Pathogenesis Of Tuberculosis Research Articles

The role of antibiotic-derived mycobacterial vesicles in tuberculosis pathogenesis.

Pulmonary tuberculosis (TB) causes progressive and irreversible damage to lung tissue, a damage that may not fully resolve after treatment. Mycobacterial vesicles (MVs), which are poorly understood, may contribute to TB pathology. This study investigated the effects of stress, such as treatment with conventional TB antibiotics rifampicin, isoniazid, ethambutol, or treatment with an antimycobacterial peptide (NZX), on mycobacterial vesiculation. Stress from minimal inhibitory concentrations of antibiotics, or peptide all increased MV formation. Electron microscopy and lipid profiling revealed that these vesicles, about 40nm in size, were released from the bacterial inner membrane and consisted of apolar lipids. Using mass spectrometry, the study identified key differences in MVs protein cargo dependent on the antibiotic used, especially with ethambutol-induced MVs that contained proteins from several mycobacterial pathways. Additionally, toxicology analysis using different concentrations of MVs on primary human macrophages and the monocytic cells indicated that MVs from the different treatments were not toxic to human cells, however induced specific inflammatory profiles. In conclusion, this study identified mycobacterial vesicles to be a potential contributor to tuberculosis pathology.

Treatment course of cavitary pulmonary tuberculosis combined with tuberculosis in a parotid Warthin's tumor: a case report and literature review.

Extrapulmonary tuberculosis (TB) is a relatively rare form of tuberculosis infection, accounting for approximately 15% of all tuberculosis infections. Lymph nodes are the most commonly affected sites, while involvement of the parotid gland is extremely rare. We present the case of a 65-year-old male patient with a one-month history of a left parotid mass. The patient has a history of diabetes and long-term smoking, and a chest X-ray revealed secondary fibrotic pulmonary tuberculosis, while sputum smears were culture-negative for Mycobacterium tuberculosis (Mtb). The parotid mass was surgically removed and subjected to routine HE staining, acid-fast staining, and PCR molecular testing for Mtb. The final diagnosis was Warthin's tumor of the parotid gland with concomitant tuberculosis. One month after removal of the parotid mass, the patient's chest CT showed cavitary tuberculosis. Subsequently, the patient received anti-tuberculosis treatment; however, due to severe gastrointestinal adverse effects, the patient stopped the medication in less than a month and did not receive regular treatment. Four months after stopping the medication, the patient's pulmonary tuberculosis progressed and worsened. Combined tuberculosis in Warthin's tumor is extremely rare, with only 14 cases reported to date. However, the specific pathogenesis of this condition is not yet fully understood, and the preliminary treatment and prognosis have not been conclusively determined. Early diagnosis of tuberculosis, standardized and effective use of anti-tuberculosis drugs, and personalized treatment are crucial in the management of tuberculosis. We have reviewed the treatment progress of this rare disease and analyzed the potential pathogenesis of the condition. Furthermore, we have summarized the current understanding of the pathogenesis of tuberculosis, drug resistance mechanisms, and the latest treatment advances. These studies have important clinical implications for better understanding and treating extrapulmonary tuberculosis and tuberculosis within Warthin's tumor of the parotid gland. This comprehensive analysis sheds light on the complexities of tuberculosis and provides valuable insights for improved management and care of affected individuals.

Discovery of a blood-based miRNA signature that can predict onset of active tuberculosis among household contacts of TB patients

BackgroundNon-sputum based predictive biomarkers capable of identifying individuals with high risk of progression to active tuberculosis (TB) are critical for global TB control. MicroRNAs (miRNAs) are significant regulators involved in TB pathogenesis and hence we aimed to identify a miRNA signature capable of predicting progression to TB disease.MethodsWe compared the differential miRNA expression profile of QuantiFERON supernatants of TB Progressors, defined as healthy household contacts (HHCs) of TB patients, who developed active TB disease during a 2-year follow-up period, and Non-progressors defined as HHCs from the same longitudinal cohort who did not develop TB disease during the entire follow-up period, using the nanostring nCounter platform. Receiver Operator Characteristic (ROC) analysis was performed to evaluate the diagnostic accuracy of the identified miRNA biomarkers, followed by random forest analysis to determine the best predictive model.ResultsWe identified 30 differentially regulated miRNAs between the two groups. Of these, hsa-miR-585-3p and hsa-miR-92a-3p were up-regulated with a maximum fold change of 1.74 and 1.71 respectively, while hsa-miR-223-3p and hsa-miR-451a were down-regulated by −2.05 and −2.04 fold respectively. Random forest analysis revealed that hsa-miR-181a-5p, hsa-miR-204-5p, hsa-miR-197-3p, hsa-miR-92a-3p, hsa-miR-451a, hsa-miR-24-3p, and hsa-miR-487a-3p exhibited 100% accuracy in identifying Progressors. This panel of 7 miRNAs demonstrated excellent diagnostic performance characteristics with 100% sensitivity and specificity.ConclusionWe propose that the identified miRNA signature has the potential to serve as a very useful tool for early identification of individuals who bear the highest risk of progression to TB, so that they can be targeted for timely intervention.

Therapeutic potential of mesenchymal stem cells and stem cell-derived extracellular vesicles in tuberculosis of various localizations: A review

Experimental and clinical studies using cell therapy are very popular. Mesenchymal stem cells (MSCs) and stem cell-derived extracellular vesicles (EV) are used as one of the components of therapy in these researches. The action of MSCs is mediated by the release of EV which play a direct role in the implementation of several important biological processes: angiogenesis, proliferation, modulation of the inflammatory process and immune response, inhibition of cellular apoptosis, etc. These properties of MSCs and stem cell-derived EV are of interest in the treatment of tuberculosis infection, because an integral part of the pathogenesis of tuberculosis is the creation of specific granulomas and the formation of fibrosis.

Fatty acid metabolism in neutrophils promotes lung damage and bacterial replication during tuberculosis.

Mycobacterium tuberculosis (Mtb) infection induces a marked influx of neutrophils into the lungs, which intensifies the severity of tuberculosis (TB). The metabolic state of neutrophils significantly influences their functional response during inflammation and interaction with bacterial pathogens. However, the effect of Mtb infection on neutrophil metabolism and its consequent role in TB pathogenesis remain unclear. In this study, we examined the contribution of glycolysis and fatty acid metabolism on neutrophil responses to Mtb HN878 infection using ex-vivo assays and murine infection models. We discover that blocking glycolysis aggravates TB pathology, whereas inhibiting fatty acid oxidation (FAO) yields protective outcomes, including reduced weight loss, immunopathology, and bacterial burden in lung. Intriguingly, FAO inhibition preferentially disrupts the recruitment of a pathogen-permissive immature neutrophil population (Ly6Glo/dim), known to accumulate during TB. Targeting carnitine palmitoyl transferase 1a (Cpt1a)-a crucial enzyme in mitochondrial β-oxidation-either through chemical or genetic methods impairs neutrophils' ability to migrate to infection sites while also enhancing their antimicrobial function. Our findings illuminate the critical influence of neutrophil immunometabolism in TB pathogenesis, suggesting that manipulating fatty acid metabolism presents a novel avenue for host-directed TB therapies by modulating neutrophil functions.

Assessment of lower respiratory tract microbiota associated with pulmonary tuberculosis in children.

The respiratory microbiota plays a crucial role in the development of tuberculosis (TB). While existing research has underscored imbalances in the respiratory microbiota of adult patients with TB, information regarding the lower respiratory tract (LRT) microbiota in pediatric patients with TB remains scarce. We employed 16S rRNA gene sequencing technology to investigate the LRT microbial communities of 85 children of different ages with active TB of different severities, 33 children with infectious diseases other than TB, and 48 sex- and age-matched healthy children. A marked imbalance in the respiratory microbiota was observed in children with TB, highlighted by reduced alpha diversity and a distinct microbial community structure. Comparative analysis indicated that patients with severe TB exhibited lower Neisseria levels than those with non-severe TB (1.01% vs. 3.93%, respectively; p = .02). Streptococcus and Gemella levels were lower in bacteriologically confirmed TB cases compared with clinically diagnosed cases, and higher in healthy children younger than 10 years old than in the older group. Spearman correlation analysis demonstrated significant associations between the microbiota of the LRT and cytokine concentrations in the sputum of children with TB (e.g., an inverse correlation between Veillonella and interleukin-17A). TB induced significant dysbiosis in the LRT microbiota of children that was associated with disease severity and the immunological response in the respiratory tract. Our findings may offer a deeper understanding of the role of the respiratory microbiome in TB pathogenesis and progression.

Expression profiling & functional characterization of candidate miRNAs in serum exosomes among Indians with & without HIV-tuberculosis coinfection.

Background & objectives Despite the evidence of population differences in miRNA expression, limited information is available about the expression profile of miRNAs in Indian tuberculosis (TB) patients. The present study aimed to investigate the expression profile of candidate serum exosomal microRNAs in Indian patients with and without HIV-TB coinfection. Methods The pool samples of serum exosomes of study participants (HIV-TB coinfection, extra-pulmonary TB, HIV mono-infection, pulmonary TB) and healthy humans were processed for the isolation of total RNA followed by miRNA analysis using miRCURY LNA human focus PCR panel by real-time PCR. The significantly altered miRNAs were identified using differential expression analysis. The target genes prediction and potential functional analysis of exclusively differentially expressed miRNAs were performed using bioinformatics tools. Results The expression profile of 57, 58, 49 and 11 miRNAs was significantly altered in exosome samples of HIV-TB coinfected, extra-pulmonary TB, HIV mono-infected and pulmonary TB patients compared to healthy controls, respectively. The set of three (hsa-let-7i-5p, hsa-miR-24-3p, hsa-miR-92a-3p), three (hsa-miR-20a-5p, hsa-let-7e-5p, hsa-miR-26a-5p) and four (hsa-miR-21-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-146a-5p) miRNAs were exclusively significantly differentially expressed in study participants with HIV-TB coinfection, extra-pulmonary TB and pulmonary TB, respectively. Most of the target genes of exclusively differentially expressed miRNAs were enriched in pathways in cancer, MAPK signalling pathway and Ras signalling pathway. Interpretation & conclusions The present study demonstrates a distinct expression profile of miRNAs in serum exosomes of the study participants and identified crucial miRNAs which may have a significant impact on the biomarker analysis and pathogenesis of TB in Indian patients.

Permissive lung neutrophils facilitate tuberculosis immunopathogenesis in male phagocyte NADPH oxidase-deficient mice.

NADPH oxidase 2 (NOX2) is an enzyme responsible for generating reactive oxygen species, primarily found in phagocytes. Chronic Granulomatous Disease (CGD), along with bacterial infections such as Mycobacterium tuberculosis (Mtb), is a representative NOX2-deficient X-linked disease characterized by uncontrolled inflammation. However, the precise roles of host-derived factors that induce infection-mediated hyperinflammation in NOX2-deficient condition remain incompletely understood. To address this, we compared Mtb-induced pathogenesis in Nox2-/- and wild type (WT) mice in a sex-dependent manner. Among age- and sex-matched mice subjected to Mtb infection, male Nox2-/- mice exhibited a notable increase in bacterial burden and lung inflammation. This was characterized by significantly elevated pro-inflammatory cytokines such as G-CSF, TNF-α, IL-1α, IL-1β, and IL-6, excessive neutrophil infiltration, and reduced pulmonary lymphocyte levels as tuberculosis (TB) progressed. Notably, lungs of male Nox2-/- mice were predominantly populated with CD11bintLy6GintCXCR2loCD62Llo immature neutrophils which featured mycobacterial permissiveness. By diminishing total lung neutrophils or reducing immature neutrophils, TB immunopathogenesis was notably abrogated in male Nox2-/- mice. Ultimately, we identified G-CSF as the pivotal trigger that exacerbates the generation of immature permissive neutrophils, leading to TB immunopathogenesis in male Nox2-/- mice. In contrast, neutralizing IL-1α and IL-1β, which are previously known factors responsible for TB pathogenesis in Nox2-/- mice, aggravated TB immunopathogenesis. Our study revealed that G-CSF-driven immature and permissive pulmonary neutrophils are the primary cause of TB immunopathogenesis and lung hyperinflammation in male Nox2-/- mice. This highlights the importance of quantitative and qualitative control of pulmonary neutrophils to alleviate TB progression in a phagocyte oxidase-deficient condition.

Overexpressing miR-222-3p in cultured <i>Mycobacterium Tuberculosis</i>-infected macrophages does not affect their bacteriostatic activity

Tuberculosis, a disease caused by the bacterium Mycobacterium tuberculosis, is a major public health concern. Innate and adaptive immunity provide robust defense against pathogens. However, M. tuberculosis, which co-evolved with humans, has acquired many mechanisms to evade the immune response and ensure its intracellular existence and long-term survival within the host. Moreover, emerging evidence suggests that this secretive bacterium can alter expression of regulatory noncoding RNAs (including microRNAs), leading to dysregulation of biological processes underlying tuberculosis pathogenesis. For example, miR-222-3p has been shown to regulate the functional reprogramming of macrophages and is involved in the regulation of host innate immunity. Previously, we demonstrated the important role of miR-222-3p as a biological marker of tuberculosis activity. To confirm their biological targets and understand their role in the pathogenesis of tuberculosis, many research groups are working to establish functional relationships between miRNA expression under different conditions and their actual biological action using molecular biology and bioinformatics methods. In the present study, we demonstrated the effect of miR-222-3p overexpression on several functions of human macrophages of monocytic origin activated with M. tuberculosis antigens in in vitro culture. Specifically, we found that miR-222-3p overexpression significantly decreased IL-6 and IFNγ expression and increased IL-1β and cxcl10 expression in cultures of uninfected macrophages. Infected macrophages overexpressing miR-222-3p were characterized by increased NF-κB and IL-6 expression, as were infected macrophages without transfection. Another important finding was that miR-222-3p overexpression caused a small but significant increase in reactive nitrogen species production by infected macrophages, but did not affect their bacteriostatic activity against M. tuberculosis. Elucidating the functions of different microRNAs in regulating different pathogenic pathways in TB may lead to discovering new therapeutic targets. The detailed study of microRNAs that regulate immune-associated pathways will be useful for the design of miRNA mimetic molecules, either as inhibitors or as activators. Immune effects induced by miRNA drugs are currently a major challenge for miRNA therapeutics.

Breaking the Cycle: Matrix Metalloproteinase Inhibitors as an Alternative Approach in Managing Tuberculosis Pathogenesis and Progression.

Mycobacterium tuberculosis (Mtb) has long posed a significant challenge to global public health, resulting in approximately 1.6 million deaths annually. Pulmonary tuberculosis (TB) instigated by Mtb is characterized by extensive lung tissue damage, leading to lesions and dissemination within the tissue matrix. Matrix metalloproteinases (MMPs) exhibit endopeptidase activity, contributing to inflammatory tissue damage and, consequently, morbidity and mortality in TB patients. MMP activities in TB are intricately regulated by various components, including cytokines, chemokines, cell receptors, and growth factors, through intracellular signaling pathways. Primarily, Mtb-infected macrophages induce MMP expression, disrupting the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), thereby impairing extracellular matrix (ECM) deposition in the lungs. Recent research underscores the significance of immunomodulatory factors in MMP secretion and granuloma formation during Mtb pathogenesis. Several studies have investigated both the activation and inhibition of MMPs using endogenous MMP inhibitors (i.e., TIMPs) and synthetic inhibitors. However, despite their promising pharmacological potential, few MMP inhibitors have been explored for TB treatment as host-directed therapy. Scientists are exploring novel strategies to enhance TB therapeutic regimens by suppressing MMP activity to mitigate Mtb-associated matrix destruction and reduce TB induced lung inflammation. These strategies include the use of MMP inhibitor molecules alone or in combination with anti-TB drugs. Additionally, there is growing interest in developing novel formulations containing MMP inhibitors or MMP-responsive drug delivery systems to suppress MMPs and release drugs at specific target sites. This review summarizes MMPs' expression and regulation in TB, their role in immune response, and the potential of MMP inhibitors as effective therapeutic targets to alleviate TB immunopathology.

Unveiling the Significance of LysE in Survival and Virulence of Mycobacterium tuberculosis: A Review Reveals It as a Potential Drug Target, Diagnostic Marker, and a Vaccine Candidate.

Tuberculosis (TB) remains a global health threat, necessitating innovative strategies for control and prevention. This comprehensive review explores the Mycobacterium tuberculosis Lysine Exporter (LysE) gene, unveiling its multifaceted roles and potential uses in controlling and preventing tuberculosis (TB). As a pivotal player in eliminating excess L-lysine and L-arginine, LysE contributes to the survival and virulence of M. tuberculosis. This review synthesizes findings from different electronic databases and includes 13 studies focused on the LysE of M. tuberculosis. The research unveils that LysE can be a potential drug target, a diagnostic marker for TB, and a promising candidate for vaccine development. The absence of LysE in the widely used BCG vaccine underscores its uniqueness and positions it as a novel area for TB prevention. In conclusion, this review underscores the significance of LysE in TB pathogenesis and its potential as a drug target, diagnostic marker, and vaccine candidate. The multifaceted nature of LysE positions it at the forefront of innovative approaches to combat TB, calling for sustained research efforts to harness its full potential in the global fight against this infectious disease.

Single and Combined Serum Proteins Expressed in TB Infection are Candidates for Point-of-care Diagnostic Testing of Active TB Patients in Lambaréné, Gabon.

Point-of-care testing using nonsputum samples like serum or plasma proteins can improve tuberculosis (TB) patients access to a definitive diagnosis, especially in resource-constrained and remote areas. Recently, approximately 400 proteins were identified as playing a role in the pathogenesis of TB, offering a translational clinical research repository for TB. In a previous manuscript, we proved the potential use of these proteins for point-of-care testing for active TB diagnosis. The present work aims to confirm the performance of single and combination proteins to select the best candidate biomarkers for further development as a diagnostic testing tool for active TB. Seventy-four participants were assessed on the diagnostic performance of 17 single proteins and combinations of 2 to 4 proteins to diagnose active TB. The selection criteria included differential expression of the proteins between active TB and community-acquired pneumonia (CAP) and a performance rate ≥70% for active TB. SULT4A1, WASPF3, SPTLC1, FAM107B, SORCS2, and CYTOb561 were differentially expressed in TB compared to CAP patients. Two single proteins, SULT4A1 and WASPF3, performed ≥70% to discriminate active TB from CAP patients. The diagnostic performance of 3 protein-based combinations of active TB was 81% after leave-one-out cross-validation. Single proteins and 3 protein-based combinations are candidate biomarkers for diagnosing active TB disease. A large and prospective study will confirm their performance as complementary diagnostic tools to rapid diagnostic methods for detecting active TB.

Agent-based model predicts that layered structure and 3D movement work synergistically to reduce bacterial load in 3D in vitro models of tuberculosis granuloma.

Tuberculosis (TB) remains a global public health threat. Understanding the dynamics of host-pathogen interactions within TB granulomas will assist in identifying what leads to the successful elimination of infection. In vitro TB models provide a controllable environment to study these granuloma dynamics. Previously we developed a biomimetic 3D spheroid granuloma model that controls bacteria better than a traditional monolayer culture counterpart. We used agent-based simulations to predict the mechanistic reason for this difference. Our calibrated simulations were able to predict heterogeneous bacterial dynamics that are consistent with experimental data. In one group of simulations, spheroids are found to have higher macrophage activation than their traditional counterparts, leading to better bacterial control. This higher macrophage activation in the spheroids was not due to higher counts of activated T cells, instead fewer activated T cells were able to activate more macrophages due to the proximity of these cells to each other within the spheroid. In a second group of simulations, spheroids again have more macrophage activation but also more T cell activation, specifically CD8+ T cells. This higher level of CD8+ T cell activation is predicted to be due to the proximity of these cells to the cells that activate them. Multiple mechanisms of control were predicted. Simulations removing individual mechanisms show that one group of simulations has a CD4+ T cell dominant response, while the other has a mixed/CD8+ T cell dominant response. Lastly, we demonstrated that in spheroids the initial structure and movement rules work synergistically to reduce bacterial load. These findings provide valuable insights into how the structural complexity of in vitro models impacts immune responses. Moreover, our study has implications for engineering more physiologically relevant in vitro models and advancing our understanding of TB pathogenesis and potential therapeutic interventions.

Meta-analysis of interleukin-10gene polymorphisms and tuberculosis susceptibility: Insights from recent studies.

Tuberculosis (TB) remains a universal health problem with significant morbidity and mortality. Understanding the genetic factors affecting TB susceptibility is crucial for effective prevention and treatment. Interleukin-10 (IL-10), a regulatory cytokine, may influence TB pathogenesis through genetic variations. The PubMed, Embase, and Google Scholar databases were searched to find studies on the relationship between IL-10gene variants and tuberculosis. Relevant studies from 2016 to 2024 were identified through database searches. The selected case-control studies met the inclusion criteria. Software such as Review Manager was used to analyze quantitative data, with statistical significance set at p< 0.05. We calculated odds ratios and their respective confidence intervals to evaluate the associations. Nine studies examined IL-10 gene polymorphisms (rs1800871 and rs1800872) in TB susceptibility. The present study did not show a notable association between IL-10 gene polymorphisms and TB among all genetic models (allelic, homozygote, heterozygote, dominant, and recessive). The obtained p-value > 0.05 indicates an insignificant association between both gene polymorphisms of IL-10. An OR-1.13; 95% CI-0.85, 1.50 was obtained for the SNP rs1800871, whereas an OR-1.02; 95% CI-0.75, 1.40 was obtained for the SNP rs1800872. Our meta-analysis revealed no significant association between IL-10 gene polymorphisms and TB susceptibility, suggesting that these variations may not significantly contribute to TB susceptibility. Further research with a larger sample size and diverse ethnicities is needed to explore additional genetic variations and their implications in TB pathogenesis.

An exploratory deep learning approach to investigate tuberculosis pathogenesis in nonhuman primate model: Combining automated radiological analysis with clinical and biomarkers data

AbstractBackgroundTuberculosis (TB) kills approximately 1.6 million people yearly despite the fact anti‐TB drugs are generally curative. Therefore, TB‐case detection and monitoring of therapy, need a comprehensive approach. Automated radiological analysis, combined with clinical, microbiological, and immunological data, by machine learning (ML), can help achieve it.MethodsSix rhesus macaques were experimentally inoculated with pathogenic Mycobacterium tuberculosis in the lung. Data, including Computed Tomography (CT), were collected at 0, 2, 4, 8, 12, 16, and 20 weeks.ResultsOur ML‐based CT analysis (TB‐Net) efficiently and accurately analyzed disease progression, performing better than standard deep learning model (LLM OpenAI's CLIP Vi4). TB‐Net based results were more consistent than, and confirmed independently by, blinded manual disease scoring by two radiologists and exhibited strong correlations with blood biomarkers, TB‐lesion volumes, and disease‐signs during disease pathogenesis.ConclusionThe proposed approach is valuable in early disease detection, monitoring efficacy of therapy, and clinical decision making.

Identification of host immune-related biomarkers in active tuberculosis: A comprehensive analysis of differentially expressed genes

Tuberculosis (TB) is a serious public health issue in India. Numerous molecular mechanisms and immunological responses play significant roles in the pathogenesis of tuberculosis. This study aimed to identify host immune-related biomarkers that are significantly differentially expressed in active TB and that play a vital role in disease progression. The methodology employed in this study included data collection, pre-processing, analysis, and interpretation of the results. Six microarray datasets were used to identify differentially expressed genes (DEGs), and only the common DEGs were used for further downstream analysis, such as hub gene identification, gene ontology, pathway enrichment analysis, and drug-gene interaction analysis. The study identified 1728 DEGs, including 906 upregulated and 822 downregulated genes. Five hub genes were identified that were: STAT1, GBP5, GBP1, FCGR1A, and BATF2. Gene ontology and pathway enrichment revealed that most of the genes were involved in interferon-gamma signaling. In addition, through drug-gene interactions, known drugs have been identified for STAT1, FCGR1A and GBP1. The findings of this study may contribute to early detection and treatment of active TB.

Modulation of riboflavin biosynthesis and utilization in mycobacteria.

The pathway for biosynthesis and utilization of riboflavin, precursor of the essential coenzymes, FMN and FAD, is of particular interest in the flavin-rich pathogen, Mycobacterium tuberculosis (Mtb), for two important reasons: (i) the pathway includes potential tuberculosis (TB) drug targets and (ii) intermediates from the riboflavin biosynthesis pathway provide ligands for mucosal-associated invariant T (MAIT) cells, which have been implicated in TB pathogenesis. However, the riboflavin pathway is poorly understood in mycobacteria, which lack canonical mechanisms to transport this vitamin and to regulate flavin coenzyme homeostasis. By conditionally disrupting each step of the pathway and assessing the impact on mycobacterial viability and on the levels of the pathway proteins as well as riboflavin, our work provides genetic validation of the riboflavin pathway as a target for TB drug discovery and offers a resource for further exploring the association between riboflavin biosynthesis, MAIT cell activation, and TB infection and disease.

Quantitative analysis of the lysine acetylome reveals the role of SIRT3-mediated HSP60 deacetylation in suppressing intracellular Mycobacterium tuberculosis survival.

Protein acetylation is crucial for the onset, development, and outcome of tuberculosis (TB). Our study comprehensively investigated the dynamics of lysine acetylation during M. tb infection, shedding light on the intricate host-pathogen interactions that underlie the pathogenesis of tuberculosis. Using an advanced quantitative lysine proteomics approach, different profiles of acetylation sites and proteins in macrophages infected with M. tb were identified. Functional enrichment and protein-protein network analyses revealed significant associations between acetylated proteins and key cellular pathways, highlighting their critical role in the host response to M. tb infection. Furthermore, the deacetylation of HSP60 and its influence on macrophage-mediated clearance of M. tb underscore the functional significance of acetylation in tuberculosis pathogenesis. In conclusion, this study provides valuable insights into the regulatory mechanisms governing host immune responses to M. tb infection and offers promising avenues for developing novel therapeutic interventions against TB.

Critical review on analytical detection of first line and second line anti tubercular agent by various modern analytical method

Tuberculosis is a chronic inflammatory, granulomatous bacterial infectious disease caused by Mycobacterium tuberculosis. About 10 million people worldwide are ill with MTB in 2018, 5.7 million are males, 3.2 million are females and 1.1 million are infants, 1.6 million died from the disease. This article includes epidemiology, classification, pathogenesis, diagnosis and treatment of Tuberculosis. It includes the drug profile of antitubercular agents such as isoniazid, pyrazinamide, ethambutol, rifampicin, paraminosalicylic acid, thiacetazone, ethionamide, kanamycin, amikacin. cycloserine, viomycin, morphazinamide and some newer drugs such as ofloxacin, ciprofloxacin, clarithromycin and rifabutin. It contains analytical detection methods of antitubercular agents by HPLC.

Human Alveolar and Monocyte-Derived Human Macrophage Responses to Mycobacterium tuberculosis.

Alveolar macrophages (AMs) and recruited monocyte-derived macrophages (MDMs) mediate early lung immune responses to Mycobacterium tuberculosis. Differences in the response of these distinct cell types are poorly understood and may provide insight into mechanisms of tuberculosis pathogenesis. The objective of this study was to determine whether M. tuberculosis induces unique and essential antimicrobial pathways in human AMs compared with MDMs. Using paired human AMs and 5-d MCSF-derived MDMs from six healthy volunteers, we infected cells with M. tuberculosis H37Rv for 6 h, isolated RNA, and analyzed transcriptomic profiles with RNA sequencing. We found 681 genes that were M. tuberculosis dependent in AMs compared with MDMs and 4538 that were M. tuberculosis dependent in MDMs, but not AMs (false discovery rate [FDR] < 0.05). Using hypergeometric enrichment of DEGs in Broad Hallmark gene sets, we found that type I and II IFN Response were the only gene sets selectively induced in M. tuberculosis-infected AM (FDR < 0.05). In contrast, MYC targets, unfolded protein response and MTORC1 signaling, were selectively enriched in MDMs (FDR < 0.05). IFNA1, IFNA8, IFNE, and IFNL1 were specifically and highly upregulated in AMs compared with MDMs at baseline and/or after M. tuberculosis infection. IFNA8 modulated M. tuberculosis-induced proinflammatory cytokines and, compared with other IFNs, stimulated unique transcriptomes. Several DNA sensors and IFN regulatory factors had higher expression at baseline and/or after M. tuberculosis infection in AMs compared with MDMs. These findings demonstrate that M. tuberculosis infection induced unique transcriptional responses in human AMs compared with MDMs, including upregulation of the IFN response pathway and specific DNA sensors.