Search Results (211)

An estimated 2.1 billion people are infected with Mycobacterium tuberculosis (Mtb) and at risk of developing active tuberculosis (TB). Because Mtb exists in replicating and dormant states, effective vaccines should target antigens from both stages. Here, we evaluated the immunogenicity and vaccine potential of Mtb dormancy antigen Rv2626c. Cellular and humoral immune responses were studied in individuals with latent TB infection (LTBI), active TB, and healthy donors (HD) using flow cytometry and ELISA. Overlapping peptides spanning Rv2626c sequence and structural mapping were employed to characterize Rv2626c immunogenic regions. Additionally, the protective efficacy of a Modified Vaccinia Ankara (MVA) vector expressing Rv2626c was evaluated in a murine challenge model. Rv2626c induced cellular immunity selectively in LTBI, characterized by increased frequencies of CD4⁺IFN-γ⁺, SLAMF1⁺, and poly-functional T lymphocytes. Immunodominant peptide regions were identified across the protein sequence. Moreover, mice immunized with MVA-Rv2626c showed a significant reduction in splenic bacterial burden following a challenge with Mtb H37Rv. Altogether, our findings indicate that the latency-associated antigen Rv2626c elicits immune responses in LTBI subjects and limits bacterial dissemination in our mice model of infection. Therefore, Rv2626c arises as a promising candidate to be combined with active phase antigens in multistage vaccines against Mtb infection. Full article

The progression of tuberculosis (TB) from a latent infection to an active disease involves intricate modifications in host immune, inflammatory, oxidative, and metabolic pathways. Ferroptosis represents a distinct form of regulated cell death that requires iron and is associated with excessive lipid peroxidation and has been associated with tissue damage in TB; however, its connection with host transcriptional changes during active TB is not fully understood. This study sought to identify and externally validate immune–inflammatory hub genes among differentially expressed genes (DEGs) in active TB that overlap with a ferroptosis-associated gene set derived from FerrDb, employing an integrated transcriptomic and systems-biology methodology. Differential expression analysis of GSE37250 revealed 1015 DEGs in active TB compared to latent TB, comprising 585 upregulated and 430 downregulated genes, and 93 DEGs in active TB compared to healthy controls, including 65 upregulated and 28 downregulated genes. Intersection analysis identified 94 DEGs common to the active TB versus latent TB comparison and the ferroptosis-associated gene set, and eight DEGs common to the active tuberculosis versus healthy-control comparison and the same gene set, with no genes shared across all three sets. Functional enrichment of the 94 intersection genes underscored immune response, defense response, stress response, Toll-like receptor signaling, NOD-like receptor signaling, IL-17 signaling, TNF signaling, glutathione metabolism, neutrophil degranulation, cytokine signaling, and antimicrobial metal sequestration. Protein–protein interaction analysis followed by cytoHubba prioritization identified 10 hub genes: IL1B, TLR4, CXCL10, MMP9, CYBB, MPO, CD36, LCN2, S100A8, and LTF. Subsequent to outcome-independent probe selection, external validation in GSE28623 demonstrated significant positive differential expression of LCN2, S100A8, and LTF, while GSE62525 showed significant positive differential expression of IL1B, TLR4, MMP9, MPO, LCN2, and LTF. LCN2 and LTF were significantly upregulated in both validation datasets, indicating the strongest cross-dataset reproducibility. These results identify an immune–inflammatory transcriptional network intersecting with ferroptosis-associated genes in active TB. Notably, the transcriptomic findings do not confirm ferroptotic cell death but suggest candidate genes and biological processes for future experimental exploration. Full article

Background/Objectives: Several subunit vaccines for tuberculosis (TB), such as MVA85A and H4:IC31, have not demonstrated ideal protective efficacy in clinical trials, which may be attributed to their limited antigenic profile and lack of effective latency-associated antigens. In this study, we combined bioinformatics with experimental validation to screen for latency-associated antigens that have immune-protective effects. Methods: Highly expressed antigens were identified from models related to latent infections, such as hypoxia and nutritional starvation. Their physicochemical properties and immunogenicity were predicted using online tools such as Expasy-ProParam, IEBD, and VaxiJen. The immunogenicity of these antigens was then evaluated in multiple mycobacterium infection models. Finally, a systematic evaluation of the immune response and protective effects induced by the candidate antigens was performed in a mouse model using intracellular cytokine detection, mycobacterium growth inhibition assays (MGIAs), antibody-dependent cellular phagocytosis (ADCP), and a latent tuberculosis infection (LTBI) mouse model. Results: The antigen Rv2656c is highly expressed in the nutritional starvation model and demonstrates strong immunogenicity in both infected humans and cattle. Moreover, Rv2656c exerted a significant inhibitory effect against Mycobacterium tuberculosis (M. tuberculosis) and Mycobacterium avium (M. avium) infections in MGIA. The humoral immune response elicited by Rv2656c enhanced the phagocytosis and killing of Mycobacteria by macrophages in vitro. Furthermore, in a mouse model of LTBI established using the attenuated M. tuberculosis H37Ra strain, treatment with Rv2656c significantly decreased the bacterial load in the lungs of the mice. Conclusions: Latency-associated Rv2656c may serve as an immune-protective antigen, offering potential for the development of novel multi-stage antigen subunit vaccine against TB. Full article

Background/Objectives: Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a major global health problem. Drug resistance and the limitations of sputum-based diagnostic methods highlight the need for additional host-response biomarkers. Protein tyrosine phosphatase receptor type O (PTPRO) has been implicated in inflammatory signaling and macrophage immune regulation, but its relationship with TB-related host transcriptional responses remains unclear. This study aimed to identify and preliminarily evaluate a PTPRO-related blood transcriptional signature with potential relevance to TB discrimination and treatment-response assessment. Methods: Genes correlated with PTPRO expression were first screened using TCGA-LUSC as a large human transcriptomic discovery resource. The resulting candidate genes were then filtered in TB-related whole-blood datasets by intersecting genes upregulated in TB compared with healthy controls, pneumonia, and lung cancer. This strategy yielded a five-gene PTPRO-related signature, termed PO5. The signature was evaluated in independent GEO cohorts and further explored by RT-qPCR in H37Ra-infected THP-1-derived macrophages and in a small clinical blood cohort. A PO5-derived TB risk score was calculated for each sample, and receiver operating characteristic analysis was used to assess discriminatory performance. Changes in TB risk scores during anti-TB treatment were also examined. Results: PTPRO expression was increased in TB whole-blood transcriptomic data and in H37Ra-infected macrophages. In public datasets, PO5 showed potential for distinguishing TB from healthy controls, latent TB, pneumonia, and lung cancer. PO5-derived TB risk scores also decreased after anti-TB treatment. In the exploratory clinical cohort, several PO5 genes showed expression changes in the same general direction as those observed in the public datasets, although the small sample size limited the strength of this evidence. Conclusions: PO5 represents a preliminary PTPRO-related blood transcriptional signature with potential relevance to TB discrimination and treatment-response assessment. These findings remain exploratory and require validation in larger prospective multicenter cohorts, together with further mechanistic studies. Full article

This study develops an integrated mathematical model to investigate the interaction between tuberculosis (TB) transmission and childhood stunting, which is aligned with the United Nations Sustainable Development Goals (SDG 3). The population is structured into two age groups (0–5 years and ≥5 years), with stunting explicitly incorporated into the pediatric population to capture its potential influence on TB dynamics. The model is formulated as a system of ordinary differential equations and analyzed using equilibrium and stability analysis, with the basic reproduction number, $R_0$. The disease-free equilibrium is locally asymptotically stable when $R_0<1$, while an endemic equilibrium exists when $R_0>1$. Sensitivity analysis indicates that the transmission rate ($\beta$), progression rate from latent to active infection ($\sigma$), and recovery rate ($\gamma$) are the most influential parameters affecting $R_0$. These parameters are therefore selected as control variables in an optimal control framework to design effective intervention strategies. Numerical simulations show that the combined control strategy significantly reduces TB transmission, resulting in a reduction of more than $80\%$ in active TB cases within a relatively short intervention period. The results suggest that integrated interventions targeting transmission, disease progression, and recovery are substantially more effective than single-measure strategies. This study provides a quantitative framework to support integrated public health policies addressing TB and childhood stunting simultaneously. Full article

Background: Tuberculosis (TB) remains a major global health challenge, with Mycobacterium tuberculosis (M. tuberculosis) causing significant morbidity and mortality mainly in high-burden countries. Following exposure to M. tuberculosis, individuals may become infected, developing TB infection (TBI) through inhalation of the bacillus: this affects approximately one-fourth of the global population and serves as a critical reservoir for potential disease reactivation and transmission. The risk of being infected with M. tuberculosis is shaped by bacterial load of people with TB, contact patterns, environmental factors, and host susceptibility, particularly in high-risk congregate settings. Elucidating these determinants is instrumental for optimising TB prevention and control strategies. Methods: A preliminary PubMed search was conducted on 25 August 2024, using the keywords “latent tuberculosis infection,” “risk factors,” and “systematic review.” Targeted reviews were then performed in November 2024 to examine factors influencing progression from exposure to M. tuberculosis to TBI. Systematic reviews published between January 2000 and November 2024 were included. Results: The scoping review analysed eight systematic reviews, grouping findings into three key themes: (1) proximity and behavioural risk factors; (2) environmental risk factors; and (3) host immune vulnerabilities. Close contact with people with TB in crowded settings, such as dormitories, healthcare facilities, and prisons, was strongly associated with an elevated risk of TBI. Healthcare workers travelling from low- to high-incidence regions faced the highest risk due to frequent exposure to M. tuberculosis, while military personnel and general travellers had lower risks. Environmental exposures, including second-hand smoke and inadequate ventilation, further heightened susceptibility among children and adults. Host immune risk factors, such as advanced age, low body mass index, lack of BCG vaccination, and metabolic disorders such as diabetes, markedly increase susceptibility to TBI. The interplay between proximity, behavioural and environmental risk factors, and host immune vulnerabilities highlights the multifactorial nature of TBI risk. Conclusion: Effective TBI control demands a multifaceted approach, combining robust infection prevention and control measures, comorbidity management, and mitigation of behavioural risk factors like smoking. Tailored strategies are crucial for high-risk settings such as healthcare facilities and prisons. Multisectoral collaboration is essential to address key risk factors and protect vulnerable populations from progressing to TBI. Full article

Background: Patients with latent tuberculosis infection are mainly asymptomatic, but they still carry a notable risk of developing active TB, particularly when the host becomes immunosuppressed. Hence, appropriate diagnosis and management for LTBI are essential. Tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) are among the most commonly utilized methods for detecting LTBI. Until now, no agreement has been established regarding the most effective diagnostic test, either TST or IGRA, so our study aims to evaluate the diagnostic utility of TST versus IGRA in detecting LTBI. Methods: An extensive literature search was executed in several databases from inception till June 2024. We included all the available studies that compared TST versus IGRA concurrently applied to the same study participants, utilizing one of the following proxy reference standards: previous contact with a tuberculosis patient, tuberculosis history, chest x-ray suggestive of tuberculosis, or a combination of them. The sensitivity (SN) and specificity (SP) were imputed with their 95% confidence interval (CI). A bivariate random-effects model within the OpenMeta-Analyst software was utilized for data analysis. Results: We included 39 studies, and our primary analysis regarding LTBI revealed that TST has an SN of 0.320 (95% CI [0.254–0.393]) and an SP of 0.808 (95% CI [0.752–0.854]). Nevertheless, the IGRA exhibited a higher SN estimated at 0.362 (95% CI [0.295–0.434]) and a lower SP estimated at 0.758 (95% CI [0.700–0.808]). Regarding the adult population, TST consistently showed a lower SN and a higher SP relative to IGRA. However, within the pediatric population, TST showed higher SN and lower SP when compared to IGRA. Furthermore, TST also showed a lower SN and a higher SP within hemodialysis and organ transplant patients than IGRA. Conclusions: Our diagnostic test meta-analysis revealed that TST was associated with a lower SN and a higher SP than IGRA. Clinicians should interpret these findings with caution, considering the substantial heterogeneity observed across the included studies, the reliance on proxy reference standards, the potential influence of BCG vaccination status, and the considerable overlap in confidence intervals between TST and IGRA estimates across most analyses. Full article

The lack of reliable diagnostic tools and relapse monitoring for latent tuberculosis infection (LTBI) constitutes a major obstacle to global tuberculosis (TB) control. This highlights an urgent need for robust animal models and predictive biomarkers. To address this, we report the successful establishment of a rapid murine model of recapitulating the active, latent, and relapse phases of TB within a compressed ten-week timeframe—hence termed the rapid multi-stage TB murine model. In this model, mice were first intravenously infected with Mycobacterium tuberculosis, followed by a four-week isoniazid (INH) regimen starting at two weeks post-infection. By week six, pulmonary bacterial loads in most mice dropped below the detection limit, signifying the establishment of latency. Reactivation was subsequently triggered by a four-week administration of anti-TNF-α (Tumor Necrosis Factor-α) monoclonal antibody. Leveraging this reproducible and time-efficient model, we performed transcriptomic profiling of peripheral blood and identified a distinct sixteen-gene signature (including Ets2, Fam111a, Fosl2, Gadd45b, Nfkbid, Rgs1, Bhlhe40, Il1r2, Clec2d, Kmo, Lynx1, Papd4, Trim34a, Wrb, Nlrp12, Spns1) that dynamically tracks disease progression. Collectively, these findings not only provide a valuable and efficient preclinical tool but also deliver transformable candidate biomarkers with immediate potential to guide the development of novel diagnostic strategies for LTBI surveillance and management. Full article

Antitubercular drug-induced liver injury (ATDILI) poses a significant obstacle to successful tuberculosis treatment, including for tuberculous lymphadenitis. Its global incidence varies considerably, typically ranging from 2% to 30%, influenced by factors like patient demographics, co-morbidities, and geographical context. Despite some findings suggesting potentially lower rates in tuberculous lymphadenitis, the inherent hepatotoxic nature of standard anti-TB drugs means the risk remains clinically relevant. Key risk factors for ATDILI encompass older age, female gender, pre-existing liver conditions, HIV co-infection, malnutrition, alcoholism, and genetic polymorphisms, particularly in N-acetyltransferase 2 which affects isoniazid metabolism. The mechanisms of injury are drug-specific: isoniazid primarily causes hepatocellular damage via oxidative stress from toxic metabolites, while rifampicin induces cholestasis and endoplasmic reticulum stress, and pyrazinamide is linked to mitochondrial dysfunction. Management involves prompt withdrawal of antitubercular therapy when liver enzyme thresholds are exceeded, followed by careful reintroduction. Challenges are amplified in resource-limited settings due to higher prevalence of risk factors and limited access to consistent monitoring and sophisticated diagnostics. Promising advancements include safer regimens like the 3-month once-weekly isoniazid-rifapentine (3HP) for latent TB, which significantly reduces hepatotoxicity. The development of shorter active TB regimens and novel anti-TB drugs with improved safety profiles further aims to enhance treatment adherence and reduce ATDILI incidence, ultimately improving patient outcomes globally. Full article

Approximately 25% of the global population is estimated to have latent tuberculosis infection (LTBI), with a 5–10% lifetime risk of progression to active disease. Although interferon-gamma release assays (IGRAs) are widely used for LTBI diagnosis, their high cost and operational complexity limit large-scale implementation in resource-limited settings. This study evaluated the diagnostic performance of a low-complexity, rapid, fluorescence-based point-of-care assay, ichroma IGRA-TB, for LTBI detection. A total of 300 participants enrolled at TB Screening and Treatment Centers and the Dhaka Hospital of icddr,b were categorized as healthy controls (n = 130), household contacts of TB patients (n = 70), GeneXpert MTB/RIF Ultra-positive active TB patients (n = 80), or individuals with a previous history of TB (n = 20). ichroma IGRA-TB was compared with QuantiFERON-TB Gold Plus (QFT-Plus) across all groups. Overall agreement between ichroma IGRA-TB and QFT-Plus was 91.9%, with a Cohen’s kappa of 0.83, indicating almost perfect concordance. Using culture as a surrogate reference standard, QFT-Plus demonstrated higher sensitivity (74.6%) than ichroma IGRA-TB (69.0%). Overall, ichroma IGRA-TB demonstrates high agreement with QFT-Plus and acceptable sensitivity, supporting its potential as a near-point-of-care tool for LTBI screening in resource-constrained settings. Full article

Background/Objectives: Mycobacterial infections and autoimmune diseases affect many worldwide, and growing evidence suggests that there is a bidirectional relationship. This review examines mechanisms by which various autoimmune diseases predispose patients to mycobacterial infections, and vice versa. Methods: We conducted a PubMed/MEDLINE search using the keywords “mycobacterium” and the names of the autoimmune conditions to identify relevant papers. Results: Rheumatoid arthritis therapies, especially TNF-α inhibitors, raise tuberculosis (TB) and non-tuberculous mycobacteria (NTM) risk. Type 1 diabetes features impaired cell-mediated immunity and macrophage dysfunction, with evidence for Mycobacterium avium subspecies paratuberculosis (MAP) mimicry involving HSP65–GAD65. In systemic lupus erythematosus, immune dysregulation plus corticosteroids and cytotoxins elevates TB and NTM risk, amplified in endemic settings. In multiple sclerosis, heightened TLR2/4/9 signaling agents that inhibit pyrimidine synthesis may increase IL-10 and reduce antimycobacterial immunity. Crohn’s disease shows genetic susceptibility (e.g., NOD2 variants) and MAP detection, supporting impaired clearance of intracellular mycobacteria. Conclusions: Overall, evidence supports a bidirectional relationship: mycobacterial antigens can initiate or amplify autoimmunity via molecular mimicry and chronic stimulation, while autoimmune biology and iatrogenic immunosuppression increase susceptibility to infection. Implications include latent TB screening before immunosuppression, attention to local epidemiology, and vigilance for NTM. Research priorities include prospective cohorts, mechanistic studies of mimicry and NOD2–TLR pathways, safety registries, and trials of screening and prophylaxis. Full article

Background/Objectives: An important diagnostic problem is to differentiate between active tuberculosis (TB) and latent TB infection (LTBI). Furthermore, the current biomarkers also offer minimal insight into disease pathogenesis to direct treatment. This triggered us to design a two-mode biomarker signature based on the multicohort analysis using a transcriptomic and stringent machine learning pipeline. Methods: When analyzing active TB, latent TB, and healthy control samples, a rigorous filter (ANOVA, p < 0.001) was used, followed by the selection of features with the help of Boruta-XGBoost and LASSO regression. This determined a small four-gene signature (TAP2, SORT1, WARS, and ANKRD22), which was selectively and highly upregulated in the active TB clinical state (p < 0.001). An ensemble staking classifier based on this signature (Random Forest and XGBoost) had a very high diagnostic performance (ROC-AUC = 0.991 (95% CI: 0.983–0.997)) in the stratification of infection phases, which was strongly confirmed in another cohort (GSE19444). Results: Importantly, the analysis of the functional pathways showed that all the genes are mapped to core dysregulated host pathways in active TB: antigen presentation (TAP2), lipid trafficking (SORT1), interferon response (WARS), and inflammasome signaling (ANKRD22). In such a way, the signature has a dual advantage: (1) high specificity, non-sputum transcriptional diagnostic of active TB, and (2) a mechanistic map of key host pathways, which describes targets of intervention. Conclusions: Thus, the signature provides a two-fold response: a biomarker panel aligned with WHO performance targets for TB triage and a mechanistic plan of therapy, which provides an easy way to implement transcriptomic discovery into clinical action against TB. Full article

Latent tuberculosis infection (LTBI) represents a major global health concern as it constitutes the principal reservoir for future tuberculosis (TB) disease. Its identification is particularly important in Bacille Calmette–Guérin (BCG)-vaccinated populations, where cross-reactivity of purified protein derivative limits the specificity of the tuberculin skin test and hampers targeted preventive therapy. Early Mycobacterium tuberculosis antigens encoded within the RD1 region, especially ESAT-6, CFP-10 and TB7.7, have enabled the development of antigen-specific interferon-gamma release assays (IGRAs) and recombinant skin tests with improved BCG-independent specificity. This narrative review integrates and critically appraises current evidence on the immunobiological properties of early and latency-associated antigens, the cellular mechanisms underlying T-cell-dependent immune reactivity, and the diagnostic performance of IGRAs and ESAT-6/CFP-10-based skin tests, rather than merely summarizing individual studies. Although these platforms rely on different assay principles (in vitro cytokine release versus in vivo delayed-type hypersensitivity), both measure antigen-specific T-cell memory and do not define the biological stage of infection or reliably distinguish latent from incipient or active TB. Across most adult populations, IGRAs demonstrate high specificity and acceptable sensitivity, whereas reduced sensitivity and higher rates of indeterminate results are observed in young children and immunocompromised individuals. ESAT-6/CFP-10-based skin tests show diagnostic accuracy comparable to IGRAs and may offer operational advantages in resource-limited settings. Latency-associated antigens and host biomarkers such as IP-10, together with multi-analyte immune signatures, represent promising avenues for improving diagnostic sensitivity and prognostic stratification but currently lack sufficient validation for routine clinical use. Overall, RD1-encoded antigens remain central to LTBI immunodiagnosis, while future research should focus on developing stage-resolving and prognostic biomarkers, optimized antigen panels, and standardized interpretive frameworks. Full article

Background: The Korea Disease Control and Prevention Agency classifies healthcare workers (HCWs) into five groups based on Mycobacterium tuberculosis exposure risk and potential transmission impact to guide TB screening strategies. However, data on actual exposure frequency and latent tuberculosis infection (LTBI) incidence across these classifications remain limited. Methods: We conducted a retrospective cohort study of HCWs at a tertiary hospital between 2023 and 2024. Baseline LTBI screening was performed for all staff, with annual follow-up testing for Groups 1–4 according to national guidelines. TB exposure history and frequency were investigated and documented by the infection prevention department. LTBI incidence was assessed among HCWs with a negative test in 2023 who underwent repeat testing in 2024. Results: Among 2116 HCWs (27.7% male; mean age, 33 years), TB exposure rates increased with higher risk classification (Group 1: 46.9%, Group 2: 31.3%, Group 3: 18.5%, Group 4: 1.2%, Group 5: 0.6%; p < 0.001), as did the mean number of exposure events per person (1.39, 0.74, 0.31, 0.01, and 0.01, respectively; p < 0.001). The incidence of LTBI was 13/1323 (1.0%). After adjustment, LTBI incidence was associated with ≥2 TB exposure events (adjusted OR, 7.03; 95% CI, 1.87–26.36; p = 0.005), but did not differ significantly by group classification. Conclusions: This study suggests that occupational classification effectively predicts the frequency of TB exposure among healthcare workers. However, LTBI incidence is more closely associated with multiple TB exposure events rather than occupational classification. Full article

Tuberculosis (TB) remains one of the leading causes of death from a single infectious agent worldwide, a burden further exacerbated by HIV co-infection and the increasing prevalence of drug-resistant strains. Although a wide range of laboratory diagnostic methods are currently available, their applicability, implementation, and clinical impact vary substantially across healthcare settings with different levels of complexity and resources. This review provides a comprehensive overview of the main laboratory diagnostic methods for active and latent TB, emphasizing their clinical applicability, implementation challenges, and role within integrated diagnostic strategies. Conventional approaches, such as smear microscopy and culture, are discussed alongside modern diagnostic technologies, including automated nucleic acid amplification tests (NAATs), loop-mediated isothermal amplification (LAMP), line probe assays (LPAs), next-generation sequencing (NGS), and lateral flow assays, highlighting their strengths and limitations in distinct epidemiological and operational contexts. Unlike existing WHO guidelines and prior reviews that predominantly focus on test performance and recommendation status, this review adopts an implementation-oriented perspective, critically examining diagnostic methods in light of real-world constraints, regional disparities, and evidence gaps. Particular attention is given to limitations related to laboratory infrastructure, biosafety, workforce capacity, and sustainability, as well as to under-addressed areas such as latent TB, metagenomic approaches, and the investigation of co-pathogens. By integrating WHO guidance with contextual and operational considerations, this review aims to support rational test selection and the development of flexible, integrated diagnostic workflows tailored to local health system capacity, patient populations, and clinical scenarios, thereby strengthening the effectiveness and equity of TB diagnostic strategies. Full article