Tuberculosis (TB) remains a global health challenge, necessitating deeper insights into the dynamics of extracellular bacterial populations within infected hosts. This study presents an in-host mathematical model that incorporates hereditary and antimicrobial factors influencing TB progression. The biological feasibility of the model is established by analyzing the boundedness of solutions within a realistic parameter space. The equilibrium states, including the disease-free and endemic equilibria, are examined, revealing conditions under which the system remains locally asymptotically stable. Sensitivity analysis is conducted to determine the key parameters driving infection dynamics, providing insights into potential control strategies. Notably, the model exhibits a backward bifurcation, indicating the possibility of multiple stable states and suggesting that reducing the basic reproduction number R0 below unity may not be sufficient for disease eradication. These findings highlight the importance of targeted interventions to effectively control extracellular bacterial populations and mitigate TB infection.
{"title":"Hereditary and antimicrobial factor shaping extracellular bacteria dynamics in an in-host mathematical model of tuberculosis for disease control","authors":"Morufu Oyedunsi Olayiwola , Ezekiel Abiodun Oluwafemi","doi":"10.1016/j.tube.2025.102668","DOIUrl":"10.1016/j.tube.2025.102668","url":null,"abstract":"<div><div>Tuberculosis (TB) remains a global health challenge, necessitating deeper insights into the dynamics of extracellular bacterial populations within infected hosts. This study presents an in-host mathematical model that incorporates hereditary and antimicrobial factors influencing TB progression. The biological feasibility of the model is established by analyzing the boundedness of solutions within a realistic parameter space. The equilibrium states, including the disease-free and endemic equilibria, are examined, revealing conditions under which the system remains locally asymptotically stable. Sensitivity analysis is conducted to determine the key parameters driving infection dynamics, providing insights into potential control strategies. Notably, the model exhibits a backward bifurcation, indicating the possibility of multiple stable states and suggesting that reducing the basic reproduction number R<sub>0</sub> below unity may not be sufficient for disease eradication. These findings highlight the importance of targeted interventions to effectively control extracellular bacterial populations and mitigate TB infection.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"154 ","pages":"Article 102668"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556722","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}
The objective of this study was to understand the descriptive epidemiology of childhood tuberculosis (TB) in Japan under the 2013 Bacillus Calmette–Guérin (BCG) immunization program modification. The median percentage of annual vaccination coverage for infants aged <13 months was 97.0 % during follow-up (2007–2022). The age at which most infants received their vaccinations was 3 months before 2013 and 5 months after 2013. During follow-up, the number of childhood TB notifications and annual incidence declined by approximately 60 % and 40 %, respectively. A multivariate-adjusted model analysis was performed by birth year to determine the association between childhood TB and the 2013 BCG immunization program modification. However, childhood TB was associated with age and BCG vaccination history but not with the 2013 BCG immunization program modification. This study represents a valuable resource for future research, elucidating the efficacy of BCG as well as the impact of BCG policies.
{"title":"Incidence of infectious diseases in children with Mycobacterium tuberculosis in Japan, 2007–2022","authors":"Yuko Hamaguchi , Takayuki Yamaguchi , Takashi Yoshiyama","doi":"10.1016/j.tube.2025.102674","DOIUrl":"10.1016/j.tube.2025.102674","url":null,"abstract":"<div><div>The objective of this study was to understand the descriptive epidemiology of childhood tuberculosis (TB) in Japan under the 2013 Bacillus Calmette–Guérin (BCG) immunization program modification. The median percentage of annual vaccination coverage for infants aged <13 months was 97.0 % during follow-up (2007–2022). The age at which most infants received their vaccinations was 3 months before 2013 and 5 months after 2013. During follow-up, the number of childhood TB notifications and annual incidence declined by approximately 60 % and 40 %, respectively. A multivariate-adjusted model analysis was performed by birth year to determine the association between childhood TB and the 2013 BCG immunization program modification. However, childhood TB was associated with age and BCG vaccination history but not with the 2013 BCG immunization program modification. This study represents a valuable resource for future research, elucidating the efficacy of BCG as well as the impact of BCG policies.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"154 ","pages":"Article 102674"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769104","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}
The Gene Xpert MTB/RIF Ultra is a Cartridge-Based Nucleic Acid Amplification Test (CBNAAT) for rapid detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) drug susceptibility testing (DST) pattern.
Objective
1)To compare the culture results of samples detected as a Trace on Gene Xpert MTB/RIF Ultra with MTB growth in liquid culture. 2) To compare the rifampicin indeterminate results from Gene Xpert MTB/RIF Ultra with MGIT RIF DST pattern.
Materials and Methods
A retrospective case record study was conducted from January 1, 2020 to August 31, 2024. Samples were evaluated using Gene Xpert MTB/RIF Ultra and MGIT liquid culture. MTB isolates from MGIT liquid culture were subjected to MGIT RIF DST.
Result
A total of 1821 samples detected as trace in Gene Xpert MTB/RIF Ultra, 538 (29.54 %) grew in MGIT liquid culture, while 1283 (70.46 %) did not grow. Among the 538 Trace detected samples with RIF indeterminate results, a comparison with MGIT RIF DST revealed that 451 (83.83 %) were rifampicin sensitive, while 87 (16.17 %) were rifampicin resistance. 49 (9.10 %) of these were pulmonary samples, while 489 (90.90 %) were extrapulmonary samples.
Conclusion
Gene Xpert MTB/RIF Ultra is more rapid, more sensitive, less specific and more cost-effective compared to MGIT liquid culture.
{"title":"Correlation of Trace detection in Gene Xpert MTB/RIF ultra with MGIT TB culture in a high TB-endemic Country","authors":"Swapna Naik, Sweta Dhaneja, Archana Khilari, Shaoli Basu, Anjali Shetty, Camilla Rodrigues","doi":"10.1016/j.tube.2025.102666","DOIUrl":"10.1016/j.tube.2025.102666","url":null,"abstract":"<div><h3>Background</h3><div>The Gene Xpert MTB/RIF Ultra is a Cartridge-Based Nucleic Acid Amplification Test (CBNAAT) for rapid detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) drug susceptibility testing (DST) pattern.</div></div><div><h3>Objective</h3><div>1)To compare the culture results of samples detected as a Trace on Gene Xpert MTB/RIF Ultra with MTB growth in liquid culture. 2) To compare the rifampicin indeterminate results from Gene Xpert MTB/RIF Ultra with MGIT RIF DST pattern.</div></div><div><h3>Materials and Methods</h3><div>A retrospective case record study was conducted from January 1, 2020 to August 31, 2024. Samples were evaluated using Gene Xpert MTB/RIF Ultra and MGIT liquid culture. MTB isolates from MGIT liquid culture were subjected to MGIT RIF DST.</div></div><div><h3>Result</h3><div>A total of 1821 samples detected as trace in Gene Xpert MTB/RIF Ultra, 538 (29.54 %) grew in MGIT liquid culture, while 1283 (70.46 %) did not grow. Among the 538 Trace detected samples with RIF indeterminate results, a comparison with MGIT RIF DST revealed that 451 (83.83 %) were rifampicin sensitive, while 87 (16.17 %) were rifampicin resistance. 49 (9.10 %) of these were pulmonary samples, while 489 (90.90 %) were extrapulmonary samples.</div></div><div><h3>Conclusion</h3><div>Gene Xpert MTB/RIF Ultra is more rapid, more sensitive, less specific and more cost-effective compared to MGIT liquid culture.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"154 ","pages":"Article 102666"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144272108","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 : 2025-09-01Epub Date: 2025-07-23DOI: 10.1016/j.tube.2025.102675
Yong-Soon Cho , Rannissa Puspita Jayanti , Hyun-Kyung Lee , Hyo-Jung Kim , Tae Won Jang , Yun Seok Kim , Yousang Ko , Jinsoo Min , Heayon Lee , Soedarsono Soedarsono , Hyeon-Jeong Seong , Young-Kyung Choi , Ho-Sook Kim , Dong Hyun Kim , Jae-Gook Shin , cPMTb
Background
Levofloxacin (LFX) has gained attention as an effective drug to reduce treatment duration in tuberculosis (TB). We aimed to evaluate factors related to interindividual variability (IIV) and describe the pharmacokinetics (PK) of LFX in both DS- and DR-TB, as well as explore the optimal dose for TB treatment.
Methods
We included demographics, clinical information, and LFX concentrations from multinational hospitals. All data were utilized for model establishment. The population PK model was built using nonlinear mixed-effects method. Dose simulation was carried out thereafter using Monte Carlo simulation.
Results
A one-compartment model with allometric scaling described LFX PK adequately. PK parameters were similar between DS- and DR-TB. eGFR significantly affected CL/F, which decreased by 22 % and 48 % in mild and moderate-severe renal impairment, respectively (normal CL/F: 6.6 L/h). Considering LFX's AUC/MIC target of 146 and epidemiological cut-off value of MIC 0.5 μg/mL, doses of 1000 mg, 1250 mg, and 1500 mg may achieve 90 % probability of target attainment in patients with normal renal function weighing <40 kg, 40–70 kg, and >70 kg, respectively.
Conclusion
Renal impairment reduced LFX clearance. Doses equal to or greater than 1000 mg may improve AUC/MIC target attainment but require cautious use considering safety and clinical efficacy.
{"title":"Population pharmacokinetics of levofloxacin in drug-susceptible and drug-resistant tuberculosis patients: Optimal dose suggestion based on renal function","authors":"Yong-Soon Cho , Rannissa Puspita Jayanti , Hyun-Kyung Lee , Hyo-Jung Kim , Tae Won Jang , Yun Seok Kim , Yousang Ko , Jinsoo Min , Heayon Lee , Soedarsono Soedarsono , Hyeon-Jeong Seong , Young-Kyung Choi , Ho-Sook Kim , Dong Hyun Kim , Jae-Gook Shin , cPMTb","doi":"10.1016/j.tube.2025.102675","DOIUrl":"10.1016/j.tube.2025.102675","url":null,"abstract":"<div><h3>Background</h3><div>Levofloxacin (LFX) has gained attention as an effective drug to reduce treatment duration in tuberculosis (TB). We aimed to evaluate factors related to interindividual variability (IIV) and describe the pharmacokinetics (PK) of LFX in both DS- and DR-TB, as well as explore the optimal dose for TB treatment.</div></div><div><h3>Methods</h3><div>We included demographics, clinical information, and LFX concentrations from multinational hospitals. All data were utilized for model establishment. The population PK model was built using nonlinear mixed-effects method. Dose simulation was carried out thereafter using Monte Carlo simulation.</div></div><div><h3>Results</h3><div>A one-compartment model with allometric scaling described LFX PK adequately. PK parameters were similar between DS- and DR-TB. eGFR significantly affected CL/F, which decreased by 22 % and 48 % in mild and moderate-severe renal impairment, respectively (normal CL/F: 6.6 L/h). Considering LFX's AUC/MIC target of 146 and epidemiological cut-off value of MIC 0.5 μg/mL, doses of 1000 mg, 1250 mg, and 1500 mg may achieve 90 % probability of target attainment in patients with normal renal function weighing <40 kg, 40–70 kg, and >70 kg, respectively.</div></div><div><h3>Conclusion</h3><div>Renal impairment reduced LFX clearance. Doses equal to or greater than 1000 mg may improve AUC/MIC target attainment but require cautious use considering safety and clinical efficacy.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"154 ","pages":"Article 102675"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724164","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 : 2025-07-01Epub Date: 2025-05-09DOI: 10.1016/j.tube.2025.102651
Jia-Yih Feng , Yen-Han Tseng , Chih-Jung Chang , Yu-Hsun Chiang , Sheng-Wei Pan , Wei-Juin Su , Yuh-Min Chen
Objectives
Circulating cell-free DNA (cfDNA), including mitochondrial cfDNA (mt-cfDNA) and nuclear cfDNA (nu-cfDNA), are potential biomarkers for infectious diseases. However, cfDNA variations in TB contacts with latent tuberculosis infection (LTBI) and their potential link to a predominance of M1 monocyte polarization in LTBI remain unexplored.
Methods
Contacts of TB patients were screened for LTBI using the Interferon gamma (IFN-γ) release assay. Blood cfDNA was extracted, and mt-cfDNA and nu-cfDNA copy numbers were quantified by qPCR. cfDNA levels in the supernatant of M1-polarized THP-1-derived macrophages were measured.
Results
Levels of mt-cfDNA and nu-cfDNA were lower in the LTBI group (n = 76) than in the uninfected group (n = 58) (p = 0.012, and p < 0.001). The results were consistent in an age- and sex-matched analysis (n = 41 pairs). mt-cfDNA and nu-cfDNA levels were negatively associated with the TB-specific IFN-γ response (p = 0.009, p < 0.001). In the LTBI group, mt-cfDNA was negatively associated with the index case's bacterial burden (p = 0.045). In cell model, mt-cfDNA and nu-cfDNA levels in the supernatant from M1-polarized macrophage were lower than those from M2-polarized cells (p = 0.030, p = 0.045).
Conclusions
TB contacts with LTBI had lower cfDNA levels, which correlated with index case infectivity. Reduced cfDNA in M1-polarized macrophages warrants further investigation into the mechanisms of cfDNA reduction in LTBI.
目的循环游离细胞DNA (cfDNA)，包括线粒体cfDNA （mt-cfDNA）和核cfDNA (nu-cfDNA)，是潜在的传染病生物标志物。然而，cfDNA在结核接触者潜伏性结核感染（LTBI）中的变异及其与LTBI中M1单核细胞极化优势的潜在联系仍未被探索。方法采用干扰素γ (IFN-γ)释放法对接触者进行LTBI筛查。提取血cfDNA，用qPCR法定量mt-cfDNA和nu-cfDNA拷贝数。检测m1极化thp -1衍生巨噬细胞上清液中cfDNA水平。结果LTBI组（n = 76） mt-cfDNA和nu-cfDNA水平低于未感染组（n = 58） (p = 0.012, p <；0.001)。在年龄和性别匹配分析（n = 41对）中，结果是一致的。mt-cfDNA和nu-cfDNA水平与结核病特异性IFN-γ反应呈负相关(p = 0.009, p <；0.001)。在LTBI组中，mt-cfDNA与指示病例的细菌负担呈负相关（p = 0.045）。在细胞模型中，m1极化巨噬细胞上清中mt-cfDNA和nu-cfDNA水平低于m2极化细胞（p = 0.030, p = 0.045）。结论stb与LTBI接触者cfDNA水平较低，与指示病例感染相关。m1极化巨噬细胞中cfDNA的减少值得进一步研究cfDNA减少在LTBI中的机制。
{"title":"Reduced host cell-free DNA as a biomarker in latent tuberculosis infection among tuberculosis contacts","authors":"Jia-Yih Feng , Yen-Han Tseng , Chih-Jung Chang , Yu-Hsun Chiang , Sheng-Wei Pan , Wei-Juin Su , Yuh-Min Chen","doi":"10.1016/j.tube.2025.102651","DOIUrl":"10.1016/j.tube.2025.102651","url":null,"abstract":"<div><h3>Objectives</h3><div>Circulating cell-free DNA (cfDNA), including mitochondrial cfDNA (mt-cfDNA) and nuclear cfDNA (nu-cfDNA), are potential biomarkers for infectious diseases. However, cfDNA variations in TB contacts with latent tuberculosis infection (LTBI) and their potential link to a predominance of M1 monocyte polarization in LTBI remain unexplored.</div></div><div><h3>Methods</h3><div>Contacts of TB patients were screened for LTBI using the Interferon gamma (IFN-γ) release assay. Blood cfDNA was extracted, and mt-cfDNA and nu-cfDNA copy numbers were quantified by qPCR. cfDNA levels in the supernatant of M1-polarized THP-1-derived macrophages were measured.</div></div><div><h3>Results</h3><div>Levels of mt-cfDNA and nu-cfDNA were lower in the LTBI group (n = 76) than in the uninfected group (n = 58) (p = 0.012, and p < 0.001). The results were consistent in an age- and sex-matched analysis (n = 41 pairs). mt-cfDNA and nu-cfDNA levels were negatively associated with the TB-specific IFN-γ response (p = 0.009, p < 0.001). In the LTBI group, mt-cfDNA was negatively associated with the index case's bacterial burden (p = 0.045). In cell model, mt-cfDNA and nu-cfDNA levels in the supernatant from M1-polarized macrophage were lower than those from M2-polarized cells (p = 0.030, p = 0.045).</div></div><div><h3>Conclusions</h3><div>TB contacts with LTBI had lower cfDNA levels, which correlated with index case infectivity. Reduced cfDNA in M1-polarized macrophages warrants further investigation into the mechanisms of cfDNA reduction in LTBI.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"153 ","pages":"Article 102651"},"PeriodicalIF":2.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943226","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 : 2025-07-01Epub Date: 2025-05-08DOI: 10.1016/j.tube.2025.102650
Dayna Croock , Yolandi Swart , Tomasz Janusz Sanko , Vuyo Mavumengwana , Marlo Möller , Caitlin Uren , Desiree C. Petersen
Mitochondria form an integral, yet frequently underappreciated, part of the immune response to Mycobacterium tuberculosis (M.tb), particularly within macrophages. Despite growing recognition for their role in infection and immunity, studies investigating how mitochondrial DNA (mtDNA) variation influences host susceptibility to tuberculosis (TB) are limited. Notably, there are no studies in African-based populations, although Africans possess unparalleled human genetic diversity, including the earliest diverged mitochondrial haplogroups, and a high TB burden. This underrepresentation limits the discovery of novel ancestry-specific genetic loci associated with TB. In this review article, we describe the unique characteristics of mtDNA, highlight key mitochondrial functions relevant to macrophage responses during M.tb infection, and summarise published studies that investigate the role of host mtDNA variation in TB susceptibility. We further advocate for the inclusion of African populations in future studies to identify novel TB susceptibility genetic risk loci and expand the current knowledgebase on host TB susceptibility.
{"title":"Uncharted territory: the role of mitochondrial DNA variation in macrophage-mediated host susceptibility to tuberculosis","authors":"Dayna Croock , Yolandi Swart , Tomasz Janusz Sanko , Vuyo Mavumengwana , Marlo Möller , Caitlin Uren , Desiree C. Petersen","doi":"10.1016/j.tube.2025.102650","DOIUrl":"10.1016/j.tube.2025.102650","url":null,"abstract":"<div><div>Mitochondria form an integral, yet frequently underappreciated, part of the immune response to <em>Mycobacterium tuberculosis (M.tb),</em> particularly within macrophages. Despite growing recognition for their role in infection and immunity, studies investigating how mitochondrial DNA (mtDNA) variation influences host susceptibility to tuberculosis (TB) are limited. Notably, there are no studies in African-based populations, although Africans possess unparalleled human genetic diversity, including the earliest diverged mitochondrial haplogroups, and a high TB burden. This underrepresentation limits the discovery of novel ancestry-specific genetic loci associated with TB. In this review article, we describe the unique characteristics of mtDNA, highlight key mitochondrial functions relevant to macrophage responses during <em>M.tb</em> infection, and summarise published studies that investigate the role of host mtDNA variation in TB susceptibility. We further advocate for the inclusion of African populations in future studies to identify novel TB susceptibility genetic risk loci and expand the current knowledgebase on host TB susceptibility.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"153 ","pages":"Article 102650"},"PeriodicalIF":2.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931917","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 : 2025-07-01Epub Date: 2025-05-08DOI: 10.1016/j.tube.2025.102649
Xutao Wang , Katie Harper , Pranay Sinha , W. Evan Johnson , Prasad Patil
Background
Tuberculosis (TB) is the leading cause of infectious disease mortality worldwide. Numerous host blood-based gene expression signatures have been proposed in the literature as alternative tools for diagnosing TB infection. However, the generalizability of these signatures to different patient contexts is not well-characterized. There is a pressing need for a well-curated database of TB gene expression studies for the systematic assessment of existing and newly developed TB gene signatures.
Results
We built curatedTBData, a manually-curated database of 49 human TB transcriptomic studies. This data resource is freely available through GitHub and as an R Bioconductor package that allows users to validate new and existing biomarkers without the challenges of harmonizing heterogeneous studies. We demonstrate the use of this data resource with cross-study comparisons for 72 human host blood-based TB gene signatures. For the comparison of subjects with active TB from healthy controls, 19 gene signatures had weighted mean AUC of 0.90 or greater, with the highest result of 0.94. In active TB disease versus latent TB infection, 7 gene signatures had weighted mean AUC of 0.90 or greater, with a maximum of 0.93.
Conclusions
The curatedTBData data package offers a comprehensive resource of curated human blood-based gene expression and clinically annotated data. This resource will facilitate the development of new signatures that are generalizable across cohorts or more applicable to specific subsets of patients.
{"title":"Analysis of the cross-study replicability of tuberculosis gene signatures using 49 curated human transcriptomic datasets","authors":"Xutao Wang , Katie Harper , Pranay Sinha , W. Evan Johnson , Prasad Patil","doi":"10.1016/j.tube.2025.102649","DOIUrl":"10.1016/j.tube.2025.102649","url":null,"abstract":"<div><h3>Background</h3><div>Tuberculosis (TB) is the leading cause of infectious disease mortality worldwide. Numerous host blood-based gene expression signatures have been proposed in the literature as alternative tools for diagnosing TB infection. However, the generalizability of these signatures to different patient contexts is not well-characterized. There is a pressing need for a well-curated database of TB gene expression studies for the systematic assessment of existing and newly developed TB gene signatures.</div></div><div><h3>Results</h3><div>We built curatedTBData, a manually-curated database of 49 human TB transcriptomic studies. This data resource is freely available through GitHub and as an R Bioconductor package that allows users to validate new and existing biomarkers without the challenges of harmonizing heterogeneous studies. We demonstrate the use of this data resource with cross-study comparisons for 72 human host blood-based TB gene signatures. For the comparison of subjects with active TB from healthy controls, 19 gene signatures had weighted mean AUC of 0.90 or greater, with the highest result of 0.94. In active TB disease versus latent TB infection, 7 gene signatures had weighted mean AUC of 0.90 or greater, with a maximum of 0.93.</div></div><div><h3>Conclusions</h3><div>The curatedTBData data package offers a comprehensive resource of curated human blood-based gene expression and clinically annotated data. This resource will facilitate the development of new signatures that are generalizable across cohorts or more applicable to specific subsets of patients.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"153 ","pages":"Article 102649"},"PeriodicalIF":2.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935982","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 : 2025-07-01Epub Date: 2025-05-26DOI: 10.1016/j.tube.2025.102653
José Cruz Mendoza-Torres , Nayar Durán-Hernández , José Alberto Choreño-Parra , Carlos Sánchez-Garibay , Citlaltepetl Salinas-Lara
Background
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a primary global health concern, with significant long-term sequelae. Central nervous system TB (CNS-TB) is a clinical spectrum with entities such as tuberculous meningitis and tuberculomas. Emerging evidence suggests that Mtb may directly or indirectly affect the hippocampus, a critical memory, learning, and cognition structure.
Objectives
This review aims to summarize the current biological understanding of Mtb's impact on the hippocampus, elucidate its potential role in neurodegeneration, and introduce the concept of “Hippocampal syndrome secondary to tuberculosis (HSST)" as a novel chronic entity within the CNS-TB spectrum.
Methods
A comprehensive literature review was conducted to analyze how Mtb gains access to the brain, its neurotropism, and the resulting neuroinflammatory and neurodegenerative effects on the hippocampus. Data from clinical, histopathological, and experimental studies were evaluated to assess potential links between TB and cognitive impairment.
Results
Mtb can access the CNS through hematogenous dissemination, the “Trojan Horse” mechanism, or via the olfactory pathway, bypassing the blood-brain barrier (BBB). Once in the brain, Mtb induces chronic neuroinflammation and disrupts hippocampal structure. Studies suggest that TB increases the risk of Alzheimer's and Parkinson's diseases, with evidence of Mtb-driven amyloid-beta accumulation and neuronal loss.
Furthermore, specific Mtb strains exhibit neurotropism and produce virulence factors that facilitate CNS invasion.
Conclusions
Understanding the interaction between TB and neurocognitive disorders is critical for improving post-TB care. Recognizing HSST as a chronic condition within the CNS-TB spectrum may support early diagnosis and targeted interventions to mitigate long-term neurological consequences.
{"title":"Hippocampal syndrome secondary to tuberculosis: From neuroinflammation to neurodegeneration","authors":"José Cruz Mendoza-Torres , Nayar Durán-Hernández , José Alberto Choreño-Parra , Carlos Sánchez-Garibay , Citlaltepetl Salinas-Lara","doi":"10.1016/j.tube.2025.102653","DOIUrl":"10.1016/j.tube.2025.102653","url":null,"abstract":"<div><h3>Background</h3><div>Tuberculosis (TB), caused by <em>Mycobacterium tuberculosis</em> (Mtb), remains a primary global health concern, with significant long-term sequelae. Central nervous system TB (CNS-TB) is a clinical spectrum with entities such as tuberculous meningitis and tuberculomas. Emerging evidence suggests that Mtb may directly or indirectly affect the hippocampus, a critical memory, learning, and cognition structure.</div></div><div><h3>Objectives</h3><div>This review aims to summarize the current biological understanding of Mtb's impact on the hippocampus, elucidate its potential role in neurodegeneration, and introduce the concept of “Hippocampal syndrome secondary to tuberculosis (HSST)\" as a novel chronic entity within the CNS-TB spectrum.</div></div><div><h3>Methods</h3><div>A comprehensive literature review was conducted to analyze how Mtb gains access to the brain, its neurotropism, and the resulting neuroinflammatory and neurodegenerative effects on the hippocampus. Data from clinical, histopathological, and experimental studies were evaluated to assess potential links between TB and cognitive impairment.</div></div><div><h3>Results</h3><div>Mtb can access the CNS through hematogenous dissemination, the “Trojan Horse” mechanism, or via the olfactory pathway, bypassing the blood-brain barrier (BBB). Once in the brain, Mtb induces chronic neuroinflammation and disrupts hippocampal structure. Studies suggest that TB increases the risk of Alzheimer's and Parkinson's diseases, with evidence of Mtb-driven amyloid-beta accumulation and neuronal loss.</div><div>Furthermore, specific Mtb strains exhibit neurotropism and produce virulence factors that facilitate CNS invasion.</div></div><div><h3>Conclusions</h3><div>Understanding the interaction between TB and neurocognitive disorders is critical for improving post-TB care. Recognizing HSST as a chronic condition within the CNS-TB spectrum may support early diagnosis and targeted interventions to mitigate long-term neurological consequences.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"153 ","pages":"Article 102653"},"PeriodicalIF":2.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144169923","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 : 2025-07-01Epub Date: 2025-05-27DOI: 10.1016/j.tube.2025.102652
Cristine Cerva , Fabio Marcelo de Lima , Ana Paula Muterle Varela , Gabriela Merker Breyer , Jerônimo Miguel Vicenzi , Angélica Cavalheiro Bertagnolli , Vinícius Freitas Klain , Franciele Maboni Siqueira , Fabiana Quoos Mayer
Bovine tuberculosis susceptibility and pathogenesis are influenced by host immunity, which may be modulated by the host microbiota. While intestinal microbiota composition affects pulmonary diseases in humans, its role in bovine tuberculosis remains unclear. This study explores the intestinal microbiota of cattle and its association with tuberculosis to better understand disease pathophysiology. A case-control study was conducted using small intestine content samples from cattle with and without tuberculosis, slaughtered in Rio Grande do Sul, Brazil. DNA extraction, 16S rRNA (V4) sequencing, and bioinformatics analyses assessed alpha and beta diversity, taxa characterization, differential abundance, and metabolic pathways. No significant differences in alpha and beta diversities between the groups were detected. However, the Bacillota/Bacteroidota ratio suggested dysbiosis associated with bovine tuberculosis. Differential abundance analysis showed that microorganisms belonging to the Bacillota phylum, the Eubacterium cellulosolvens group, Colidextribacter and Coprococcus genera were enriched in healthy cattle. Conversely, animals with tuberculosis showed higher abundances of Verrucomicrobiota phylum, Sphingomonadaceae and Eubacteriaceae families, and Solobacterium and Clostridia-UCG-014 genera. Moreover, metabolic pathways related to carbohydrate degradation were enriched in healthy animals, and biosynthetic pathways related to disease were enriched in tuberculosis animals. This study highlights associations between intestinal microbiota and bovine tuberculosis, providing insights into disease mechanisms.
{"title":"Gut bacterial diversity in bovines infected with Mycobacterium tuberculosis var. bovis: insights on tuberculosis pathogenesis","authors":"Cristine Cerva , Fabio Marcelo de Lima , Ana Paula Muterle Varela , Gabriela Merker Breyer , Jerônimo Miguel Vicenzi , Angélica Cavalheiro Bertagnolli , Vinícius Freitas Klain , Franciele Maboni Siqueira , Fabiana Quoos Mayer","doi":"10.1016/j.tube.2025.102652","DOIUrl":"10.1016/j.tube.2025.102652","url":null,"abstract":"<div><div>Bovine tuberculosis susceptibility and pathogenesis are influenced by host immunity, which may be modulated by the host microbiota. While intestinal microbiota composition affects pulmonary diseases in humans, its role in bovine tuberculosis remains unclear. This study explores the intestinal microbiota of cattle and its association with tuberculosis to better understand disease pathophysiology. A case-control study was conducted using small intestine content samples from cattle with and without tuberculosis, slaughtered in Rio Grande do Sul, Brazil. DNA extraction, <em>16S rRNA</em> (V4) sequencing, and bioinformatics analyses assessed alpha and beta diversity, taxa characterization, differential abundance, and metabolic pathways. No significant differences in alpha and beta diversities between the groups were detected. However, the <em>Bacillota</em>/<em>Bacteroidota</em> ratio suggested dysbiosis associated with bovine tuberculosis. Differential abundance analysis showed that microorganisms belonging to the <em>Bacillota</em> phylum, the <em>Eubacterium cellulosolvens</em> group, <em>Colidextribacter</em> and <em>Coprococcus</em> genera were enriched in healthy cattle. Conversely, animals with tuberculosis showed higher abundances of <em>Verrucomicrobiota</em> phylum, <em>Sphingomonadaceae</em> and <em>Eubacteriaceae</em> families, and <em>Solobacterium</em> and <em>Clostridia-UCG-014</em> genera. Moreover, metabolic pathways related to carbohydrate degradation were enriched in healthy animals, and biosynthetic pathways related to disease were enriched in tuberculosis animals. This study highlights associations between intestinal microbiota and bovine tuberculosis, providing insights into disease mechanisms.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"153 ","pages":"Article 102652"},"PeriodicalIF":2.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144177947","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 : 2025-07-01Epub Date: 2025-04-23DOI: 10.1016/j.tube.2025.102641
Ashley M. Divens , Kenneth J. Ryan , Alessandro Sette , Cecilia S. Lindestam Arlehamn , Cory M. Robinson
Tuberculosis (TB) is the leading cause of death due to a pathogen. The live-attenuated BCG vaccine is the only approved vaccine to prevent TB, but it fails to confer long-term protection. We hypothesize that the immunosuppressive cytokine IL-27 may contribute to the inefficacies of the BCG vaccine. IL-27 is elevated in neonates, the population most commonly administered BCG, and levels increase further upon vaccination. IL-27 interferes with the phagolysosomal pathway, suggesting it may limit the diversity of antigens processed and presented to T cells. We hypothesized that in the absence of IL-27 signaling, BCG vaccination induces antigen-specific T cells that recognize a greater number of antigens and provide enhanced protection during M. tuberculosis (Mtb) challenge. CD3+ T cells isolated from IL-27Rα KO mice vaccinated with BCG as neonates were more responsive to BCG and a Mtb peptide pool than T cells from vaccinated WT mice. Adoptive transfer of IL-27Rα KO T cells provided more consistent protection against Mtb than WT, but this was not observed in TCRα−/− mice. A principal component analysis suggested a more consistent multifunctional cytokine response was associated IL-27Rα KO T cells. These findings enhance our understanding of IL-27 during neonatal vaccination and development of protective immunity.
结核病（TB）是由病原体导致死亡的主要原因。减毒卡介苗是唯一被批准用于预防结核病的疫苗，但它不能提供长期保护。我们推测免疫抑制因子IL-27可能是卡介苗无效的原因之一。IL-27在最常接种卡介苗的新生儿中升高，接种后水平进一步升高。IL-27干扰吞噬溶酶体途径，表明它可能限制抗原加工并呈递给T细胞的多样性。我们假设，在缺乏IL-27信号的情况下，卡介苗接种诱导抗原特异性T细胞识别更多的抗原，并在结核分枝杆菌（Mtb）攻击期间提供增强的保护。新生期接种卡介苗的IL-27Rα KO小鼠分离的CD3+ T细胞对卡介苗和结核分枝杆菌肽库的反应强于接种WT小鼠的T细胞。IL-27Rα KO T细胞的过继转移比WT对Mtb具有更一致的保护作用，但在TCRα−/−小鼠中没有观察到这一点。主成分分析表明，更一致的多功能细胞因子反应与IL-27Rα KO T细胞有关。这些发现增强了我们对新生儿免疫接种和保护性免疫发展过程中IL-27的理解。
{"title":"IL-27 signaling limits the diversity of antigen-specific T cells and interferes with protection induced by BCG vaccination","authors":"Ashley M. Divens , Kenneth J. Ryan , Alessandro Sette , Cecilia S. Lindestam Arlehamn , Cory M. Robinson","doi":"10.1016/j.tube.2025.102641","DOIUrl":"10.1016/j.tube.2025.102641","url":null,"abstract":"<div><div>Tuberculosis (TB) is the leading cause of death due to a pathogen. The live-attenuated BCG vaccine is the only approved vaccine to prevent TB, but it fails to confer long-term protection. We hypothesize that the immunosuppressive cytokine IL-27 may contribute to the inefficacies of the BCG vaccine. IL-27 is elevated in neonates, the population most commonly administered BCG, and levels increase further upon vaccination. IL-27 interferes with the phagolysosomal pathway, suggesting it may limit the diversity of antigens processed and presented to T cells. We hypothesized that in the absence of IL-27 signaling, BCG vaccination induces antigen-specific T cells that recognize a greater number of antigens and provide enhanced protection during <em>M. tuberculosis</em> (Mtb) challenge. CD3<sup>+</sup> T cells isolated from IL-27Rα KO mice vaccinated with BCG as neonates were more responsive to BCG and a Mtb peptide pool than T cells from vaccinated WT mice. Adoptive transfer of IL-27Rα KO T cells provided more consistent protection against Mtb than WT, but this was not observed in TCRα<sup>−/−</sup> mice. A principal component analysis suggested a more consistent multifunctional cytokine response was associated IL-27Rα KO T cells. These findings enhance our understanding of IL-27 during neonatal vaccination and development of protective immunity.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"153 ","pages":"Article 102641"},"PeriodicalIF":2.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143907778","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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