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Blood transcriptomics analysis of tuberculosis has revealed an interferon-inducible gene signature that diminishes in expression after successful treatment; this promises improved diagnostics and treatment monitoring, which are essential for the eradication of tuberculosis. Sensitive radiography revealing lung abnormalities and blood transcriptomics have demonstrated heterogeneity in patients with active tuberculosis and exposed asymptomatic people with latent tuberculosis, suggestive of a continuum of infection and immune states. Here we describe the immune response to infection with Mycobacterium tuberculosis revealed through the use of transcriptomics, as well as differences among clinical phenotypes of infection that might provide information on temporal changes in host immunity associated with evolving infection. We also review the diverse blood transcriptional signatures, composed of small sets of genes, that have been proposed for the diagnosis of tuberculosis and the identification of at-risk asymptomatic people and suggest novel approaches for the development of such biomarkers for clinical use. O’Garra and colleagues describe the immune response to infection with Mycobacterium tuberculosis revealed through the use of transcriptomics and the value of blood transcriptional gene signatures for the diagnosis of tuberculosis.

Although mouse infection models have been extensively used to study the host response to Mycobacterium tuberculosis , their validity in revealing determinants of human tuberculosis (TB) resistance and disease progression has been heavily debated. Here, we show that the modular transcriptional signature in the blood of susceptible mice infected with a clinical isolate of M. tuberculosis resembles that of active human TB disease, with dominance of a type I interferon response and neutrophil activation and recruitment, together with a loss in B lymphocyte, natural killer and T cell effector responses. In addition, resistant but not susceptible strains of mice show increased lung B cell, natural killer and T cell effector responses in the lung upon infection. Notably, the blood signature of active disease shared by mice and humans is also evident in latent TB progressors before diagnosis, suggesting that these responses both predict and contribute to the pathogenesis of progressive M. tuberculosis infection. The pathobiological validity of mouse models of mycobacteria infection is sometimes questioned. O’Garra and colleagues demonstrate that mice share transcriptomic modules with active human tuberculosis and a characteristic type I IFN signature.

Whole blood transcriptional signatures distinguishing active tuberculosis patients from asymptomatic latently infected individuals exist. Consensus has not been achieved regarding the optimal reduced gene sets as diagnostic biomarkers that also achieve discrimination from other diseases. Here we show a blood transcriptional signature of active tuberculosis using RNA-Seq, confirming microarray results, that discriminates active tuberculosis from latently infected and healthy individuals, validating this signature in an independent cohort. Using an advanced modular approach, we utilise the information from the entire transcriptome, which includes overabundance of type I interferon-inducible genes and underabundance of IFNG and TBX21 , to develop a signature that discriminates active tuberculosis patients from latently infected individuals or those with acute viral and bacterial infections. We suggest that methods targeting gene selection across multiple discriminant modules can improve the development of diagnostic biomarkers with improved performance. Finally, utilising the modular approach, we demonstrate dynamic heterogeneity in a longitudinal study of recent tuberculosis contacts. Mass screening diagnostics for Mycobacterium tuberculosis exist, but criticisms exist regarding the sensitivity and specificity of these tools. Here the authors use RNA-Seq and a modular bioinformatics approach using data from their own cohorts and meta-analysis of published cohorts to create a reduced signature for detection of tuberculosis that does not detect other diseases.

Reports Mepolizumab (Nucala®) is an effective and specific anti-eosinophil molecular therapy that has recently been approved as add-on therapy for management of severe eosinophilic asthma by US, European and UK drug administration agencies. Indicates this molecular therapy offers improved specificity and effectiveness of biological effect. Cautions the need to identify responder subgroups as one size fits all is not appropriate with this treatment option. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.

The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosis infection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 systematically identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% confidence interval (CI), 8.0–29.2%) among child contacts, 4.8% (95% CI, 3.0–7.7%) among adult contacts, 5.0% (95% CI, 1.6–14.5%) among migrants and 4.8% (95% CI, 1.5–14.3%) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk stratification. Therefore, we developed a personalized risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell sensitization and clinical covariates. Internal–external cross-validation of the model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI, 0.82–0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the current crude approach to TB risk estimation among people with LTBI in favor of our evidence-based and patient-centered method, in settings aiming for pre-elimination worldwide. The risk of developing active tuberculosis (TB) in individuals with latent TB infection is highly variable within and among different risk groups. A personalized risk predictor was developed to better target preventative treatment to individuals at greatest risk, supporting evidence-based clinical decision-making for latent TB.

Asthma exacerbations are characterized by increased symptoms of cough and chest tightness, diminished expiratory airflow, and increased numbers of inflammatory cells in the sputum. In these two small “proof of concept” trials involving patients with eosinophilic asthma and a history of exacerbations, patients treated with an antibody directed against interleukin-5 had fewer exacerbations than did those given placebo. Asthma exacerbations are characterized by increased symptoms of cough and chest tightness, diminished expiratory airflow, and increased numbers of inflammatory cells in the sputum. In these two small “proof of concept” trials involving patients with eosinophilic asthma and a history of exacerbations, patients treated with an antibody directed against interleukin-5 had fewer exacerbations than did those given placebo. Asthma is a complex chronic inflammatory disorder of the bronchial tree. Persons with asthma present with variable symptoms of cough, breathlessness, and wheezing; these episodes may be punctuated by periods of more severe and sustained deterioration in control of symptoms — termed exacerbations — that necessitate emergency treatment. Exacerbations are associated with substantial morbidity and mortality and with considerable health care costs. 1 Exacerbations differ from day-to-day symptoms in that they respond poorly to usual inhaled therapy and are more closely linked to increased airway inflammation. 2 The link to eosinophilic airway inflammation may be particularly important, since infiltration of the airway . . .

Chronic inflammation triggers development of metabolic disease, and pulmonary tuberculosis (TB) generates chronic systemic inflammation. Whether TB induced-inflammation impacts metabolic organs and leads to metabolic disorder is ill defined. The liver is the master regulator of metabolism and to determine the impact of pulmonary TB on this organ we undertook an unbiased mRNA and protein analyses of the liver in mice with TB and reanalysed published data on human disease. Pulmonary TB led to upregulation of genes in the liver related to immune signalling and downregulation of genes encoding metabolic processes. In liver, IFN signalling pathway genes were upregulated and this was reflected in increased biochemical evidence of IFN signalling, including nuclear location of phosphorylated Stat-1 in hepatocytes. The liver also exhibited reduced expression of genes encoding the gluconeogenesis rate-limiting enzymes Pck1 and G6pc. Phosphorylation of CREB, a transcription factor controlling gluconeogenesis was drastically reduced in the livers of mice with pulmonary TB as was phosphorylation of other glucose metabolism-related kinases, including GSK3a, AMPK, and p42. In support of the upregulated IFN signalling being linked to the downregulated metabolic functions in the liver, we found suppression of gluconeogenic gene expression and reduced CREB phosphorylation in hepatocyte cell lines treated with interferons. The impact of reduced gluconeogenic gene expression in the liver was seen when infected mice were less able to convert pyruvate, a gluconeogenesis substrate, to the same extent as uninfected mice. Infected mice also showed evidence of reduced systemic and hepatic insulin sensitivity. Similarly, in humans with TB, we found that changes in a metabolite-based signature of insulin resistance correlates temporally with successful treatment of active TB and with progression to active TB following exposure. These data support the hypothesis that TB drives interferon-mediated alteration of hepatic metabolism resulting in reduced gluconeogenesis and drives systemic reduction of insulin sensitivity.

BackgroundTuberculosis (TB) survivors experience high mortality and long-term morbidity, contributing substantially to the global TB burden. In the UK, where TB incidence is rising, the scale of post-TB health needs is unknown and current guidelines do not recommend follow-up. We conducted the first nationwide survey of UK TB services to assess approaches to post-TB care.MethodsWe conducted a digital survey between February and May 2025 across National Health Service TB services in all four nations, targeting specialist clinicians. The questionnaire captured data on types of post-TB morbidity encountered and current practice. We analysed descriptively and stratified by caseload.ResultsWe received responses from 113 of 135 TB services (84%). Most respondents were lead clinicians (81%), and nearly all (96%) had encountered post-TB morbidity in their patient populations, including lung disease (82%), social vulnerabilities (79%), and financial issues (66%). High caseload services (≥30 cases/year) reported more types of morbidity (mean 4.2 vs 2.9; p<0.001). While end of treatment symptom screening and chest X-rays are routine (>95%), fewer than half of services perform assessments for broader post-TB sequelae and comorbidities, or provide direct ongoing medical care (41%). Most services cited staffing (78%), clinic capacity (70%) and funding (59%) as challenges to post-TB care.ConclusionsA high proportion of UK TB clinicians recognise post-TB morbidity among their patient groups. TB services are introducing elements of post-TB care, but provision is heterogenous and often informal, with multiple resource-related challenges. Robust UK-specific data, stakeholder engagement and clear guidance are needed to support post-TB care pathways.

BackgroundTuberculosis (TB) diagnosis in the UK is impacted by delay and suboptimal culture-based microbiological confirmation rates due to the high prevalence of paucibacillary disease. We examine the real-world clinical utility of Xpert MTB/RIF Ultra (Xpert-Ultra) as a diagnostic test and biomarker of transmissible infection in a UK TB service.MethodsClinical specimens from suspected TB cases triple tested (smear microscopy, mycobacterial culture and Xpert-Ultra) at University Hospitals of Leicester NHS Trust (1 March 2018–28 February 2019) were retrospectively analysed. Diagnostic sensitivity and specificity were calculated using positive MTB culture and clinical TB diagnosis as reference standards. The QuantiFERON (QFT) positive proportion of pulmonary TB (PTB) contacts was used as a metric of transmitted infection to evaluate Xpert-Ultra and smear grade as markers of infectiousness.Results251 samples (188 respiratory) from 231 patients (86 TB) were analysed. Compared with microscopy, Xpert-Ultra had higher diagnostic sensitivity (24.7% vs 78.7%, p<0.001) and comparable specificity (97.5% vs 99.4%). Xpert-Ultra and culture had comparable sensitivity (78.7% vs 71.9%) and specificity (99.4% vs 100.0%). Incorporating Xpert-Ultra with culture increased microbiologically verified diagnosis to 91.7% for PTB and 75.9% for extrapulmonary TB, compared with 85.0% and 44.8%, using culture alone. In PTB, both smear and Xpert-Ultra grade were positively associated with the proportion of contacts testing QFT positive. However, Xpert-Ultra had a higher negative predictive value than smear (QFT-positive contacts 6.7% vs 17.7%).ConclusionIn low-TB-burden settings, systematic adoption of Xpert-Ultra for clinical assessment of suspected TB can improve the proportion of microbiologically verified diagnoses and improve the stratification of transmission risk.

While a subgroup of patients with exacerbations of chronic obstructive pulmonary disease (COPD) clearly benefit from antibiotics, their identification remains challenging. We hypothesised that selective assessment of the balance between the two dominant bacterial groups (Gammaproteobacteria (G) and Firmicutes (F)) in COPD sputum samples might reveal a subgroup with a bacterial community structure change at exacerbation that was restored to baseline on recovery and potentially reflects effective antibiotic treatment. Phylogenetically specific 16S rRNA genes were determined by quantitative real time PCR to derive a G:F ratio in serial sputum samples from 66 extensively-phenotyped COPD exacerbation episodes. Cluster analysis based on Euclidean distance measures, generated across the 4 visit times (stable and exacerbation day: 0,14 and 42) for the 66 exacerbation episodes, revealed three subgroups designated HG, HF, and GF reflecting predominance or equivalence of the two target bacterial groups. While the other subgroups showed no change at exacerbation, the HG cluster (n = 20) was characterized by G:F ratios that increased significantly at exacerbation and returned to baseline on recovery (p<0.00001); ratios in the HG group also correlated positively with inflammatory markers and negatively with FEV1. At exacerbation G:F showed a significant receiver-operator-characteristic curve to identify the HG subgroup (AUC 0.90, p<0.0001). The G:F ratio at exacerbation can be determined on a timescale compatible with decisions regarding clinical management. We propose that the G:F ratio has potential for use as a biomarker enabling selective use of antibiotics in COPD exacerbations and hence warrants further clinical evaluation.