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At least 19 recordsLinked to original sources
PubMed2026

Genetic diversity of clinical Mycobacterium bovis BCG isolates from an immunocompromised patient with BCG infection.

BACKGROUND: The Bacillus Calmette-Guérin (BCG) vaccine is widely administered to prevent severe tuberculosis but can cause serious adverse events, including disseminated BCGosis, in immunocompromised individuals. However, studies investigating the in vivo genetic adaptation and microevolution of this live-attenuated vaccine during prolonged infection remain limited. METHODS: Two clinical Mycobacterium bovis BCG isolates (BCG01 and BCG02) and a lot-matched vaccine strain (VAC) underwent whole-genome sequencing. Phenotypic drug susceptibility testing was performed on the clinical isolates. Genomic relatedness was assessed using SNP-distance clustering and maximum-likelihood phylogeny against global reference strains. Comparative variant analysis was performed to identify mutations specific to BCG01 and BCG02 relative to VAC, and genotypic drug resistance was assessed using TB-Profiler. RESULTS: Phylogenomic analyses and SNP distance confirmed that both clinical isolates were derived from the BCG Tokyo 172 vaccine strain. BCG02 exhibited twice the mutational burden of BCG01, acquiring mutations in genes associated with cell wall biosynthesis (mas, ppsA), regulatory adaptation (pknK, dnaA), and surface antigens (pecA, PE/PPE). Crucially, whereas BCG01 remained susceptible to first-line drugs, BCG02 acquired a canonical rpoB Ser450Leu mutation (100% frequency) and a heteroresistant inhA Ile194Thr mutation (13% frequency), resulting in multidrug-resistant (MDR) BCGosis. CONCLUSION: Although structurally stable, the BCG Tokyo 172 vaccine strain can undergo rapid, clinically significant microevolution and clonal selection within immunocompromised hosts. The in vivo acquisition of multidrug resistance underscores the critical need for pre-vaccination immune screening and comprehensive laboratory monitoring of BCG-associated adverse events.

BCGosis↗
PubMed2026

The TRIM-cancer paradox: BCG as a programmable vaccine platform and a mechanistic probe for rational immunotherapy design.

BCG, a first-generation live vaccine, is being reconsidered as an immunological platform. Interest in its heterologous protection intensified during the pandemic. However, large-scale clinical trials revealed inconsistencies in the efficacy of native BCG. This review argues that BCG's main value lies in its potential as a modifiable vector platform and in its ability to reveal tractable molecular pathways for therapeutic design. This review summarizes the molecular basis of BCG-induced trained immunity (TRIM), focusing on PRR-driven signaling, metabolic rewiring, and epigenetic remodeling in innate immune cells and hematopoietic progenitors. It also maps their convergence with pathways that sustain pro-tumorigenic inflammation. The original conceptual paradigm of the "TRIM-Cancer Paradox" is presented. This paradigm posits that the same innate immune circuits that mediate protective heterologous responses can drive tumor-promoting inflammation and immune escape under conditions of chronic dysregulation. Recombinant BCG (rBCG) is further analyzed as a strategy to rationally amplify or redirect these circuits, the current clinical landscape of BCG-based interventions across various diseases and oncological malignancies is highlighted, and specific molecular nodes that could be exploited to increase the precision, efficacy, and safety of rBCG-based therapies are identified. Overall, this review proposes BCG a programmable immunological platform and to use the TRIM-Cancer Paradox as a novel design principle for next-generation rBCG platforms that transcend traditional vaccinology and cancer immunotherapy applications.

Humans↗
PubMed1976

Immunity to Mycobacterium leprae infections in mice stimulated by M. leprae, BCG, and graft-versus-host reactions.

Infections of mice with Mycobacterium leprae in one rear foot pad immunized them against a second infection in the other rear foot pad. Purified bacilli harvested from the first infection also produced immuniy when injection into the foot pads of previously uninfected mice. Injections of BCG afforded similar protection, but had no adjuvant effect on M. leprae. M. duvali, a cultivable mycobacterium that is reported to be more closely related antigenically to M. leprae than BCG is, provided much less protection against M. leprae challenge than BCG did. Moreover, when M. duvali was mixed with BCG, it was not any more effective than BCG alone. Graft-versus-host reactions, induced by injections of parental spleen cells into F1 hybrids, provided no protection against M. tuberculosis and M. marinum challenge. They gave moderate protection against M. leprae in one experiment but not in another with a different schedule. Allogenic spleen cells had a protective effect when injected locally into the infected foot pad. The effect produced by these injections of spleen cells was a delay in the appearance of bacterial growth; however, there was no decrease in the rate of logarithmic growth when it did appear and no reduction in the eventual plateau level.

Animals↗
PubMed1979

Superoxide production in pulmonary alveolar macrophages and killing of BCG by the superoxide-generating system with or without catalase.

The superoxide production of BCG-infected and noninfected alveolar macrophages was measured by superoxide dismutase-inhibitable nitro blue tetrazolium reduction. The cells were incubated with or without cell-free bronchial lavage fluid (pulmonary washings). When control alveolar macrophages were infected by BCG, superoxide production was decreased markedly, probably due to bacterial cytotoxic factors. In contrast, the production of superoxide in alveolar macrophages exposed to pulmonary washings was increased and not appreciably influenced by BCG infection. Superoxide production by alveolar macrophages was dependent on time and on the protein concentration in the pulmonary washings. In controls, it was inversely proportional to the infecting dose of BCG. We observed previously that alveolar macrophages activated by pulmonary washings inhibited intracellular growth of BCG. We now present evidence that enhanced production of superoxide contributes to such inhibition, especially in the presence of catalase at acid pH. These findings are pertinent to the defense of inflamed lungs, where serum and serum immunoglobulin G transuded from blood into alveolar spaces probably induce such activation on alveolar macrophages.

Animals↗
PubMed2024

Multilevel Proteomics Reveals Epigenetic Signatures in BCG-Mediated Macrophage Activation.

The bacillus Calmette-Guérin BCG vaccine (Mycobacterium bovis) is primarily used to prevent tuberculosis (TB) infections but has wide-ranging immunogenic effects. One of its most notable properties is its ability to induce trained immunity, a memory-like response in innate immune cells such as macrophages. Through targeted analyses of well-established histone marks, prior research has shown that these changes are generated through epigenetic modification. Mass spectrometry-based proteomic approaches provide a way to globally profile various aspects of the proteome, providing data to further identify unexplored mechanisms of BCG-mediated immunomodulation. Here we use multi-level proteomics (total, histone, and phospho to identify networks and potential mechanisms that mediate BCG-induced immunomodulation in macrophages. Histone-focused proteomics and total proteomics were performed at the University of Cape Town (data available via ProteomeXchange with identifier PXD051187), while phosphoproteomics data was retrieved from the ProteomeXchange Repository (identifier PXD013171). We identify several epigenetic mechanisms that may drive BCG-induced training phenotypes. Evidence across the proteomics and histone-focused proteomics data set pair 6 epigenetic effectors (NuA4, NuRD, NSL, Sin3A, SIRT2, SIRT6) and their substrates.

Epigenesis, Genetic↗
PubMed1979

Interferon and cytotoxic factor (cytotoxin) released in the blood of mice infected with Mycobacterium bovis BCG. I. Enhanced production of interferon and appearance of cytotoxin stimulated by capsular polysaccharide of Klebsiella pneumoniae or bacterial lipopolysaccharide.

Interferon production stimulated by the active substance (neutral fraction) of the capsular polysaccharide of Klebsiella pneumoniae (neutral CPS-K) in BCG-infected mice was compared with that by bacterial lipopolysaccharide (LPS). Prior infection with BCG increased the responsiveness of mice to the lethal effect of neutral CPS-K as well as to that of LPS. Associated with this, BCG-infected mice showed a markedly enhanced ability to produce interferon after stimulation not only by LPS but also by neutral CPS-K. In addition, a cytotoxic factor (cytotoxin) was found to be released in the serum of BCG-infected mice after injection of these inducers. The kinetics of production of interferon and cytotoxin stimulated by neutral CPS-K were very similar to those stimulated by LPS. The time pattern of cytotoxin production was not in parallel with that of interferon production. Interferon reached a peak 2 hr and cytotoxin 3 hr after injection with these inducers. Interferon and cytotoxin produced by neutral CPS-K showed essentially the same stabilities to heating at 56 C and to treatment at pH 2 respectively as those produced by LPS. Interferon was inactivated by heating at 56 C more rapidly than cytotoxin. Cytotoxin was inactivated by treatment at pH 2 for 24 hr, whereas interferon activity was well preserved after this treatment. These results suggest that both activities are the result of different substances.

Animals↗
PubMed2025

HLA-E and NKG2A Mediate Resistance to BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) is the first-line therapy for high-grade non-muscle-invasive bladder cancer (NMIBC), yet many patients experience recurrence due to immune evasion. We identify HLA-E and NKG2A as mediators of adaptive resistance involving chronic activation of NK and T cells in BCG-unresponsive tumors. Prolonged IFN-γ exposure enhances HLA-E and PD-L1 expression on recurrent tumors, accompanied by the accumulation of NKG2A+ NK and CD8 T cells. HLA-Ehigh tumor cells preferentially cluster near CXCL12-rich stromal regions with dense effector cell presence, underscoring a spatially segregated tumor architecture. Although cytotoxic lymphocytes retain effector potential, their activity is restrained by HLA-E/NKG2A and PD-L1/PD-1 pathways located in their immediate neighborhood within the bladder tumor microenvironment. These data reveal a spatially organized immune escape program that limits anti-tumor immunity. Our findings support dually targeting NKG2A and PD-L1 checkpoint blockade as a rational, bladder-sparing strategy for patients with BCG-unresponsive NMIBC.

BCG-unresponsive↗
PubMedDate not supplied

[Spleen reactivity after BCG treatement: test and strain dependency of the response].

According to the strain used, spleen cells from mice injected two weeks before with 3 mg BCG, when they are engaged in a graft-versus-host reaction show a decrease in reactivity (C57Bl/6or AKR), an increase (DBA/2, BALB/C or SJL/J) or no modification (CBA, C3H). The in vitro responsiveness to PHA and conA of the treated spleen cells was lower than controls for all the strains studied. However, nylon column purified T cells from BCG treated mice showed a dissociated response, being less stimulated than normal cells by PHA and more so by ConA.

Animals↗
PubMed2025

Assembly of the Mycobacterium tuberculosis type VII ESX-1 secretion system in Mycobacterium smegmatis identifies a new transcriptional activator of esx-1 genes and a novel TB vaccine.

Mycobacterium tuberculosis (M. tb) uses its type VII secretion system (T7SS) ESX-1 to export immunogenic, virulence-mediating protein effectors. In this study, the fast-growing, non-pathogenic model mycobacteria Mycobacterium smegmatis mc2-155 was engineered to express the M. tb T7SS ESX-1 system. We found that M. smegmatis transformed with M. tb esx-1 locus genes only, as well as M. smegmatis transformed with M. tb esx-1 and espACD operon genes (designated MSX-1), produces and secretes the M. tb ESX-1 protein effectors EsxA, EsxB, and EspB. However, the abundance of these proteins was higher inside the cell and culture filtrate of the MSX-1 strain. Although ESX-1 is critical for M. tb pathogenesis, expression of M. tb ESX-1 did not make the recombinant M. smegmatis strains virulent in macrophages. Serendipitously, transformation of M. smegmatis with a modified esx-1 locus in this study revealed rv3860, a gene of previously unknown function, to be required for the transcription of pe35, ppe68, esxB, and esxA genes. Finally, mice vaccinated with MSX-1 were found to be as protected as mice vaccinated with Mycobacterium bovis BCG against M. tb infection, without becoming sensitized to tuberculin. These results show that a functional M. tb ESX-1 system can be assembled in M. smegmatis to uncover novel facets of the secretion machinery and that the modified M. smegmatis strain can function as a tuberculosis (TB) vaccine. Unlike BCG, however, its deployment may be compatible with tests currently used to diagnose TB.IMPORTANCEIn this study, we modified Mycobacterium smegmatis, which is often used as a surrogate model organism in mycobacterial research, to produce and assemble a functional Mycobacterium tuberculosis (M. tb) ESX-1 protein secretion system. One such M. smegmatis strain named MSX-1 was found to make a functional M. tb ESX-1 system without becoming virulent. And in using M. smegmatis as a chassis to study the ESX-1 system, we found that rv3860, an M. tb gene of previously unknown function, is needed for the production of key ESX-1 proteins. Finally, mice vaccinated with MSX-1 were as protected from tuberculosis (TB) as mice given BCG, the only approved TB vaccine. Notably, we found that unlike BCG, MSX-1 does not sensitize mice to the antigens used in existing TB diagnostic tests. These observations, taken together, highlight the utility of M. smegmatis as a chassis to study the M. tb ESX-1 secretion machinery.

Mycobacterium smegmatis↗
PubMed2026

Transcriptome-based high-frequency recurrence index predicts frequent recurrence in non-muscle-invasive bladder cancer after Bacillus Calmette-Guérin therapy.

BACKGROUND: High-frequency recurrence (HfR,&#x2009;&#x2265;&#x2009;2 recurrences) in non-muscle-invasive bladder cancer (NMIBC) poses a significant clinical burden. Current risk models, such as the European Organization for Research and Treatment of Cancer (EORTC), the European Association of Urology (EAU), and the UROMOL classification, offer limited predictive accuracy for identifying patients at risk for frequent recurrence despite appropriate treatment. METHODS: A 75-gene high-frequency recurrence index (HfRI) was constructed by selecting recurrence-associated genes using differential expression and Cox regression analyses. The HfRI was computed as a weighted sum of normalized gene expression values. The model was trained on a discovery cohort and validated in multiple cohorts (n&#x2009;=&#x2009;1379) using machine-learning approaches. Clinical relevance was assessed using recurrence-free survival (RFS) and Cox models, and predictive performance was compared with that of the EORTC, EAU, and UROMOL classifications using the area under the curve (AUC) and the concordance index (c-index). RESULTS: The HfRI robustly stratified patients into high-risk and low-risk groups across six independent NMIBC cohorts. Patients classified as HfRI-high had a significantly greater likelihood of experiencing&#x2009;&#x2265;&#x2009;2 recurrences (&#x3c7;2, p&#x2009;=&#x2009;0.001) and showed markedly reduced RFS (log-rank test, p&#x2009;<&#x2009;0.001). The adverse prognostic effect of the HfRI persisted even among patients treated with BCG therapy (log-rank test, p&#x2009;=&#x2009;0.02). Multivariate analysis revealed that the HfRI was an independent predictor of HfR (HR&#x2009;=&#x2009;2.82, 95% CI&#x2009;=&#x2009;1.89-4.20, p&#x2009;<&#x2009;0.001). Compared with established clinical risk classifiers, the HfRI demonstrated superior predictive performance (AUC&#x2009;=&#x2009;0.736, c-index&#x2009;=&#x2009;0.673) in terms of the EORTC (AUC&#x2009;=&#x2009;0.594), EAU (AUC&#x2009;=&#x2009;0.557) risk groups, and UROMOL2021 (AUC&#x2009;=&#x2009;0.596) classification. Pathway analysis revealed that HfRI-high tumors were characterized by upregulation of cell cycle progression and DNA replication pathways, accompanied by suppression of immune signaling pathways. These biological features provide a mechanistic explanation for the reduced responsiveness to intravesical BCG therapy, underscoring the role of HfRI not only as a predictor of recurrence risk but also as a biomarker capable of identifying patients unlikely to benefit from standard BCG treatment. CONCLUSIONS: HfRI represents a robust, transcriptome-based tool for predicting frequent recurrence in NMIBC patients. The HfRI supports earlier identification of patients at risk of high-frequency recurrence, thereby supporting personalized treatment strategies.

Humans↗
PubMed1978

Urinary albumin determination by the immediate bromcresol green method.

It has been demonstrated recently that the reaction of serum samples with bromcresol green (BCG) reagent proceeds in two steps. Albumin is responsible for the immediate reaction while other serum proteins produce the slow reaction. In this paper the immediate BCG reaction has been used for the determination of urinary albumin concentration in patients with proteinuria by a slightly modified method with a primary pH adjustment of the urine and the use of a urine blank. Comparison of the immediate BCG method (y) with Laurell "rocket" technique (x) gave the following equation: y = 17.2 + 1.006x (n = 98; r = 0.99) mg/l. The coefficient of variation (within-day), C.V. (%), ranged between 0.9 and 2.7% depending on the albumin concentration. It is thus possible to carry out rapid, accurate and precise albumin determinations in urine samples using this simple method.

Albuminuria↗
PubMed1978

Immunotherapy of human acute leukaemia.

Conclusions are difficult to draw. In the six studies of immunotherapy of AML discussed, all the three employing BCG and cells showed a prolongation of survival and the major contributing factor to this prolongation of survival was extension of life after relapse. In the three studies using BCG alone only one shows a beneficial effect, but some more time must be allowed to elapse before this can be concluded with confidence.

Acute Disease↗
PubMed2026

Biomarker-guided selection of intravesical therapy in high-risk non-muscle invasive bladder cancer: A contemporary review.

High-risk non-muscle invasive bladder cancer poses therapeutic challenges, with significant rates of recurrence and progression with standard intravesical bacillus Calmette-Gu&#xe9;rin (BCG) therapy. Current surveillance strategies lack accurate risk stratification models to predict individual treatment response and personalized treatment options. Simultaneously, there are no well-validated alternatives to replace the current gold-standard approach based on clinical and pathologic features. This review examines emerging biomarkers and advanced technologies with the potential to enhance patient selection and personalize intravesical therapy in HR-NMIBC. Artificial intelligence(AI)-driven histopathologic tools, such as the computer histological AI biomarker, have demonstrated the ability to identify non-responders to standard therapy using whole-slide digital pathology images. In parallel, radiomics-enhanced imaging has shown promise in assessing tumor biology and immune microenvironment features predictive of BCG responsiveness. Liquid biopsy, especially urine tumor DNA analysis, is now available in the arsenal to detect minimal residual disease, stratify recurrence risk, and predict treatment response even before clinical or radiographic evidence of recurrence. Tissue-based genomic profiling has also revealed molecular alterations associated with treatment resistance, though additional validation is needed. Together, these next-generation biomarkers may represent a pivotal shift toward precision oncology in bladder cancer and their incorporation into NMIBC future clinical guidelines is both anticipated and necessary.

BCG-unresponsive disease↗
PubMed1979

Augmentation of immune responses after methotrexate administration.

A single intraperitoneal injection of 0.5 mg methotrexate (MTX) has been found to increase the immune reactivity of spleen cells from (C57B1/6 X DBA/2)F1 mice. Five days after injection, spleen cells from MTX-treated mice exhibited greater PHA responsiveness and GvH reactivity, and mice given SRBC at this time developed greater than normal direct PFC responses. This pattern of effects of MTX was particularly evident in mice that had been given high doses of BCG intravenously 14 days before testing, a treatment that generally depressed the measured activities. MTX enhancement of GvH was also observed in mice that had been depleted of short-lived T lymphocytes by adult thymectomy. We suggest that MTX-sensitive cells possible exert, particularly in BCG-treated mice, a suppressive action on the responding cells.

Animals↗