Search Results (113)

Tuberculosis (TB) treatment is severely hampered by the rise in multi-drug-resistant strains and the prevalence of drug-induced toxicities. Host-Directed Therapies (HDTs) have emerged as a promising strategy to overcome these challenges by modulating innate immunity and circumventing Mycobacterium tuberculosis (Mtb) evasion mechanisms. A hallmark of Mtb pathogenesis is the arrest of phagosome maturation and the induction of host cell necrosis over protective apoptosis. In this study, we investigated the potential HDT effects of α-Lipoic acid (α-LA), a well-known antioxidant and metabolic cofactor, within an in vitro model of Mtb-infected THP-1 macrophages. Our findings indicate that α-LA treatment modulates the macrophage redox state and selectively promotes apoptosis in infected cells without increasing necrotic lysis. Furthermore, α-LA administration led to a significant, dose-dependent restoration of phagolysosome acidification, effectively reversing the maturation blockade imposed by Mtb. Notably, this enhanced acidification inversely correlated with intracellular bacterial survival. These results suggest that α-LA might act as a multifaceted HDT agent capable of restoring both host-protective cell death and phagosomal microbicidal mechanisms. Given its established safety profile and its ability to complement standard anti-TB drugs like Bedaquiline (BDQ), α-LA represents a highly promising candidate for adjunct therapy to improve TB treatment outcomes and mitigate the impact of antibiotic resistance. Full article

Zoonotic tuberculosis (zoonotic TB) caused by Mycobacterium bovis (M. bovis) accounts for up to 10% of human tuberculosis cases in some regions, but the underlying pathogenic mechanisms remain incompletely understood, especially those involved in cellular pyroptosis. This study aimed to explore the regulatory roles of non-coding RNA (ncRNA) in the pyroptosis of human monocytic THP-1 cells induced by M. bovis infection. An in vitro pyroptosis model was established by infecting THP-1 cells with M. bovis, followed by whole-transcriptome sequencing to identify differentially expressed messenger RNA (mRNA), long non-coding RNA (lncRNA), microRNA (miRNA), and circular RNA (circRNA). Bioinformatics analysis was performed to construct an lncRNA–miRNA–mRNA regulatory network associated with infection-induced pyroptosis; in addition, overexpression, knockdown, and dual-luciferase reporter assays and quantitative PCR were conducted to verify the interactions and functions of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), miR-20b-5p, and purinergic receptor P2X7 (P2RX7). Transcriptome analysis detected 741 mRNAs, 1049 lncRNAs, 25 circRNAs, and 40 miRNAs with significant differential expression in infected THP-1 cells. Specifically, MALAT1 and P2RX7 were upregulated, while miR-20b-5p was downregulated after infection. Knockdown of MALAT1 or P2RX7 and overexpression of miR-20b-5p relieved M. bovis-induced pyroptosis in THP-1 cells. Mechanistically, MALAT1 targeted miR-20b-5p, which directly targeted P2RX7, and overexpression of miR-20b-5p partially reversed P2RX7 upregulation mediated by MALAT1 overexpression. This study provides a transcriptomic characterization of M. bovis-induced pyroptosis in THP-1 cells and supports the MALAT1–miR-20b-5p–P2RX7 axis as a potential regulatory mechanism involved in this process, offering initial molecular insights into the pathogenesis of zoonotic TB. Full article

Glaucoma is a chronic progressive optic neuropathy and one of the leading causes of irreversible blindness worldwide. Although elevated intraocular pressure remains the most important modifiable risk factor, increasing evidence suggests that immune dysregulation and autoimmune responses also contribute substantially to disease onset and progression. Clinical studies across different glaucoma subtypes have identified subtype-dependent immune abnormalities, including altered serum autoantibody profiles, dysregulated cytokine and chemokine expression, and changes in peripheral immune cell subsets. Experimental and translational studies further indicate that multiple immunopathogenic mechanisms are involved in glaucomatous neurodegeneration, including glial cell-mediated immune responses, activation of pattern recognition receptor signalling pathways, adaptive immune responses, and complement cascade dysregulation. These processes may interact to sustain chronic neuroinflammation, promote retinal ganglion cell injury, and accelerate optic nerve degeneration. Importantly, a better understanding of immune involvement in glaucoma has generated growing interest in immunomodulatory therapy as a potential strategy beyond intraocular pressure lowering. Targeting microglial activation, inflammatory signalling pathways, adaptive immune imbalance, and complement-mediated injury has shown neuroprotective potential in animal or in vitro models, whereas clinical evidence in glaucoma patients remains limited. These findings may provide preliminary directions for future therapeutic development. In this review, we summarise the current clinical evidence linking glaucoma with autoimmunity, discuss the major immune mechanisms implicated in disease pathogenesis, and highlight recent advances in immunomodulatory therapeutic strategies. Elucidating the immune basis of glaucoma may help pave the way for more precise and effective treatments for this complex optic neuropathy. We believe that immune dysregulation in glaucoma functions as a context-dependent amplifier of retinal ganglion cell injury rather than a uniform primary driver, with innate (microglia/astrocytes), adaptive (T/B cells, HSP-specific immunity), and complement pathways interacting to sustain neuroinflammation and neurodegeneration. This integrated immune response contributes to subtype- and stage-specific vulnerability, and targeting these maladaptive immune mechanisms represents a promising, precision-guided strategy for neuroprotection beyond intraocular pressure lowering. Full article

Chronic obstructive pulmonary disease (COPD) and pulmonary tuberculosis (TB) are major causes of morbidity and mortality worldwide. Epidemiologic studies indicate an increased risk of tuberculosis in patients with COPD; however, the shared molecular mechanisms underlying the pathogenesis of these two diseases remain insufficiently understood. Objective. Based on a comparative bioinformatics analysis of peripheral blood transcriptomic profiles in patients with COPD and pulmonary tuberculosis, to identify common systemic immune mechanisms associated with the pathogenesis of both diseases. Gene expression data from the NCBI GEO public database were analyzed. GSE34608 included blood samples from 8 patients with tuberculosis and 18 healthy controls. The GSE76705 dataset contained peripheral-blood samples from 364 former smokers (225 with COPD and 139 without). Functional enrichment (GO Biological Process and KEGG) was run in ShinyGO; protein–protein interaction networks were built in STRING, and the top-15 hub genes were ranked by the MCC algorithm in CytoHubba. In tuberculosis, 892 up-regulated and 1448 down-regulated genes were identified; in COPD, 520 up-regulated and 1329 down-regulated. Common upregulated DEGs are involved in toll-like receptor signaling pathways, NOD-like receptor signaling pathways, neutrophil extracellular trap (NET) formation, phagosomes, and tuberculosis. Downregulated genes in each of the diseases were associated with processes of transcriptional regulation and RNA metabolism, which may indicate common transcriptional abnormalities in COPD and tuberculosis. COPD and tuberculosis share common pathogenic mechanisms, including the activation of innate immune signaling pathways (TLR, NOD), neutrophilic inflammation, the formation of neutrophil extracellular traps (NETosis), and phagocyte dysfunction. The identified common genes and signaling pathways may serve as a basis for the development of biomarkers and therapeutic targets; however, they require further validation in independent cohorts. 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

Pediatric tuberculosis (TB) remains a critically underrecognized contributor to global childhood morbidity and mortality, with the highest burden concentrated in low-resource settings. Although children comprise a minority of overall TB cases, mortality is disproportionately high, particularly among those under five years of age, driven largely by delayed diagnosis, inadequate linkage to care, and limited access to effective treatment. The continued rise of pediatric multidrug-resistant TB (MDR-TB), especially in regions with low sociodemographic development, further highlights persistent gaps in current control strategies. This review synthesizes key aspects of pediatric TB pathogenesis and host immune responses that predispose young children to rapid disease progression and severe outcomes, including immune immaturity and paucibacillary infection. We summarize pulmonary and extrapulmonary disease manifestations and identify populations at heightened risk, including children with HIV, malnutrition, type 1 diabetes mellitus, and congenital or treatment-related immunosuppression. Ongoing challenges in diagnosis and treatment are discussed, including limitations of existing microbiologic and immunologic tests, specimen collection constraints, regimen toxicity, and barriers to adherence. Prevention remains central to reducing pediatric TB mortality. We highlight the sustained importance of bacille Calmette–Guérin (BCG) vaccination in preventing severe disease and death, the context-dependent variability in vaccine effectiveness, and the structural and socioeconomic determinants of vaccine coverage. We conclude that integrating equitable vaccine delivery, scalable preventive therapy, and child-adapted diagnostic strategies is essential to meaningfully reduce the global pediatric TB burden. Full article

Immune dysregulation is a hallmark of human immunodeficiency virus (HIV) infection, characterized by persistent immune activation and systemic inflammation that drive T cell exhaustion and senescence, contributing to disease progression and non-AIDS comorbidities, most notably tuberculosis (TB). With rising HIV prevalence, the incidence of HIV-TB co-infection continues to rise, highlighting the need to understand their immunopathological interplay. This narrative review aims to examine the association between immune dysregulation in HIV-TB co-infection, with a focus on cytokine profiles and immunological biomarkers. Relevant literature was retrieved from multiple databases, with evidence demonstrating differential expression of cytokines—IL-17A, IFN-γ, TNF, IL-10, IL-6, IL-4, and IL-2—and T cell activation markers, such as CD38 and HLA-DR on CD4⁺ T cells in latent and active TB among HIV-infected individuals. These immune mediators are consistently co-expressed at higher levels in active TB compared to latent TB, suggesting heightened immune activation of both innate and adaptive immune responses in HIV-TB co-infection. However, these findings are largely based on observational data, and the precise mechanism by which cytokine and T cell biomarker dysregulation contributes to HIV-TB pathogenesis remains incompletely understood, underscoring the need for larger, mechanistic studies to address these gaps in the pathogenic pathway. Full article

Sjögren’s disease (SjD), which is also known as Sjögren’s syndrome (SS), is a chronic autoimmune disease characterized by dysfunction of exocrine glands, such as the salivary and lacrimal glands, resulting in xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Mice in which the SATB1 gene is conditionally deleted in hematopoietic cells (SATB1cKO mice) develop SS as early as 4 weeks of age; however, the etiology of the disease remains to be elucidated. Here, we found that the frequency of abnormally appearing CD4⁺CD8⁺ double positive (DP) T cells in the periphery of SATB1cKO mice was higher in the salivary glands than that in the spleen, suggesting a possible involvement of DP T cells in the pathogenesis of SS in SATB1cKO mice. To investigate the nature of DP T cells, we established DP T cell hybridomas by fusing T cells from the cervical lymph nodes of SATB1cKO mice with the BW5147 thymoma cell line. Among six DP hybridoma clones, the TCRβ gene from five clones exhibited a fetal or immature phenotype. In addition, four out of five clones exhibited upregulated transcription of IL-2 in the salivary glands of T/B cell-deficient RAG2^−/− mice, suggesting that autoreactive T cells were enriched in the DP T cell population of SATB1cKO mice. These results suggest that unusual DP T cells in SATB1cKO mice may be involved in autoimmune pathogenesis in SATB1cKO mice. Full article

Toxin–antitoxin (TA) modules represent sophisticated regulatory networks that have evolved from simple plasmid maintenance factors into multifunctional genetic modules orchestrating bacterial stress responses, pathogenesis, and ecological adaptation. This review highlights a compelling correlation between the abundance of toxin–antitoxin (TA) modules and bacterial pathogenicity, as exemplified by Mycobacterium tuberculosis (M.tb), which encodes 118 TA loci—significantly more than the fewer than 10 found in closely related saprophytic species. The clinical significance of TA modules extends beyond traditional stress response roles to encompass antimicrobial persistence, where systems like VapBC and MazEF facilitate dormant subpopulations that survive antibiotic therapy while maintaining chronic infections. Recent discoveries have revealed TA modules as sophisticated bacterial defense mechanisms against bacteriophage infection, with DarTG and ToxIN systems representing novel antiviral immunity components that complement CRISPR-Cas and restriction–modification systems. The immunomodulatory capacity of TA modules demonstrates their role in host–pathogen interactions, where systems such as VapC12 in M.tb promote macrophage polarization toward permissive M2 phenotypes while inducing anti-inflammatory cytokine production. Large-scale genomic analyses reveal that TA modules function as drivers of horizontal gene transfer networks, with their signatures enabling accurate prediction of plasmid community membership and serving as determinants of microbial community structure. The biotechnological applications of TA modules have expanded to include genetic circuit stabilization, biocontainment device construction, and multi-species microbial community engineering, while therapeutic strategies focus on developing multi-target inhibitors against conserved TA protein families as promising approaches for combating drug-resistant bacterial infections. The evolutionary conservation of TA modules across diverse bacterial lineages underscores their fundamental importance as central organizing principles in bacterial adaptation strategies, where their multifunctional nature reflects complex selective pressures operating across environmental niches and host-associated ecosystems. This review provides an integrated perspective on TA modules as dynamic regulatory elements that support bacterial persistence, immune evasion, and ecological versatility, establishing them as genetic elements with truly “many faces and functions” in prokaryotic biology. Full article

Background and Objectives: Preterm birth (PTB) imposes a substantial medical and economic burden on perinatal care. Recent advances in 16S rRNA gene sequencing help detailed microbiota analysis. Understanding microbiota’s contribution may help in understanding PTB pathogenesis. We aim to investigate the microbiota profiles of the oral, vaginal, and placental microbiota in pregnant Japanese women hospitalized for care of preterm labor and examine the association between them and perinatal outcomes. Materials and Methods: This cross-sectional study included 20 pregnant Japanese women admitted to a single perinatal center for preterm labor between 2022 and 2023. Oral, vaginal, and placental samples were collected aseptically during hospitalization. The patients were retrospectively categorized into: term birth (TB, n = 10), chronic abruption-oligohydramnios sequence (CAOS, n = 3), and PTB without CAOS (PTB, n = 7) perinatal outcomes. Microbiota profiles were analyzed using 16S rRNA gene sequencing, and group comparisons were performed using univariate statistical methods. Results: Alpha or beta diversity of the oral and vaginal microbiota among the three groups did not differ significantly. CAOS and PTB groups showed a trend toward altered vaginal microbial composition, but not the TB group. In the placental microbiota, beta diversity differed significantly among the TB, PTB, and CAOS groups. Ureaplasma urealyticum was more abundant in the PTB group, whereas Ureaplasma parvum was more abundant in the CAOS group. Conclusions: A potential shift in the vaginal microbiota and alterations in the placental microbiota, observed in PTB, including CAOS, suggested a possible microbial contribution. Full article

Alzheimer’s disease (AD) is a complex neurodegenerative disease. The pathogenesis of AD remains incompletely understood. It is characterized by a variety of neuropathological changes, including neuroinflammation, neuronal loss and synaptic damage. Multiple pathological changes make achieving good therapeutic effects with a single drug treatment difficult, and using multiple drugs for combination therapy is currently the most effective method. Currently, the mainstay drugs used for AD treatment are hydrophobic drugs, such as curcumin, donepezil, and resveratrol. Because hydrophobic drugs cannot dissolve in bodily fluids and often aggregate or precipitate, their efficacy is greatly reduced. Therefore, there is an urgent need for a drug carrier that can effectively load and continuously release drugs. However, currently, there are few drug carriers that can achieve efficient co-loading of multiple hydrophobic drugs. Therefore, three of two-dimensional imine covalent organic frameworks (COFs) with different monomers were synthesized through rational design and screening. These three synthesized COFs are simultaneously loaded with curcumin (CUR) and benzofurazan (BZ) to achieve combined therapy. The results indicate that among this series of synthesized COFs, the COF synthesized from 4,4′,4″-(1,3,5-Triazine-2,4,6-triyl) trianiline and benzene-1,3,5-tricarboxaldehyde (COF-TB) exhibits optimal hydrophobic drug-loading capacity, enabling effective co-loading of CUR and BZ (BC@COF-TB). After treatment with BC@COF-TB, the cognitive function of 5×FAD mice was significantly improved. The COF platform provides a new way to deliver hydrophobic drugs for AD treatment. Full article

Understanding how HIV-1 pathogenesis affects systemic and TB specific immunity in the setting of latent (LTBI+) compared to active TB infection could provide actionable insights for the prevention of reactivation. Fifty HIV-seronegative and 112 HIV-1-positive anti-retroviral therapy (ART)-naïve participants were stratified as LTBI+ (n = 35), active TB+ (n = 22) and non-coinfected (n = 55) based on an interferon gamma release assay (IGRA) and clinical confirmation prior to receiving TB therapy. Systemic and TB-specific (DosR and Rpf) immune monitoring of cellular subsets, together with multi-analyte plasma analysis, was carried out. Pursuant to isoniazid prophylaxis therapy (IPT) and ART initiation, HIV-1-positive LTBI+ participants (HLTBI+) were followed for up to two years. Before ART initiation, HLTBI+ individuals exhibited the lowest levels of circulating intermediate monocytes, T-cell activation and PD-1 expression, with a decreased frequency of T-regulatory cells and higher circulating IL-10 and IL-17A. PD-1 expression on CD4+ T cell memory subsets, together with opposing anamnestic TNF-α responses to DosR and Rpf, was a discriminatory signature for the HLTBI+ group, as was preserved (following ART) TB-specific TNF-α production, which positively correlated with the CD4/CD8 ratio. Our results highlight an immunomodulatory phenotype conferred by latent TB infection in PLHIV, whose preservation may provide strategies to mitigate TB reactivation. Full article

Tuberculosis (TB), primarily caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of infectious disease mortality worldwide. Global TB control efforts face several hurdles, including the lack of a broadly effective vaccine, limited sensitivity of current diagnostics, particularly for paucibacillary and extrapulmonary TB, and significant adverse effects associated with prolonged small-molecule drug regimens. The growing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains further underscores the urgent need for innovative therapeutic strategies. We outline characteristics of next-generation TB therapeutics. We show that antibody (Ab)-drug conjugates (ADCs) satisfy many of those desirable characteristics. Since a major hurdle to this approach lies in Mtb-specific Abs, we highlight an open-access resource comprising a broad panel of Mtb-specific mouse monoclonal antibodies targeting key factors involved in Mtb survival, immune evasion, and pathogenesis. These critical Mtb virulence factors include heat shock proteins (GroES, DnaK, and HspX), surface-associated or secreted proteins (LAM, Ag85, HBHA, Mpt64/CFP-21, and PhoS1/PstS1), cell wall/envelope-associated proteins (LprG/p27), and detoxifying enzymes (KatG and SodA). The resource provides full-length sequences of the immunoglobulin variable regions, enabling antibody engineering and facilitating translational TB research across vaccine design, diagnostic development, and immunotherapeutic applications, in addition to ADCs. This ADC targeted delivery strategy holds promise for overcoming TB heterogeneity and eliminating both active and dormant Mtb populations within a single therapeutic formulation and offers a novel avenue for precision TB treatment. Full article

Mast cells (MC) are key effector cells in allergic diseases and are increasingly recognized for their roles in the immunopathogenesis of tuberculosis (TB). In allergic conditions, MCs are hyperactivated, driving T-helper Type 2 (Th2)-skewed immune responses that may antagonize the T-helper Type 1 (Th1)-mediated immunity essential for controlling Mycobacterium tuberculosis (Mtb) infection. This immunological imbalance may contribute to increased TB susceptibility, altered granuloma dynamics, and accelerated fibrotic remodeling. Histopathological and in vivo studies have revealed that MCs are recruited to TB lesions, where they release a spectrum of mediators, including histamine, IL-17A, TNF-α, TGF-β, tryptase, and chymase. These mediators can either support initial immune defense or promote chronic inflammation and tissue damage, depending on context and regulation. Moreover, individuals with chronic allergic diseases such as asthma and allergic rhinitis may experience worse TB outcomes due to their baseline immune dysregulation. Environmental exposures (e.g., air pollution, smoking), genetic polymorphisms (e.g., IL-4 −589C/T, IL-13 R130Q), and gut-lung axis disturbances further modulate MC activity and TB pathogenesis. This review synthesizes current findings on MC involvement in TB, particularly in allergic settings, and highlights the need for epidemiological studies and mechanistic research. It also explores the promise of host-directed therapies (HDTs) that target MCs or their mediators, such as antihistamines, MC stabilizers, leukotriene inhibitors, and cytokine modulators, as novel adjuncts to standard TB treatment. Personalized approaches that consider immune profiles, genetic risk, and comorbid allergies may improve TB outcomes and inform future clinical guidelines. Full article

Mycobacterium tuberculosis—an acid-fast staining bacterium—is a serious global health challenge that can have both short-term and long-term complications. Although the immune response helps trap the infection, it can also cause necrosis and calcification, leading to lung tissue damage. Calcification is a known outcome of chronic granuloma evolution in TB. Multiple pathways contribute to fibrosis and calcification; some examples are IL-1β, TGF-β, and TNF-α. Current antifibrotic drugs, such as nintedanib and pirfenidone, are effective but may increase the risk of latent tuberculosis reactivation in certain patients. Experimental therapies such as artemisinin derivatives have shown promise in preclinical TB fibrosis models, while cell-based therapies like bone marrow-derived mononuclear cells are also under early investigation for dual antifibrotic and immunomodulatory effects. This literature review will explore recent studies on the pathogenesis of M. tuberculosis, the mechanisms underlying calcification in granuloma formation, and subsequent complications of the disease process. Full article