Despite recent advances, tuberculosis (TB) remains a complex global health challenge, with its causative bacterium, Mtb, actively manipulating host cellular metabolism to survive. Therefore, studying mitochondrial metabolism-related genes is crucial, as they offer a promising avenue for identifying diagnostic biomarkers and developing new host-directed therapies to combat the disease. This study integrated transcriptomic datasets from three TB cohorts in the Gene Expression Omnibus (GEO) database (training set: GSE83456; validation sets: GSE42826 and GSE19444). Differential analysis was performed using the “limma” package (with |logFC| > 1 and adjusted p-value < 0.05) to identify mitochondrial metabolism-related differentially expressed genes. Diagnostic biomarkers were determined by combining weighted gene co-expression network analysis (WGCNA), and the effectiveness of the model was evaluated using receiver operating characteristic (ROC) curve analysis. Immune infiltration characteristics were assessed via single-sample gene set enrichment analysis (ssGSEA) and Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), pathway enrichment analysis was conducted through GSEA, molecular subtypes were classified using the non-negative matrix factorization (NMF) algorithm, and MicroRNA (miRNA) and transcription factor (TF) regulatory networks were predicted using “miRNet” and “NetworkAnalyst”. We identified 3 mitochondrial metabolism-related biomarkers (TYMP, SCO2, GK) with remarkable diagnostic performance (area under the curve [AUC] = 0.973 across cohorts). These genes were closely associated with altered immune infiltration patterns, characterized by enhanced inflammatory responses in macrophages and monocytes, along with a reduction in T-cell subsets. These genes are associated with ribosome and innate immune pathways. Furthermore, tuberculosis patients were stratified into two distinct molecular subtypes exhibiting specific immune microenvironment features. Regulatory network analysis revealed hsa-miR-10b-5p and transcription factor hubs (SP3/SP1) as potential master regulators. This study identifies a mitochondrial metabolism-based gene signature for TB diagnosis, revealing novel host-pathogen mechanisms and enabling potential targeted therapies for precision medicine. Identification of a 3-gene diagnostic signature: The study reveals TYMP, SCO2, and GK as mitochondrial metabolism-related biomarkers for tuberculosis, achieving exceptional diagnostic accuracy (AUC = 0.973) across multiple cohorts. Immune microenvironment dysregulation: TB patients exhibit heightened pro-inflammatory responses in macrophages/monocytes alongside reduced adaptive T-cell subsets, providing new insights into the host-pathogen interaction. Molecular subtyping and regulatory networks: Two distinct TB subtypes with divergent immune profiles were identified, alongside novel miRNA (hsa-miR-10b-5p) and transcription factor (SP3/SP1) hubs regulating the diagnostic genes, offering targets for precision therapies.
Selective autophagy of the endoplasmic reticulum (ER-phagy) maintains intracellular homeostasis by selectively removing damaged ER membranes and contained misfolded proteins. This review delineates the core molecular mechanisms of canonical autophagy, then systematically describes three types of ER-phagy (macro-ER-phagy, micro-ER-phagy, and vesicular ER-phagy), their signature receptors, subdomain specificities, and regulatory mechanisms, alongside a comparative analysis of the evolutionary divergence between yeast and mammalian ER-phagy receptor systems. At the direct regulation level, diverse intracellular pathogen strategies targeting ER-phagy receptors are examined, including proteasomal degradation and spatial sequestration of FAM134B by viruses, non-canonical micro-ER-phagy hijacking by retroviruses, constitutive antiviral defense mediated by FAM134B against Ebola virus, and bidirectional modulation of this receptor by bacterial effectors and pathogen-associated molecular patterns. At the indirect regulation level, intracellular pathogen-mediated perturbation of upstream nodes—including the UPR, ERAD, ER-RQC/UFMylation, and core macroautophagy machinery—is summarized. These findings underscore the dual role of ER-phagy as both a host defense barrier and a target for pathogen exploitation, providing novel insights into intracellular pathogenic mechanism.
The understanding of host responses to pulmonary infection with non-tuberculous mycobacteria (NTM) is incomplete and immunodiagnostic tools are not established. Unlike mycobacteria of the Mycobacterium tuberculosis complex, several NTM express glycopeptidolipids (GPLs) in their cell wall. Here, we investigate the interferon-γ response to mycobacterial GPLs and its diagnostic use in patients with pulmonary NTM infection. M. avium-derived GPLs were used for in vitro stimulation of peripheral blood mononuclear cells in an ELISpot assay of patients with pulmonary NTM infection and 3 control groups, (1) patients with tuberculosis (TB), (2) patients with cystic fibrosis without evidence of NTM infection (CF) and (3) healthy controls (HC). Immune responses were compared between the groups and for the subgroup of NTM patients with either M. avium complex (MAC) or M. abscessus complex (MABC). Interferon-γ responses of 31 patients with NTM (16 MABC, 11 MAC, 1 MABC MAC, and 3 other NTM) were compared to 43 controls (15 TB, 15 CF, 13 HC). Responses to GPLs were significantly stronger in the NTM group compared to controls (13.5 vs. 1.5 spots per 300,000 PBMC, p < 0.0001, data represent median values). MAC patients had an overall stronger reaction than MABC patients. Assay sensitivity and specificity were 64 and 98
Pentatrichomonas hominis (P. hominis), a protozoan inhabiting the cecum and colon of humans and vertebrates, is associated with diarrhea. The innate immunity plays a crucial role in defending against parasitic infections. Among these, macrophages are involved in immune evasion, immune surveillance, and tissue repair. Parasites alter the host’s immune homeostasis by modulating macrophage polarization. However, the regulation of macrophage polarization by P. hominis remains unreported. Herein, we found that co-incubation of peritoneal macrophages with P. hominis for 6 h increased CD11c expression, IL-6 and IL-12 levels, and NF-κB p65 phosphorylation. After 24 h of co-culture, CD206 and PPAR-γ expression, as well as IL-4 and IL-10 levels, were elevated in peritoneal macrophages. PPAR-γ agonist GW1929 increased expression of CD206, PPAR-γ, IL-4, and IL-10 in peritoneal macrophages and cecal tissue induced by P. hominis, whereas PPAR-γ antagonist GW9662 had the opposite effect. In mice, GW1929 was validated to alleviate inflammation and injury, whereas GW9662 exacerbated them. Taken together, this study first unveiled that P. hominis modulates macrophage polarization in vitro and that PPAR-γ is associated with this process. GW1929 treatment alleviates inflammation and pathological damage caused by P. hominis infection. These findings provide insights and evidence for further investigation into the innate immune response against P. hominis infection in the host.
The immunogenicity of pneumococcal vaccines is commonly assessed using post-vaccination serotype-specific IgG antibody concentrations. Therefore, characterization of baseline antibody levels in vaccine-naïve populations is essential for understanding naturally acquired immunity and accurately interpreting vaccine responses. However, data on baseline serotype-specific IgG levels in healthy, unvaccinated Indian children remain limited. This study aimed to measure baseline serotype-specific pneumococcal IgG antibody levels in healthy vaccine-naïve Indian children. Baseline serotype-specific IgG antibody concentrations against 24 pneumococcal vaccine serotypes were measured in 600 healthy PCV-unvaccinated Indian children aged ≤ 5 years using the WHO-recommended ELISA method. Geometric mean concentrations (GMCs) were calculated for each pneumococcal serotype, and variations in antibody levels were analyzed according to age, gender, and season. Baseline IgG GMCs varied widely across serotypes, ranging from 0.14 µg/mL for serotype 12 F to 5.65 µg/mL for serotype 14. Overall, 71
