Greater understanding of the role of tryptophan metabolism in the immune response to tuberculosis (TB) has provided promising avenues to explore new diagnostic and therapeutic modalities. Animal and human studies have demonstrated that host indoleamine 2,3-dioxygenase 1 (IDO1) is upregulated in response to infection with Mycobacterium tuberculosis, resulting in increased tryptophan metabolism to kynurenine. In TB disease, this is evidenced by elevation of the plasma kynurenine to tryptophan ratio, which is reversed with effective TB treatment, thus showing utility as a potential diagnostic and therapeutic biomarker. Kynurenine and downstream metabolites promote an immunosuppressive microenvironment in TB granulomas, which may facilitate immune evasion. IDO inhibition in nonhuman primates has highlighted its potential role as host-directed therapy by demonstrating increased T-cell trafficking to the granuloma core, reduced bacterial burden, and decreased immunopathology. To realize the potential of exploiting the tryptophan to kynurenine metabolic pathway, innovative biomarker and host-directed therapy trials are needed.

Global Tuberculosis Research Landscape: A Comprehensive Bibliometric Analysis of PubMed Literature (2017–2024)

Tuberculosis in lung and heart transplant recipients.

Young children and children living with HIV are at high risk of progressing to tuberculosis (TB) disease following Mycobacterium tuberculosis (Mtb) exposure and infection, and also of developing severe forms of disease and TB-related mortality. Identifying children who have very early (sub-clinical) TB disease, prior to progression to clinically apparent TB, would mean that TB preventive treatment (TPT) could be more efficiently targeted to this group. Identifying biomarker changes on drug therapy in children with Mtb infection or very early disease could pave the way for the development of tests that can identify which children have viable bacilli and are therefore at increased risk of disease progression. The INTREPID study will use already collected samples taken from well-phenotyped paediatric cohorts in three clinical studies conducted in South Africa in children <5 years, including a drug-resistant TPT trial (TB-CHAMP), an observational household contact study (interferon-gamma release assay studies) and a prospective diagnostic study (Umoya), all conducted in a setting with a high burden of TB and HIV. We will employ transcriptomic, proteomic, metabolomic and serology approaches to analyse changes in host blood profiles at every stage along the TB continuum, from Mtb exposure to disease and from children treated for Mtb infection and early TB disease, as well as targeted Mtb antibody analysis. Data on viral co-infections and relevant clinical and epidemiological parameters will be integrated and evaluated to identify the optimal biosignatures that can predict future progression to clinically overt disease in children below 5 years of age, including those living with HIV. The study protocol received ethical approval from the Stellenbosch University Health Research Ethics Committee (N23/03/025). The study findings will be disseminated through peer-reviewed publications, scientific conferences and formal presentations to healthcare professionals and to local communities, in collaboration with the Desmond Tutu TB Centre Community Advisory Board.

Background: Diabetes mellitus (DM) is associated with increased susceptibility to tuberculosis (TB) and unfavorable treatment outcomes.Objective: To evaluate the risk of pulmonary tuberculosis (PT)-related mortality attributable to DM in Brazil and to identify subgroups that may require differentiated clinical management.Methods: Descriptive and retrospective cohort study using data from Brazil’s national health surveillance system. Data on new PT cases in individuals aged ≥18 years, diagnosed between 2012 and 2017, were analyzed. Fatality rates were compared between patients with and without self-reported DM, stratified by relevant covariates, to estimate the attributable risk due to DM (ARDM%).Results: A total of 355,659 patients with PT were included in the analysis of this study, of whom 29,579 (8.3%) had PT-DM, and 326,080 (91.7%) had PT alone, without DM. Patients with PT-DM exhibited higher PT fatality rates (1,691, 5.7%) and lower treatment discontinuation rates (2,425, 8.2%) than those without DM (12,203, 3.7%) or who completed the full course of treatment (50,216, 15.4%). Overall, DM accounted for a 34.6% increase in PT fatality (ARDM%). The highest ARDM% (>50%) was observed among patients with higher education levels, those aged 18-39 years, residents of peri-urban areas, recipients of the Brazilian Cash Transfer Program (BCTP), and incarcerated individuals.Conclusions: DM substantially increases the fatality rate among patients with PT in Brazil, particularly in specific subgroups that may benefit from targeted clinical and public health interventions.

Recommendations on the Diagnosis and Treatment of Tuberculosis Infection: SEPAR/SEIMC/Spanish Ministry of Health Consensus Statement.

National Tuberculosis Reference Laboratories (NTRLs) are central to tuberculosis (TB) control programs. Between 2018 and 2024, the Republic of Congo, a country of 6 million inhabitants, achieved a transformative strengthening of its TB diagnostic system, coordinated by the NTRL. Strategic investments, supported mainly by international partners, enabled a substantial decentralization of services, expanding the diagnostic network from 38 to 113 diagnostic and testing centers and increasing GeneXpert sites from 3 to 31. The expansion of the diagnostic network and specimen referral system was associated with a reduced structural gap in diagnostic coverage by extending access to GeneXpert testing to a larger number of peripheral and previously underserved centers. Critically, the establishment of a BSL-3 laboratory and the deployment of advanced assays like Xpert MTB/XDR ended the reliance on overseas testing by introducing in-country capacity for multidrug-resistant and pre-extensively drug-resistant TB detection. These systemic improvements were associated with significant positive outcomes, including an annual molecular testing surging from 11,609 in 2022 to over 27,000 in 2024 and bacteriological confirmation rates rising from 34 to 73%. This comprehensive laboratory systems strengthening, which also facilitated cross-programmatic initiatives like HIV and Mpox testing integration, underscores how sustained investment in infrastructure, logistics, and quality management is fundamental to improving case detection, surveillance, and progress toward the WHO End TB Strategy milestones.

Early immune containment of mycobacteria at the infection site is key to tuberculosis (TB) vaccine development. Intranasal delivery strategies offer a promising alternative to parenteral BCG vaccination, particularly for pulmonary TB, the predominant clinical form in humans and livestock. This study evaluated the immunogenicity of intranasal BCG and heat-inactivated M. bovis (HIMB) with or without adjuvant, as well as prime-boost strategies combining parenteral BCG or HIMB followed by intranasal HIMB in young goats. Intranasal BCG elicited systemic antigen-specific IFNγ production, with enhanced expansion of CD4+IFNγ+ and CD8+IFNγ+ T-cells, comparable to prime-boost regimens. Intranasal BCG and prime-boosted groups also induced higher local proinflammatory responses at the lung mucosa, including proinflammatory cytokine production, expansion of antigen-specific T-cells, and polarization of alveolar macrophages toward activated proinflammatory phenotype. The results underscore the potential of respiratory mucosal BCG delivery to enhance early immune responses against TB infection and support further investigation into its protective efficacy.

Abstract Background Tumor necrosis factor alpha (TNF-α) inhibitors, significantly improve outcomes in moderate-to-severe Crohn’s disease (CD) but increase susceptibility to tuberculosis (TB). Screening before treatment initiation reduces risks, yet TB may still develop during therapy. Herein, we report a case illustrating the challenges of managing severe Crohn’s disease on biologic therapy complicated by TB infection and paradoxical autoimmune phenomena. Methods An 24 year old female patient diagnosed with Crohn’s disease at age 18 (Montreal classification A1, L3+L4, B1) was treated with corticosteroids and azathioprine, then escalated to infliximab due to inadequate disease control. Baseline interferon-gamma release assay (IGRA) and chest radiography were negative. After a clinical flare, the infliximab dose was intensified. Shortly thereafter, a repeat IGRA converted to positive, indicating latent TB infection. Isoniazid prophylaxis was initiated while infliximab therapy continued under close monitoring. Results Under anti TNF- α agents, the patient achieved clinical remission of Crohn’s disease; however, she subsequently developed severe paradoxical psoriasis and alopecia areata, presumed to represent immune-mediated complications of anti-TNF therapy, for which methotrexate was initiated. One year later, she presented with ascites, pleural effusion, and low-grade fever in the emergency room. Cross-sectional imaging revealed peritoneal and pleural lesions suspicious for TB, although serial microbiological cultures remained negative. An exploratory laparotomy with biopsy demonstrated caseating granulomas in the peritoneum, confirming peritoneal tuberculosis, which subsequently progressed to miliary TB. Infliximab and methotrexate were discontinued, and a 12-month course of anti-tuberculous therapy was initiated. Conclusion This case highlights the importance of vigilant TB screening and continued monitoring in inflammatory bowel disease patients receiving anti-TNF therapy, even after negative baseline screening and prophylaxis. It also underscores the need to recognize and manage paradoxical immune-related adverse effects. Multidisciplinary monitoring is essential for early detection of TB. Reference: 1. G.R. D’Haens, et al.Gut, 70 (2021), pp. 1396-1405 Conflict of interest: Dr. Mare, Ruxandra: No conflict of interest Pienar, Corina: none Taban, Sorina: none Popescu, Alina: none Sirli, Roxana: none Goldiș, Adrian Eugen: none

Most HIV-negative individuals exposed to Mycobacterium tuberculosis (Mtb) control infection as latent TB infection (LTBI), but HIV co-infection greatly increases progression to tuberculosis (TB), the leading cause of death in people living with HIV (PLHIV). Although combination antiretroviral therapy (cART) reduces LTBI reactivation, immune control of Mtb is not fully restored, as shown by persistent TB incidence in PLHIV on cART. In macaques, skewed pulmonary effector memory CD4⁺ T-cell (TEM) responses and new TB lesions persist despite cART. We hypothesize that concurrent anti-TB therapy with cART would improve bacterial control and immune restoration compared to cART alone. Using rhesus macaques (RM) with LTBI and Simian Immunodeficiency Virus (SIV) co-infection, we tested three months of weekly isoniazid and rifapentine (3HP) plus daily cART. Concurrent cART+3HP improves clinical and microbiological outcomes but fails to fully restore lung CD4⁺ T-cell immunity. Treated RMs retain caseous granulomas with high FDG uptake and incomplete CD4⁺ T-cell reconstitution, marked by persistent activation, exhaustion, and inflammation. CD4⁺ TEM cells remain depleted. Concurrent therapy induces Type I IFN signatures and enhances Mtb-specific TH1/TH17—but reduces TNFα—responses. These findings reveal persistent pulmonary immune defects underlying TB risk in HIV co-infection and identify potential targets for host-directed adjunctive therapies.

In spite of decades of studying the role for CD8+ T-cells in response to tuberculosis (TB) infection, it remains only partly understood. Even less is known how the level of host genetic susceptibility to TB infection influences the involvement of these cells in immune response. Our lab established MHC II-congenic mouse strains with different levels of genetic susceptibility to TB infection dependent exclusively upon quantitative and qualitative differences in organization of relevant CD4 T-cell populations and lacking major defects in immune systems. In the present work, we investigated how the in vivo lack of CD8+ T-cells affects related capacity to combat TB infection. To this end, we developed a novel double-congenic mouse strain В6.I-9.3-β2M–/– that lacks CD8 T cells due to a knockout mutation in the gene encoding β2-microglobulin and differs from the parental B6 strain by the MHC II allele. We performed a comparative study of TB development and immune response using four mouse strains: the ancestor В6 and B6.I-9.3 pair vs. CD8-deficient В6-β2M–/– and В6.I-9.3-β2M–/– pair. CD8 T-cell deficiency did not alter lung mycobacterial multiplication during the first 4 weeks post TB challenge; however, at day 90 lung mycobacterial population increased to significantly higher levels in В6-β2M–/– compared to B6 mice. Post-infection life span of both CD8 T-cell-deficient mouse strains was dramatically shorter than that of the wild type animals. En mass, negative effects of CD8 cell deficiency looked more pronounced on the MHC II allele background, which in the presence of CD8 cells is associated with better protection against infection. In addition, the lack of CD8+ cells resulted in significantly decreased size of TNF-positive CD4+ T-cell populations in mice from both β2M–/– strains at week 4 post-challenge. This is consistent with a previously non-described helper function of CD8 cells for the TNF synthesis by CD4 cells. We discuss the results obtained within the context of dynamical interactions between T-cell populations during chronic TB infection.

Background: Adhering to tuberculosis (TB) treatment is vital for preventing the spread of the disease and the rise of drug-resistant strains. However, low adherence rates remain challenging, reflecting the public's limited understanding of the importance of completing treatment, underscoring the need for better health education. Objective: This scoping review aims to explore and synthesize existing health education strategies designed to enhance adherence to tuberculosis treatment. Methods: A scoping review using Arksey and O'Malley was conducted. Relevant articles published within the last 10 years, from 2014 to 2024, were selected for this review. The research literature was gathered from six databases: PubMed, Science Direct, Sage, Cochrane Library, ProQuest, and Google Scholar. The Joanna Briggs Institute guidelines were used for data extraction. Results: Out of 1,213 studies reviewed, 14 articles were included in this analysis. This review identifies five key themes related to health education strategies: the purpose of health education, the media of intervention, the methods of intervention, the duration of intervention, and the outcomes of education. Conclusion: Effective health education strategies to promote treatment adherence among tuberculosis patients can significantly improve patient compliance. A wider adoption of these strategies will help control tuberculosis and achieve global elimination goals. In the future, telemedicine and tele-nursing will be vital for enhancing adherence in areas with limited healthcare access.

The current global shortage of organs from human donors has resulted in long wait lists and increasing mortality among patients with end-stage organ failure. Pig-to-human xenotransplantation has been touted as a solution to this problem. However, significant infectious diseases and public health considerations exist with such a technological advancement. Infectious diseases hazards with public health implications of pig-to-human xenotransplantation may be categorized taxonomically, according to temporality of potential exposure and/or reactivation, or according to anthroponotic versus zoonotic transmission. Additionally, the potential for escalating proportions of immunosuppression-at-scale in the context of the theoretically less-constrained resource of xenografts warrants particular consideration given that impacts will be differentially borne by those most affected by reactivating infections including but not limited to tuberculosis (TB), hepatitis B (HBV), and strongyloidiasis. TB, HBV, and strongyloidiasis all represent chronic infections with potential for reactivation under circumstances of immunosuppression - owing to either allograft or xenograft transplantation - that differentially impact those living in rural poverty globally, and those with risk factors for acquisition related to crowding, poor sanitation, undernutrition, and economic disenfranchisement. Chagas disease and leishmaniasis portend similar possibility of reactivation and differentially affect those residing in the global South. We herein situate the public health implications of xenotransplantation at scale within the broader landscape of infectious diseases hazards related to the technology, and propose a health equity and human rights based framework for global risk assessment.

OP 34: Diseases and Interventions 2, B304 (FCSH), September 5, 2025, 10:15 - 11:15BackgroundMigrants are at increased risk of chronic infections and have poorer outcomes. Early diagnosis and management can reduce morbidity, mortality and onward infection transmission.MethodsWe evaluated the effectiveness of an integrated approach to screening migrants for exposure to tuberculosis (TB) with an interferon gamma release assay (IGRA) test, HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection when patients first registered with general practices (GPs) in Leicester, UK, using test yields, numbers of new diagnoses and numbers linked to care.Findings4004 new migrant GP patients referred for testing were included (74% <36 years, 53% female, with a range of self-reported ethnicities: 63% Asian ethnicities, 9% Black ethnicities, 5% White and 12% Mixed/Other). Test yield was 0·48% (17/3545, 95%CI 0·30-0·77%) for HIV, 3·34% (117/3502, 95%CI 2·80-3·99%) for HBV and 0·18% (6/3402, 0·08-0·38%) for HCV, with 19·38% (496/2560, 95%CI 17·89-20·95%) positive on the IGRA test. There were two HIV-HBV, three HIV-TB and 19 HBV-TB coinfections. Of IGRA-positive patients attending clinic, 7% had active TB and 92% had latent TB infection. 55% of active TB, 99% of latent TB, 61% of HBV, 35% of HIV and 83% of HCV infections were new diagnoses. There were high rates of linkage to care for those newly diagnosed. 98% of new latent TB patients were offered chemoprophylaxis, of whom 94% started treatment and of these, 95% completed the course. 100%, 97% and 100% of newly HIV-, HBV- and HCV-diagnosed patients attended follow-up, respectively.Interpretation: This first primary care-based combined infection testing programme for recent migrants found high test yields for latent/active TB, HBV and HIV, substantial numbers of new diagnoses for these infections and excellent linkage to care. To influence UK screening guidelines, its cost-effectiveness and acceptability to other primary care settings must be evaluated.

Background. Undernutrition due to tuberculosis (TB) infection is high in children and is often accompanied by micronutrient deficiency resulting from insufficient nutritional intake such as iron deficiency anemia. Undernutrition also caused a decrease in IL-6, making children vulnerable to the infection. This study was aimed at analyzing the effect of oral nutritional supplements on hemoglobin, interleukin (IL)-6 levels, weight and length increment in stunted children with TB. Materials and methods. A pre-experimental study with one-group pre-test/post-test design was conducted from October 2022 to July 2023 in a private hospital, Surabaya, East Java, involving stunted children with TB infection aged 12 to 60 months. The statistical analysis included descriptive statistics (mean ± standard deviation or n (%)), independent sample T-test or Mann-Whitney U test, and paired sample T-test or Wilcoxon sign rank test, depending on the normality. Results. A total of 29 subjects were enrolled in this study, with a mean age of 25.40 ± 11.30 months. 58.62 % of subjects were aged below 24 months old, and 41.38 % were aged between 25 and 60 months. No significant differenсе was seen in IL-6 and hemoglobin before and after the intervention. The average hemoglobin level before the intervention was 12.07 ± 1.22 mg/dL, and after the intervention it was 12.00 ± 1.09 mg/dL, while for IL-6, these indicators were 125.76 ± 116.87 and 122.41 ± 104.43 µg/L, respectively (p = 0.441). Conclusions. Oral nutritional supplements intervention for 90 days did not affect IL-6 and hemoglobin levels of children with TB.

Incidence of tubercular lymphadenitis in cases of cervical lymphadenopathy by fine needle aspiration cytology-A single center study.

Poor geographical accessibility to tuberculosis (TB) diagnostic services in Ghana is a key barrier to timely diagnosis. Decentralizing molecular testing for TB could improve TB case notification among underserved populations and enhance treatment initiation while avoiding unnecessary treatments. This study aims to project the epidemiological impact of decentralized TB testing at the country level. We developed an individual-based simulation of the TB diagnostic system and treatment cascade in Ghana, calibrated to key TB care targets using data from the District Health Information Management System (DHIMSII) from 2019-2022. We assessed the effects of expanding molecular (Xpert MTB/RIF) testing to (1) all 218 district hospitals and (2) all 703 modeled facilities reporting TB notifications, comparing these scenarios to the current diagnostic network. Under the baseline scenario, 26% of samples remained untested, with over 30% of diagnoses made through clinical judgment alone, and 35% with false positive diagnoses. Decentralizing Xpert to district-level facilities could reduce the proportion of untested samples to 20%, lowering false positive diagnosis to 32%. While projected TB notifications and treatment rates in 2030 remained similar, this shift could result in 51 additional treatment initiations for individuals with undiagnosed TB, prevent 36 unnecessary treatments, and save 43 lives per million people over an eight-year period by 2030. Full Xpert decentralization could eliminate untested samples by enabling on site testing at all facilities, reduce false positive diagnosis to 25%, and lead to 220 additional treatment initiations, 140 fewer unnecessary treatments, and 180 lives saved per million relative to baseline from 2023-2030. Decentralizing Xpert testing offers significant benefits, improving diagnostic accuracy, reducing untested samples, and enhancing TB treatment outcomes – but wide-scale implementation is required to realize full benefits at a country level.

Assigning antigen specificity to T cell receptor (TCR) sequences is challenging due to the TCR repertoire's diversity and the complexity of TCR-antigen recognition. We developed the peptide-driven identification of TCRs (PDI-TCR) assay that combines in vitro expansion of cells with peptide pools, bulk TCR sequencing, and statistical analysis to identify antigen-specific TCRs from human blood. A key feature of PDI-TCR is the ability to distinguish true antigen-specific TCR clonotypes from TCRs associated with unspecific bystander activation by comparing responses to nonoverlapping peptide pools. We applied PDI-TCR to tuberculosis (TB) patients, sampling blood at diagnosis and throughout treatment, and Mycobacterium tuberculosis (Mtb)-sensitized healthy individuals (IGRA+). We identified hundreds of Mtb-specific TCRs, as well as unspecific TCRs, and characterized their phenotype in each cohort by single-cell RNA sequencing ex vivo. Mtb-specific T cells were highly diverse, with short-lived effector phenotypes only present in TB at diagnosis, while memory phenotypes were maintained through treatment. In contrast, unspecific expanded T cells were more clonally restricted, had a cytotoxic phenotype, and were maintained throughout treatment. While the PDI-TCR parameters used in this study are specific to Mtb, the underlying approach is broadly applicable to the study of antigen-specific T cells and can be adapted as needed for other antigen systems. Thus, PDI-TCR is a powerful tool for identifying antigen-specific TCRs and enables direct ex vivo identification and monitoring of antigen-specific T cells.

A mixed methods evaluation of 99DOTS digital adherence technology uptake among adolescents treated for pulmonary tuberculosis in Uganda

Biological sex significantly influences susceptibility to tuberculosis (TB), with males typically experiencing a greater disease burden than females. However, the mechanisms underlying sex-specific immune regulation during TB pathogenesis remain incompletely understood. In this study, we examined sex-based differences in pulmonary immune cell composition, inflammatory signaling pathways, and macrophage transcriptomic responses in C57BL/6 mice infected with the Mycobacterium tuberculosis (Mtb) HN878 strain during the sub-acute stage of infection. Our results show that female mice had significantly lower pulmonary Mtb burdens and enhanced protein kinase B (AKT)-interferon gamma (IFN-γ) signaling, which is associated with autophagy, lysosomal activation, and effective intracellular bacterial clearance. In contrast, male mice exhibited higher bacterial loads and elevated IL-6 signaling, a pathway linked to exacerbated inflammation and impaired pathogen control. Histological analysis revealed greater lymphocytic aggregation in female lungs, despite comparable levels of pulmonary macrophages between sexes. Importantly, transcriptomic profiling of lung macrophages uncovered distinct sex-specific gene expression patterns, wherein female macrophages upregulated genes involved in tissue remodeling, phagocytosis, autophagy/lipophagy, and cell survival, whereas male macrophages showed enrichment of genes related to pro-inflammatory and adaptive immune responses. Notably, male macrophages expressed higher levels of Ighg1 (Immunoglobulin Heavy Constant Gamma 1), suggesting a potential sex-dependent modulation of humoral immunity during TB. Together, these findings demonstrate that biological sex shapes immune cell programming and host-pathogen interactions during TB, underscoring the importance of incorporating sex as a biological variable in TB research and therapeutic development.IMPORTANCEMen and women often respond differently to diseases like tuberculosis (TB), with men typically facing more severe illness, though the underlying reasons are unclear. To this end, our study investigated how male and female mice combat TB infection at a cellular and molecular level. We discovered that female mice controlled TB more effectively, as their immune systems activated specific pathways to break down and clear bacteria efficiently. Conversely, male mice showed higher bacterial loads and triggered more inflammatory, yet less effective, immune responses. Crucially, despite similar numbers of key immune cells (macrophages) in the lungs, their functional responses differed significantly by sex. These findings underscore that biological sex profoundly impacts the immune system's fight against TB, paving the way for more personalized treatments and improved outcomes for all.