreover, treatment of <em>M. tuberculosis</em>-infected cells with AS605240 increased TNF-α and decreased IL-1β levels compared to the infected group. Importantly, we found that AS605240 is bacteriostatic in the lungs and bactericidal in spleens from <em>M. tuberculosis</em>-infected mice. Our data provide novel evidence on the relevance of PI3Kγ as a novel molecular target for new anti-tubercular drugs.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102704"},"PeriodicalIF":2.9,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145424585","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 : 2025-10-24DOI: 10.1016/j.tube.2025.102701
Theophilus Afum, Prince Asare, Stephen Osei-Wusu, Dorothy Yeboah-Manu
Tuberculosis (TB), a disease of old, continues to plague humans after its declaration as a global health emergency in 1993. Over the years, studies have focused on understanding the causative pathogen, Mycobacterium tuberculosis complex (MTBC), and its interaction with humans from TB infection to progression to active disease. It is now known that MTBC lineage diversity impacts several disease presentations and outcomes, including disease progression and severity, virulence and antimicrobial resistance, transmissibility, and host response. Some of these lineages are highly geographically restricted, and prominent amongst them are lineages 5 and 6 of Mycobacterium africanum (Maf), mainly found in West Africa, with cases outside of this region usually prevalent in individuals of West African descent. Several hypotheses have been propounded to investigate these restrictions, ranging from the locality of an animal reservoir in certain areas to the emigration of Maf into West Africa but not spreading globally because Mycobacterium tuberculosis sensu stricto (Mtbss) outcompeted it. Another hypothesis, which states that host genetic factors can influence host susceptibility to some MTBC lineages, as well as TB progression to the severe disease state, appears more widely accepted. However, the exact mechanisms mediating this susceptibility have not been fully explored. This review seeks to highlight the advances made towards understanding the geographical restrictions of Maf and the host-pathogen interactions leading to the coevolution of Maf and humans in West Africa.
{"title":"Restriction of the main lineages of Mycobacterium africanum to West Africa: Insights from host-pathogen interaction studies","authors":"Theophilus Afum, Prince Asare, Stephen Osei-Wusu, Dorothy Yeboah-Manu","doi":"10.1016/j.tube.2025.102701","DOIUrl":"10.1016/j.tube.2025.102701","url":null,"abstract":"<div><div>Tuberculosis (TB), a disease of old, continues to plague humans after its declaration as a global health emergency in 1993. Over the years, studies have focused on understanding the causative pathogen, <em>Mycobacterium tuberculosis</em> complex (MTBC), and its interaction with humans from TB infection to progression to active disease. It is now known that MTBC lineage diversity impacts several disease presentations and outcomes, including disease progression and severity, virulence and antimicrobial resistance, transmissibility, and host response. Some of these lineages are highly geographically restricted, and prominent amongst them are lineages 5 and 6 of <em>Mycobacterium africanum (Maf</em>), mainly found in West Africa, with cases outside of this region usually prevalent in individuals of West African descent. Several hypotheses have been propounded to investigate these restrictions, ranging from the locality of an animal reservoir in certain areas to the emigration of <em>Maf</em> into West Africa but not spreading globally because <em>Mycobacterium tuberculosis</em> sensu stricto (<em>Mtbss</em>) outcompeted it. Another hypothesis, which states that host genetic factors can influence host susceptibility to some MTBC lineages, as well as TB progression to the severe disease state, appears more widely accepted. However, the exact mechanisms mediating this susceptibility have not been fully explored. This review seeks to highlight the advances made towards understanding the geographical restrictions of <em>Maf</em> and the host-pathogen interactions leading to the coevolution of <em>Maf</em> and humans in West Africa.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"155 ","pages":"Article 102701"},"PeriodicalIF":2.9,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145422961","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 : 2025-10-23DOI: 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}
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