RARE DISEASE
Central nervous system tuberculosis
Central nervous system tuberculosis
Central nervous system tuberculosis
Synonyms: CNS tuberculosis
Synonyms: CNS tuberculosis
Synonyms: CNS tuberculosis
Drug discovery
3
drugs
With orphan designations
Overview
Central nervous system tuberculosis (CNS-TB) is a severe extrapulmonary manifestation of tuberculosis, primarily presenting as tuberculous meningitis (TBM). It causes high mortality (20–50%) and neurological morbidity due to inflammatory complications like vasculitis, hydrocephalus, and stroke. Diagnosis remains challenging due to insensitive microbiological methods. Treatment involves prolonged multidrug regimens (e.g., HRZE), adjunctive corticosteroids, and surgical interventions for complications, though drug resistance and blood-brain barrier penetration limit efficacy [1][3][7][13].
Categories: rare infectious diseases, rare neurological diseases
Research Papers
758 drug discovery papers about Central nervous system tuberculosis, with 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
758 drug discovery papers about Central nervous system tuberculosis, with 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-11 | Hypothetical applications of MR-guided focused ultrasound in central nervous system tuberculosis: blood-brain barrier disruption, granulomatous lesion modulation, targeted drug delivery, and immune microenvironment reprogramming.
Central nervous system tuberculosis (CNS-TB) comprises tuberculous meningitis (TBM), parenchymal tuberculomas, and spinal arachnoiditis. It accounts for 5% to 10% of extrapulmonary TB and is more common in immunocompromised individuals, particularly those with HIV. Despite early diagnosis and treatment, mortality remains high, exceeding 30% in TB meningitis, and, as a consequence, many survivors develop cognitive, motor, or visual deficits. Management has proven to be difficult due to the blood-brain barrier and blood-cerebrospinal fluid barrier, which limit drug penetration, especially in early or non-inflammatory stages. Even after disruption of these barriers owing to inflammation, drug delivery remains inconsistent and often fails to reach the required concentrations. Tuberculomas further compound this problem due to their granulomatous, avascular, and fibrotic architecture, which protects Mycobacterium tuberculosis from both host immunity and antibiotics. Magnetic resonance-guided focused ultrasound (MRgFUS) is an established, non-invasive neurosurgical technology that may offer a platform to transiently disrupt physiological barriers or modulate lesion structure using microbubble-mediated cavitation. Although MRgFUS is FDA-approved for movement disorders and under investigation in brain tumors, its application in CNS-TB remains entirely untested. Conceptually, MRgFUS could enhance drug delivery to protected CNS compartments, theoretically alter granulomatous architecture to improve antimicrobial penetration, and facilitate targeted delivery of immunomodulatory agents. This narrative and hypothesis-generating review explores the theoretical role of MRgFUS as an adjunctive strategy in CNS-TB, while explicitly acknowledging current evidence gaps and safety uncertainties.
2026-09-04 | Isolated Central Nervous System Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome-Case Report and Literature Review.
An immunocompetent young male in his early 20s presented with a 1-month history of central chest pain, dyspepsia and significant weight loss. Initial evaluation revealed a large, deep oesophageal ulcer and extensive necrotic mediastinal lymphadenopathy. Endobronchial ultrasound-guided fine-needle aspiration of the mediastinal nodes confirmed necrotising granulomatous inflammation, suggestive of tuberculosis. Following initiation of anti-tuberculosis treatment (ATT), he initially showed systemic improvement. However, within 2 weeks, he developed drug-induced liver injury along with new-onset focal neurological deficits, including right-sided hemiparesis and vocal cord palsy. Neuroimaging revealed multiple new intracranial lesions involving the left temporal lobe, right posterior parietal region and brainstem, whilst repeat cross-sectional imaging of the chest and abdomen was suggestive of interval improvement. A diagnosis of paradoxical isolated central nervous system tuberculosis-associated immune reconstitution inflammatory syndrome was made. He was managed with high-dose systemic corticosteroids and a modified hepatoprotective ATT regimen, resulting in clinical improvement.
2026-08-26 | Microglia-Mediated Ependymal Injury in Bacille Calmette-Guérin-Induced Meningitis Is Attenuated by Sodium Butyrate with Restoration of Hmgcs2 Expression.
Tuberculous meningitis (TBM) is the most severe form of central nervous system tuberculosis, associated with high mortality and neurological sequelae. Microglia-driven neuroinflammation is a key contributor to TBM pathogenesis; however, its specific effects on ependymal cells-critical for cerebrospinal fluid dynamics and barrier function-and potential therapeutic strategies remain unclear. A murine TBM model was established by tail vein injection of BCG. Although the virulence of BCG, an attenuated strain of Mycobacterium bovis, is different from that of clinically isolated human Mycobacterium tuberculosis, its induced phenotypes such as periventricular inflammatory infiltration, microglia activation, and ependymal dysfunction highly reproduce the key histopathological features of human TBM. Primary ependymal cells were cultured and treated either directly with BCG or indirectly with conditioned medium from BCG-stimulated BV2 microglial cells (BCG+BV2-CM). Transcriptomic profiling was conducted via RNA sequencing, with validation by qPCR and Western blot. Functional outcomes, including ciliary morphology and apoptosis, were assessed using immunofluorescence and flow cytometry. The therapeutic effect of sodium butyrate (NaB) was evaluated through pretreatment experiments. BCG infection induced characteristic TBM pathology, with persistent bacteria in the brain and lungs, ventricular inflammation, and pulmonary damage. Transcriptomic analysis showed that direct BCG treatment altered the expression of 1036 genes in ependymal cells, whereas BCG+BV2-CM treatment induced 3558 differentially expressed genes, highlighting microglia's role in amplifying ependymal injury. Integrated analysis identified 64 consistently dysregulated genes across in vitro and in vivo models, enriched in immune and metabolic pathways. BCG challenge significantly downregulated Hmgcs2, leading to ciliary shortening and increased apoptosis. Sodium butyrate treatment restored Hmgcs2 expression, preserved ciliary structure, and reduced apoptosis. Microglia profoundly exacerbate transcriptional dysregulation in ependymal cells during TBM. Sodium butyrate confers protection against BCG-induced ependymal damage by upregulating Hmgcs2, revealing a novel therapeutic target for tuberculous meningitis.
2026-07-28 | Tuberculous meningitis complicated by acute hydrocephalus and bilateral optic neuropathy: a case report
Tuberculosis remains a major global health burden, particularly in low-and middle-income countries.Although pulmonary disease accounts for the majority of cases, extrapulmonary tuberculosis contributes substantially to morbidity and mortality.Among these forms, tuberculous meningitis (TBM) represents the most severe manifestation of central nervous system tuberculosis, associated
2026-07-18 | When Tuberculosis Strikes Twice: Cerebral Tuberculoma as a paradoxical reaction during antituberculous therapy in an immunocompetent patient: A case report
Cerebral tuberculoma is an uncommon manifestation of central nervous system tuberculosis (CNS-TB) and may develop as a paradoxical reaction during antituberculous therapy, even in immunocompetent individuals. Its clinical and radiological presentation poses a significant diagnostic challenge because it closely mimics other intracranial space-occupying lesions. We report the case of a 36-year-old immunocompetent man with pulmonary tuberculosis confirmed by Xpert MTB/RIF, demonstrating rifampicin susceptibility. Human immunodeficiency virus (HIV) infection and diabetes mellitus were excluded. Two months after initiating standard first-line antituberculous therapy with isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE), he developed progressive headache and left-sided hemiparesis. Brain computed tomography revealed two ring-enhancing lesions in the right frontoparietal region associated with marked vasogenic edema, consistent with cerebral tuberculomas. Cerebrospinal fluid analysis, including Xpert MTB/RIF testing, was negative for tuberculous meningitis. Toxoplasmosis, primary central nervous system lymphoma, and other infectious and neoplastic etiologies were excluded through comprehensive clinical, microbiological, and radiological evaluation. Given the high suspicion of a paradoxical inflammatory reaction, antituberculous therapy was continued without modification, and adjunctive dexamethasone was initiated, resulting in progressive neurological recovery without the need for neurosurgical intervention. This case highlights the importance of recognizing paradoxical reactions as a cause of newly developed intracranial lesions during otherwise effective antituberculous treatment. The integration of clinical, microbiological, and neuroimaging findings, together with the systematic exclusion of alternative diagnoses, allowed an accurate diagnosis and prevented unnecessary modifications to antimicrobial therapy. Early recognition of this entity may improve neurological outcomes and optimize the management of patients with central nervous system tuberculosis.
proteins
2026-08-25 | Successful Therapy of CNS Tuberculosis With Granulomatous Inflammation in Immunodeficiency.
Central nervous system (CNS) tuberculosis (TB) carries high mortality and neurologic sequelae, especially when unrecognized inborn errors of immunity are present. We report a young woman with refractory TB meningitis, multiple intracranial tuberculomas, hydrocephalus, and intracranial hypertension despite 10 months of standard anti-TB therapy and corticosteroids. Severe vomiting led to poor adherence and severe weight loss. As immunologic evaluation suggested atypical combined immunodeficiency (CID); monthly intravenous immunoglobulin (IVIG) was started. Neurosurgery did not give indication for shunt surgery. Given the severity and presumed impaired antimycobacterial immunity, adjuvant interferon-γ (IFN-γ; 50 µg/m² 3 times weekly) was added to therapy with steroids. Vomiting resolved, weight improved, and treatment was tolerated. Serial magnetic resonance imaging showed reduction in leptomeningeal enhancement and tuberculoma burden without surgery; no neurologic sequelae developed. Next-generation sequencing identified a homozygous NHEJ1 variant, not confirmed by Sanger, but findings supported CID. In refractory CNS-TB with suspected immunodeficiency, IFN-γ, steroids, IVIG in addition to anti-TB therapy may improve outcomes and avoid neurosurgical intervention. Early immunological evaluation and host-directed therapy should be considered.
2025-05-31 | Hippocampal syndrome secondary to tuberculosis: From neuroinflammation to neurodegeneration.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a primary global health concern, with significant long-term sequelae. Central nervous system TB (CNS-TB) is a clinical spectrum with entities such as tuberculous meningitis and tuberculomas. Emerging evidence suggests that Mtb may directly or indirectly affect the hippocampus, a critical memory, learning, and cognition structure. This review aims to summarize the current biological understanding of Mtb's impact on the hippocampus, elucidate its potential role in neurodegeneration, and introduce the concept of "Hippocampal syndrome secondary to tuberculosis (HSST)" as a novel chronic entity within the CNS-TB spectrum. A comprehensive literature review was conducted to analyze how Mtb gains access to the brain, its neurotropism, and the resulting neuroinflammatory and neurodegenerative effects on the hippocampus. Data from clinical, histopathological, and experimental studies were evaluated to assess potential links between TB and cognitive impairment. Mtb can access the CNS through hematogenous dissemination, the "Trojan Horse" mechanism, or via the olfactory pathway, bypassing the blood-brain barrier (BBB). Once in the brain, Mtb induces chronic neuroinflammation and disrupts hippocampal structure. Studies suggest that TB increases the risk of Alzheimer's and Parkinson's diseases, with evidence of Mtb-driven amyloid-beta accumulation and neuronal loss. Furthermore, specific Mtb strains exhibit neurotropism and produce virulence factors that facilitate CNS invasion. Understanding the interaction between TB and neurocognitive disorders is critical for improving post-TB care. Recognizing HSST as a chronic condition within the CNS-TB spectrum may support early diagnosis and targeted interventions to mitigate long-term neurological consequences.
2025-03-06 | Tuberculosis of the central nervous system: current concepts in diagnosis and treatment.
The outcome of central nervous system (CNS) tuberculosis has shown little improvement over several decades, with diagnosis remaining unconfirmed in nearly half of the cases. This review highlights current insights and advancements in the diagnosis and treatment of CNS tuberculosis. Miliary pulmonary tuberculosis is often linked to CNS tuberculosis and is associated with a worse prognosis. Complications, such as, optochiasmatic arachnoiditis, strokes, and transverse myelitis severely affect prognosis and quality of life. Nearly half of tuberculous meningitis patients exhibited impaired cognition. Diagnosing CNS tuberculosis is challenging because of the low accuracy of standard tests. Advanced techniques like metagenomic and nanopore sequencing enhance detection but are hindered by high costs and limited access. Treatment outcomes remain suboptimal but approaches such as higher drug doses, novel medications, and host-directed therapies are being explored. Drug-resistant tuberculous meningitis is increasingly recognized, posing significant challenges to both diagnosis and treatment. Artificial intelligence (AI) enhances care by enabling early diagnosis, disease monitoring, and personalized treatments, improving outcomes. CNS tuberculosis diagnosis faces challenges due to limited sensitivity and delayed results of available tests. Treatments remain suboptimal, with multidrug-resistant cases posing high mortality risks. AI aids in early diagnosis and personalized care.
2025-01-17 | Additive Effects of Glutathione in Improving Antibiotic Efficacy in HIV–M.tb Co-Infection in the Central Nervous System: A Systematic Review
Background: HIV and tuberculosis (TB) co-infection poses a significant health challenge, particularly when involving the central nervous system (CNS), where it leads to severe morbidity and mortality. Current treatments face challenges such as drug resistance, immune reconstitution inflammatory syndrome (IRIS), and persistent inflammation. Glutathione (GSH) has the therapeutic potential to enhance treatment outcomes by improving antibiotic efficacy, reducing inflammation, and mitigating immune dysfunction. Methods: Relevant studies were identified through systematic searches of PubMed, Elsevier, WHO, and related databases. Inclusion criteria focused on preclinical and clinical research examining GSH or its precursors in HIV, TB, or co-infection, with emphasis on microbial control, immune modulation, and CNS-related outcomes. Results: Preclinical studies showed that GSH improves macrophage antimicrobial function, reduces oxidative stress, and limits Mycobacterium tuberculosis (M.tb) growth. Animal models demonstrated reduced bacterial burden in the lungs, liver, and spleen with GSH supplementation, along with enhanced granuloma stability. Clinical studies highlighted increased TH1 cytokine production, reduced inflammatory markers, and improved CD4+ T cell counts in HIV–M.tb co-infected patients. N-acetylcysteine (NAC), a GSH precursor, was shown to significantly enhance the efficacy of first-line TB antibiotics and mitigate treatment-associated toxicity. Discussion: GSH shows promise as an adjunct therapy for HIV–M.tb co-infection, particularly for cases involving the CNS, where it may improve immune recovery and reduce inflammation. However, evidence is limited by small sample sizes and a lack of randomized trials. Future research should focus on developing CNS-directed GSH formulations and evaluating its integration into current treatment protocols to address the dual burden of HIV and TB, ultimately improving patient outcomes.
2023-04-20 | Tubercular Optochiasmatic Arachnoiditis: A Case Report with Current Therapeutics and Management
Central nervous system tuberculosis (CNS TB) involves the brain parenchyma, meninges, and spinal cord. The primary pathology in CNS TB includes thick basal exudates leading to intense meningeal inflammation, vasculitis, and hydrocephalus. When these exudates and inflammation predominantly involve the structure in and around suprasellar cistern region, it results in a condition called optochiasmatic arachnoiditis (OCA). OCA is one of the cataclysmal complications of CNS TB, leading to vision loss. A previously healthy young woman came to our center with the complaints of low-grade fever, headache, weight loss, and visual obscuration. For further evaluation, she underwent lumbar puncture, and based on cerebrospinal fluid analysis, she was a diagnosed with CNS TB and was promptly started on antitubercular therapy along with steroid. A contrast-enhanced magnetic resonance imaging of the brain and orbit showed OCA. For OCA, she was given pulse-dose dexamethasone along with intrathecal hyaluronidase with which there was marginal improvement in vision. Management of OCA can be very challenging with unsatisfactory response. Many agents such as pulse steroid, intrathecal hyaluronidase, thalidomide, tumor necrosis factor alpha inhibitors, and cyclophosphamide have been used with inconsistent results. We have also done a review of the literature for the current evidence and newer therapeutics available for the management of OCA.
antibodies
2025-11-01 | The role of neural progenitor cells in brain tuberculosis 4691
Abstract Description Tuberculosis (TB) of the central nervous system (CNS) is one of the rarest but highly destructive manifestations of Mycobacterium tuberculosis (Mtb) infection in humans. Only half of the patients survive and cognitive diseases are common. The existing knowledge about the infectious mechanisms and anti-mycobacterial immune responses in the brain is restricted by the lack of an optimal human CNS-TB model. In this research, we applied a new human in vitro model to investigate CNS-TB by infecting neural organoids and neural progenitor cells (NPC) with Mtb. Our research reveals that the phagocytic ability of NPCs towards Mtb offers a new perspective on CNS-TB studies. Internalized Mtb bacilli are found co-localized within late endosomal and phagolysosomal compartments, as well as in the cytoplasm of the NPCs. The Mtb infection induces NPC death and disrupts proliferation, further substantiating the pathological consequences of CNS-TB. Additionally, prominent type-1 IFN responses were observed in Mtb-infected NPCs. The treatments with anti-IFN alpha neutralization antibodies could partially rescue the NPCs from Mtb-induced proliferation impairments and cell death. Ultimately our findings demonstrate that these neural organoids and NPC-based in vitro systems offer a new approach for understanding the pathogenesis of CNS-TB and the associated learning deficiencies. Organoid cultures may offer a new platform for evaluating anti-mycobacterial treatment strategies for human CNS-TB. Topic Categories Immune Mechanisms of Human Disease (HUM)
2024-01-25 | Recent advances in understanding the human host immune response in tuberculous meningitis.
Tuberculous meningitis (TBM), the most severe form of tuberculosis, causes death in approximately 25% cases despite antibiotic therapy, and half of survivors are left with neurological disability. Mortality and morbidity are contributed to by a dysregulated immune response, and adjunctive host-directed therapies are required to modulate this response and improve outcomes. Developing such therapies relies on improved understanding of the host immune response to TBM. The historical challenges in TBM research of limited in vivo and in vitro models have been partially overcome by recent developments in proteomics, transcriptomics, and metabolomics, and the use of these technologies in nested substudies of large clinical trials. We review the current understanding of the human immune response in TBM. We begin with M. tuberculosis entry into the central nervous system (CNS), microglial infection and blood-brain and other CNS barrier dysfunction. We then outline the innate response, including the early cytokine response, role of canonical and non-canonical inflammasomes, eicosanoids and specialised pro-resolving mediators. Next, we review the adaptive response including T cells, microRNAs and B cells, followed by the role of the glutamate-GABA neurotransmitter cycle and the tryptophan pathway. We discuss host genetic immune factors, differences between adults and children, paradoxical reaction, and the impact of HIV-1 co-infection including immune reconstitution inflammatory syndrome. Promising immunomodulatory therapies, research gaps, ongoing challenges and future paths are discussed.
2023-11-28 | Effectiveness of Adjunctive High-Dose Infliximab Therapy to Improve Disability-Free Survival Among Patients With Severe Central Nervous System Tuberculosis: A Matched Retrospective Cohort Study.
Few treatment options exist for patients with severe central nervous system (CNS) tuberculosis (TB) worsening due to inflammatory lesions, despite optimal antitubercular therapy (ATT) and steroids. Data regarding the efficacy and safety of infliximab in these patients are sparse. We performed a matched retrospective cohort study based on Medical Research Council (MRC) grading system and modified Rankin Scale (mRS) scores comparing 2 groups of adults with CNS TB. Cohort A received at least 1 dose of infliximab after optimal ATT and steroids between March 2019 and July 2022. Cohort B received only ATT and steroids. Disability-free survival (mRS score ≤2) at 6 months was the primary outcome. Baseline MRC grades and mRS scores were similar between the cohorts. Median duration before initiation of infliximab therapy from start of ATT and steroids was 6 (IQR: 3.7-13) months and for neurological deficits was 4 (IQR: 2-6.2) months. Indications for infliximab were symptomatic tuberculomas (20/30; 66.7%), spinal cord involvement with paraparesis (8/30; 26.7%), and optochiasmatic arachnoiditis (3/30; 10%), worsening despite adequate ATT and steroids. Severe disability (5/30 [16.7%] and 21/60 [35%]) and all-cause mortality (2/30 [6.7%] and 13/60 [21.7%]) at 6 months were lower in cohort A versus cohort B, respectively. In the combined study population, only exposure to infliximab was positively associated (aRR: 6.2; 95% CI: 2.18-17.83; P = .001) with disability-free survival at 6 months. There were no clear infliximab-related side effects noted. Infliximab may be an effective and safe adjunctive strategy among severely disabled patients with CNS TB not improving despite optimal ATT and steroids. Adequately powered phase 3 clinical trials are required to confirm these early findings.
2021-11-03 | Cerebrospinal fluid IL-1β is elevated in tuberculous meningitis patients but not associated with mortality.
Inflammation contributes to the pathophysiology and high mortality of tuberculous meningitis. The IL-1β pathway has been implicated in immunopathology and could be a target for host-directed therapy. IL-1β was elevated in the cerebrospinal fluid (CSF) of 225 HIV-uninfected tuberculous meningitis patients in Indonesia compared to controls, but did not predict subsequent mortality, nor did IL-6 or IL-1Ra. Furthermore, genetic loci known to regulate IL1B gene expression did not predict mortality in 443 tuberculous meningitis patients, although two of these loci did predict CSF IL-1β concentrations. Collectively, these data argue against a role for IL-1β targeted host-directed therapy in tuberculous meningitis.
2021-09-28 | Infliximab for Paradoxical Reactions in Pediatric Central Nervous System Tuberculosis
Paradoxical reactions in central nervous system tuberculosis (CNS-TB) are associated with significant morbidity and mortality. We describe 4 HIV-uninfected children treated for CNS-TB with severe paradoxical reactions unresponsive to corticosteroids. All made recovery after treatment with infliximab, highlighting the safety and effectiveness of infliximab for this complication, and need for prospective trials.
oligonucleotides
2024-09-06 | Development of innovative multi-epitope mRNA vaccine against central nervous system tuberculosis using in silico approaches.
Tuberculosis(TB) of the Central nervous system (CNS) is a rare and highly destructive disease. The emergence of drug resistance has increased treatment difficulty, leaving the Bacillus Calmette-Guérin (BCG) vaccine as the only licensed preventative immunization available. This study focused on identifying the epitopes of PknD (Rv0931c) and Rv0986 from Mycobacterium tuberculosis(Mtb) strain H37Rv using an in silico method. The goal was to develop a therapeutic mRNA vaccine for preventing CNS TB. The vaccine was designed to be non-allergenic, non-toxic, and highly antigenic. Codon optimization was performed to ensure effective translation in the human host. Additionally, the secondary and tertiary structures of the vaccine were predicted, and molecular docking with TLR-4 was carried out. A molecular dynamics simulation confirmed the stability of the complex. The results indicate that the vaccine structure shows effectiveness. Overall, the constructed vaccine exhibits ideal physicochemical properties, immune response, and stability, laying a theoretical foundation for future laboratory experiments.
2024-04-01 | Role of MicroRNAs as post transcription regulators of matrix metalloproteinases and their association in tuberculous meningitis.
Matrix metalloproteinases (MMPs) have a role in driving neuroinflammation in infectious as well as non-infectious diseases; however, recent reports have potentiated the role of microRNAs in regulating MMPs at post-transcriptional levels, leading to dysregulation of crucial MMP functions like tissue remodelling, blood brain barrier integrity, etc. In present study, microRNAs regulating MMPs (MMP2 and MMP3) were selected from database search followed by literature support. Expression of these microRNAs i.e., hsa-miR-495-3p, hsa-miR-132-3p and hsa-miR-21-5p was assessed by RT-PCR and the protein levels of MMPs were assessed by ELISA in the cerebrospinal fluid (CSF) of tuberculous meningitis (TBM) patients, healthy controls (HC) and non-infectious neuroinflammatory disease (NID) patients. The expression of hsa-miR-495-3p and hsa-miR-132-3p showed downregulation in TBM while hsa-miR-21-5p was overexpressed as compared to healthy controls. Moreover, MMP levels were found to be deranged with a significant increase in MMP3 levels in the TBM and NID patients compared to HC group. These observations highlight dysregulated microRNAs (hsa-miR-495-3p, hsa-miR-21-5p and hsa-miR-132-3p) levels might impair the levels of MMPs (MMP2 and MMP3) leading to neuroinflammation in TBM and NID population. These findings can further be applied to target these microRNAs for developing newer treatment modalities for better complication management.
2013-03-13 | Modulation of angiogenic factor VEGF by DNA-hsp65 vaccination in a murine CNS tuberculosis model
Tuberculosis (TB) is a serious public health problem. Development of experimental models and vaccines are essential to elucidate physiopathological mechanisms and to control the disease. Vascular endothelial growth factor (VEGF) is a potent activator of vascular permeability and angiogenesis. VEGF seems to participate in breakdown of the blood brain-barrier (BBB) in tuberculous meningitis (TBM), contributing to worsening of disease. Therefore, the objective here was to extent the characterization of our previously described murine model of central nervous system TB (CNS-TB) by describing the VEGF participation in the CNS disease, and suggesting a vaccination plan in mice. Plasmid encoding DNA protein antigen DNA-hsp65 has been described as a protector against TB infection and was used here to test its effectiveness in the prevention of VEGF production and TB disease. Vaccinated mice and its controls were injected with Mycobacterium bovis bacillus Calmette-Guerin (BCG) in cerebellum. Four weeks after BCG injection, mice were perfused and brains were paraffin-embedded for VEGF expression analysis. We observed VEGF immunohistochemical expression in TBM and granulomas in non-vaccinated mice. The DNA-hsp65 treatment blocked the expression of VEGF in mice TBM. Therefore, our murine model indicated the VEGF participation in the physiopathology of CNS-TB and the potential prevention of the DNA-hsp65 in the disease progression.
other
2022-04-08 | Preclinical Safety Evaluation: Acute and Repeated-Dose Toxicity of a New Intranasal Recombinant Vector Vaccine TB/FLU-04L Against Tuberculosis.
Vaccination against tuberculosis is one of the most successful medical measures to reduce morbidity and mortality. The BCG vaccine has been in use for more than 100 years, but its efficacy is still controversial. New vaccine candidates may offer better protection than available BCG vaccine. In this work, we studied the acute and the repeated-dose toxicity study of a new vector vaccine TB/Flu-04L against tuberculosis. The study was conducted on 60 BALB/c mice and 150 Wistar rats. The vaccine was administered intranasally and intravenously for the acute toxicity study. For the repeated-dose toxicity study, rats were intranasally immunized by 6.5 log10 TCID50 or 7.5 log10 TCID50 three times with 21-day intervals. Mortality, temperature, body weight, food and water consumption, hematological and biochemical parameters, urine analysis, as well as cardiovascular, respiratory, and central nervous system parameters were evaluated. A macroscopic examination of internal organs was performed. The TB/FLU-04L vaccine did not cause death among the mice and rats in the acute toxicity study. There were no pathological abnormalities in animal condition, behavior, food and water consumption, temperature, and body weight during the observation period. The results suggest that intranasal repeated-dose administration of the TB/FLU-04L vaccine does not exhibit significant toxicity in rats.Hematological and biochemistry analysis and the histological examination identified no toxicity-associated changes. The toxicity study in mice and rats showed that the intranasal vector vaccine TB/FLU-04L had no toxic effect. The tests confirm no adverse effects for laboratory animals in the studied parameters.
2013-06-11 | Vaccination with Recombinant Mycobacterium tuberculosis PknD Attenuates Bacterial Dissemination to the Brain in Guinea Pigs
We have previously identified Mycobacterium tuberculosis PknD to be an important virulence factor required for the pathogenesis of central nervous system (CNS) tuberculosis (TB). Specifically, PknD mediates bacillary invasion of the blood-brain barrier, which can be neutralized by specific antisera, suggesting its potential role as a therapeutic target against TB meningitis.We utilized an aerosol challenge guinea pig model of CNS TB and compared the protective efficacy of recombinant M. tuberculosis PknD subunit protein with that of M. bovis BCG against bacillary dissemination to the brain. BCG vaccination limited the pulmonary bacillary burden after aerosol challenge with virulent M. tuberculosis in guinea pigs and also reduced bacillary dissemination to the brain (P = 0.01). PknD vaccination also offered significant protection against bacterial dissemination to the brain, which was no different from BCG (P>0.24), even though PknD vaccinated animals had almost 100-fold higher pulmonary bacterial burdens. Higher levels of PknD-specific IgG were noted in animals immunized with PknD, but not in BCG-vaccinated or control animals. Furthermore, pre-incubation of M. tuberculosis with sera from PknD-vaccinated animals, but not with sera from BCG-vaccinated or control animals, significantly reduced bacterial invasion in a human blood-brain barrier model (P<0.01).Current recommendations for administering BCG at birth are based on protection gained against severe disease, such as TB meningitis, during infancy. We demonstrate that vaccination with recombinant M. tuberculosis PknD subunit offers a novel strategy to protect against TB meningitis, which is equivalent to BCG in a guinea pig model. Moreover, since BCG lacks the PknD sensor, BCG could also be boosted to develop a more effective vaccine against TB meningitis, a devastating disease that disproportionately affects young children.
small molecules
2026-09-11 | Hypothetical applications of MR-guided focused ultrasound in central nervous system tuberculosis: blood-brain barrier disruption, granulomatous lesion modulation, targeted drug delivery, and immune microenvironment reprogramming.
Central nervous system tuberculosis (CNS-TB) comprises tuberculous meningitis (TBM), parenchymal tuberculomas, and spinal arachnoiditis. It accounts for 5% to 10% of extrapulmonary TB and is more common in immunocompromised individuals, particularly those with HIV. Despite early diagnosis and treatment, mortality remains high, exceeding 30% in TB meningitis, and, as a consequence, many survivors develop cognitive, motor, or visual deficits. Management has proven to be difficult due to the blood-brain barrier and blood-cerebrospinal fluid barrier, which limit drug penetration, especially in early or non-inflammatory stages. Even after disruption of these barriers owing to inflammation, drug delivery remains inconsistent and often fails to reach the required concentrations. Tuberculomas further compound this problem due to their granulomatous, avascular, and fibrotic architecture, which protects Mycobacterium tuberculosis from both host immunity and antibiotics. Magnetic resonance-guided focused ultrasound (MRgFUS) is an established, non-invasive neurosurgical technology that may offer a platform to transiently disrupt physiological barriers or modulate lesion structure using microbubble-mediated cavitation. Although MRgFUS is FDA-approved for movement disorders and under investigation in brain tumors, its application in CNS-TB remains entirely untested. Conceptually, MRgFUS could enhance drug delivery to protected CNS compartments, theoretically alter granulomatous architecture to improve antimicrobial penetration, and facilitate targeted delivery of immunomodulatory agents. This narrative and hypothesis-generating review explores the theoretical role of MRgFUS as an adjunctive strategy in CNS-TB, while explicitly acknowledging current evidence gaps and safety uncertainties.
2026-09-04 | Isolated Central Nervous System Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome-Case Report and Literature Review.
An immunocompetent young male in his early 20s presented with a 1-month history of central chest pain, dyspepsia and significant weight loss. Initial evaluation revealed a large, deep oesophageal ulcer and extensive necrotic mediastinal lymphadenopathy. Endobronchial ultrasound-guided fine-needle aspiration of the mediastinal nodes confirmed necrotising granulomatous inflammation, suggestive of tuberculosis. Following initiation of anti-tuberculosis treatment (ATT), he initially showed systemic improvement. However, within 2 weeks, he developed drug-induced liver injury along with new-onset focal neurological deficits, including right-sided hemiparesis and vocal cord palsy. Neuroimaging revealed multiple new intracranial lesions involving the left temporal lobe, right posterior parietal region and brainstem, whilst repeat cross-sectional imaging of the chest and abdomen was suggestive of interval improvement. A diagnosis of paradoxical isolated central nervous system tuberculosis-associated immune reconstitution inflammatory syndrome was made. He was managed with high-dose systemic corticosteroids and a modified hepatoprotective ATT regimen, resulting in clinical improvement.
2026-08-26 | Microglia-Mediated Ependymal Injury in Bacille Calmette-Guérin-Induced Meningitis Is Attenuated by Sodium Butyrate with Restoration of Hmgcs2 Expression.
Tuberculous meningitis (TBM) is the most severe form of central nervous system tuberculosis, associated with high mortality and neurological sequelae. Microglia-driven neuroinflammation is a key contributor to TBM pathogenesis; however, its specific effects on ependymal cells-critical for cerebrospinal fluid dynamics and barrier function-and potential therapeutic strategies remain unclear. A murine TBM model was established by tail vein injection of BCG. Although the virulence of BCG, an attenuated strain of Mycobacterium bovis, is different from that of clinically isolated human Mycobacterium tuberculosis, its induced phenotypes such as periventricular inflammatory infiltration, microglia activation, and ependymal dysfunction highly reproduce the key histopathological features of human TBM. Primary ependymal cells were cultured and treated either directly with BCG or indirectly with conditioned medium from BCG-stimulated BV2 microglial cells (BCG+BV2-CM). Transcriptomic profiling was conducted via RNA sequencing, with validation by qPCR and Western blot. Functional outcomes, including ciliary morphology and apoptosis, were assessed using immunofluorescence and flow cytometry. The therapeutic effect of sodium butyrate (NaB) was evaluated through pretreatment experiments. BCG infection induced characteristic TBM pathology, with persistent bacteria in the brain and lungs, ventricular inflammation, and pulmonary damage. Transcriptomic analysis showed that direct BCG treatment altered the expression of 1036 genes in ependymal cells, whereas BCG+BV2-CM treatment induced 3558 differentially expressed genes, highlighting microglia's role in amplifying ependymal injury. Integrated analysis identified 64 consistently dysregulated genes across in vitro and in vivo models, enriched in immune and metabolic pathways. BCG challenge significantly downregulated Hmgcs2, leading to ciliary shortening and increased apoptosis. Sodium butyrate treatment restored Hmgcs2 expression, preserved ciliary structure, and reduced apoptosis. Microglia profoundly exacerbate transcriptional dysregulation in ependymal cells during TBM. Sodium butyrate confers protection against BCG-induced ependymal damage by upregulating Hmgcs2, revealing a novel therapeutic target for tuberculous meningitis.
2026-07-28 | Tuberculous meningitis complicated by acute hydrocephalus and bilateral optic neuropathy: a case report
Tuberculosis remains a major global health burden, particularly in low-and middle-income countries.Although pulmonary disease accounts for the majority of cases, extrapulmonary tuberculosis contributes substantially to morbidity and mortality.Among these forms, tuberculous meningitis (TBM) represents the most severe manifestation of central nervous system tuberculosis, associated
2026-07-18 | When Tuberculosis Strikes Twice: Cerebral Tuberculoma as a paradoxical reaction during antituberculous therapy in an immunocompetent patient: A case report
Cerebral tuberculoma is an uncommon manifestation of central nervous system tuberculosis (CNS-TB) and may develop as a paradoxical reaction during antituberculous therapy, even in immunocompetent individuals. Its clinical and radiological presentation poses a significant diagnostic challenge because it closely mimics other intracranial space-occupying lesions. We report the case of a 36-year-old immunocompetent man with pulmonary tuberculosis confirmed by Xpert MTB/RIF, demonstrating rifampicin susceptibility. Human immunodeficiency virus (HIV) infection and diabetes mellitus were excluded. Two months after initiating standard first-line antituberculous therapy with isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE), he developed progressive headache and left-sided hemiparesis. Brain computed tomography revealed two ring-enhancing lesions in the right frontoparietal region associated with marked vasogenic edema, consistent with cerebral tuberculomas. Cerebrospinal fluid analysis, including Xpert MTB/RIF testing, was negative for tuberculous meningitis. Toxoplasmosis, primary central nervous system lymphoma, and other infectious and neoplastic etiologies were excluded through comprehensive clinical, microbiological, and radiological evaluation. Given the high suspicion of a paradoxical inflammatory reaction, antituberculous therapy was continued without modification, and adjunctive dexamethasone was initiated, resulting in progressive neurological recovery without the need for neurosurgical intervention. This case highlights the importance of recognizing paradoxical reactions as a cause of newly developed intracranial lesions during otherwise effective antituberculous treatment. The integration of clinical, microbiological, and neuroimaging findings, together with the systematic exclusion of alternative diagnoses, allowed an accurate diagnosis and prevented unnecessary modifications to antimicrobial therapy. Early recognition of this entity may improve neurological outcomes and optimize the management of patients with central nervous system tuberculosis.
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2026-08-25 | Successful Therapy of CNS Tuberculosis With Granulomatous Inflammation in Immunodeficiency.
Central nervous system (CNS) tuberculosis (TB) carries high mortality and neurologic sequelae, especially when unrecognized inborn errors of immunity are present. We report a young woman with refractory TB meningitis, multiple intracranial tuberculomas, hydrocephalus, and intracranial hypertension despite 10 months of standard anti-TB therapy and corticosteroids. Severe vomiting led to poor adherence and severe weight loss. As immunologic evaluation suggested atypical combined immunodeficiency (CID); monthly intravenous immunoglobulin (IVIG) was started. Neurosurgery did not give indication for shunt surgery. Given the severity and presumed impaired antimycobacterial immunity, adjuvant interferon-γ (IFN-γ; 50 µg/m² 3 times weekly) was added to therapy with steroids. Vomiting resolved, weight improved, and treatment was tolerated. Serial magnetic resonance imaging showed reduction in leptomeningeal enhancement and tuberculoma burden without surgery; no neurologic sequelae developed. Next-generation sequencing identified a homozygous NHEJ1 variant, not confirmed by Sanger, but findings supported CID. In refractory CNS-TB with suspected immunodeficiency, IFN-γ, steroids, IVIG in addition to anti-TB therapy may improve outcomes and avoid neurosurgical intervention. Early immunological evaluation and host-directed therapy should be considered.
2025-05-31 | Hippocampal syndrome secondary to tuberculosis: From neuroinflammation to neurodegeneration.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a primary global health concern, with significant long-term sequelae. Central nervous system TB (CNS-TB) is a clinical spectrum with entities such as tuberculous meningitis and tuberculomas. Emerging evidence suggests that Mtb may directly or indirectly affect the hippocampus, a critical memory, learning, and cognition structure. This review aims to summarize the current biological understanding of Mtb's impact on the hippocampus, elucidate its potential role in neurodegeneration, and introduce the concept of "Hippocampal syndrome secondary to tuberculosis (HSST)" as a novel chronic entity within the CNS-TB spectrum. A comprehensive literature review was conducted to analyze how Mtb gains access to the brain, its neurotropism, and the resulting neuroinflammatory and neurodegenerative effects on the hippocampus. Data from clinical, histopathological, and experimental studies were evaluated to assess potential links between TB and cognitive impairment. Mtb can access the CNS through hematogenous dissemination, the "Trojan Horse" mechanism, or via the olfactory pathway, bypassing the blood-brain barrier (BBB). Once in the brain, Mtb induces chronic neuroinflammation and disrupts hippocampal structure. Studies suggest that TB increases the risk of Alzheimer's and Parkinson's diseases, with evidence of Mtb-driven amyloid-beta accumulation and neuronal loss. Furthermore, specific Mtb strains exhibit neurotropism and produce virulence factors that facilitate CNS invasion. Understanding the interaction between TB and neurocognitive disorders is critical for improving post-TB care. Recognizing HSST as a chronic condition within the CNS-TB spectrum may support early diagnosis and targeted interventions to mitigate long-term neurological consequences.
2025-03-06 | Tuberculosis of the central nervous system: current concepts in diagnosis and treatment.
The outcome of central nervous system (CNS) tuberculosis has shown little improvement over several decades, with diagnosis remaining unconfirmed in nearly half of the cases. This review highlights current insights and advancements in the diagnosis and treatment of CNS tuberculosis. Miliary pulmonary tuberculosis is often linked to CNS tuberculosis and is associated with a worse prognosis. Complications, such as, optochiasmatic arachnoiditis, strokes, and transverse myelitis severely affect prognosis and quality of life. Nearly half of tuberculous meningitis patients exhibited impaired cognition. Diagnosing CNS tuberculosis is challenging because of the low accuracy of standard tests. Advanced techniques like metagenomic and nanopore sequencing enhance detection but are hindered by high costs and limited access. Treatment outcomes remain suboptimal but approaches such as higher drug doses, novel medications, and host-directed therapies are being explored. Drug-resistant tuberculous meningitis is increasingly recognized, posing significant challenges to both diagnosis and treatment. Artificial intelligence (AI) enhances care by enabling early diagnosis, disease monitoring, and personalized treatments, improving outcomes. CNS tuberculosis diagnosis faces challenges due to limited sensitivity and delayed results of available tests. Treatments remain suboptimal, with multidrug-resistant cases posing high mortality risks. AI aids in early diagnosis and personalized care.
2025-01-17 | Additive Effects of Glutathione in Improving Antibiotic Efficacy in HIV–M.tb Co-Infection in the Central Nervous System: A Systematic Review
Background: HIV and tuberculosis (TB) co-infection poses a significant health challenge, particularly when involving the central nervous system (CNS), where it leads to severe morbidity and mortality. Current treatments face challenges such as drug resistance, immune reconstitution inflammatory syndrome (IRIS), and persistent inflammation. Glutathione (GSH) has the therapeutic potential to enhance treatment outcomes by improving antibiotic efficacy, reducing inflammation, and mitigating immune dysfunction. Methods: Relevant studies were identified through systematic searches of PubMed, Elsevier, WHO, and related databases. Inclusion criteria focused on preclinical and clinical research examining GSH or its precursors in HIV, TB, or co-infection, with emphasis on microbial control, immune modulation, and CNS-related outcomes. Results: Preclinical studies showed that GSH improves macrophage antimicrobial function, reduces oxidative stress, and limits Mycobacterium tuberculosis (M.tb) growth. Animal models demonstrated reduced bacterial burden in the lungs, liver, and spleen with GSH supplementation, along with enhanced granuloma stability. Clinical studies highlighted increased TH1 cytokine production, reduced inflammatory markers, and improved CD4+ T cell counts in HIV–M.tb co-infected patients. N-acetylcysteine (NAC), a GSH precursor, was shown to significantly enhance the efficacy of first-line TB antibiotics and mitigate treatment-associated toxicity. Discussion: GSH shows promise as an adjunct therapy for HIV–M.tb co-infection, particularly for cases involving the CNS, where it may improve immune recovery and reduce inflammation. However, evidence is limited by small sample sizes and a lack of randomized trials. Future research should focus on developing CNS-directed GSH formulations and evaluating its integration into current treatment protocols to address the dual burden of HIV and TB, ultimately improving patient outcomes.
2023-04-20 | Tubercular Optochiasmatic Arachnoiditis: A Case Report with Current Therapeutics and Management
Central nervous system tuberculosis (CNS TB) involves the brain parenchyma, meninges, and spinal cord. The primary pathology in CNS TB includes thick basal exudates leading to intense meningeal inflammation, vasculitis, and hydrocephalus. When these exudates and inflammation predominantly involve the structure in and around suprasellar cistern region, it results in a condition called optochiasmatic arachnoiditis (OCA). OCA is one of the cataclysmal complications of CNS TB, leading to vision loss. A previously healthy young woman came to our center with the complaints of low-grade fever, headache, weight loss, and visual obscuration. For further evaluation, she underwent lumbar puncture, and based on cerebrospinal fluid analysis, she was a diagnosed with CNS TB and was promptly started on antitubercular therapy along with steroid. A contrast-enhanced magnetic resonance imaging of the brain and orbit showed OCA. For OCA, she was given pulse-dose dexamethasone along with intrathecal hyaluronidase with which there was marginal improvement in vision. Management of OCA can be very challenging with unsatisfactory response. Many agents such as pulse steroid, intrathecal hyaluronidase, thalidomide, tumor necrosis factor alpha inhibitors, and cyclophosphamide have been used with inconsistent results. We have also done a review of the literature for the current evidence and newer therapeutics available for the management of OCA.
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2025-11-01 | The role of neural progenitor cells in brain tuberculosis 4691
Abstract Description Tuberculosis (TB) of the central nervous system (CNS) is one of the rarest but highly destructive manifestations of Mycobacterium tuberculosis (Mtb) infection in humans. Only half of the patients survive and cognitive diseases are common. The existing knowledge about the infectious mechanisms and anti-mycobacterial immune responses in the brain is restricted by the lack of an optimal human CNS-TB model. In this research, we applied a new human in vitro model to investigate CNS-TB by infecting neural organoids and neural progenitor cells (NPC) with Mtb. Our research reveals that the phagocytic ability of NPCs towards Mtb offers a new perspective on CNS-TB studies. Internalized Mtb bacilli are found co-localized within late endosomal and phagolysosomal compartments, as well as in the cytoplasm of the NPCs. The Mtb infection induces NPC death and disrupts proliferation, further substantiating the pathological consequences of CNS-TB. Additionally, prominent type-1 IFN responses were observed in Mtb-infected NPCs. The treatments with anti-IFN alpha neutralization antibodies could partially rescue the NPCs from Mtb-induced proliferation impairments and cell death. Ultimately our findings demonstrate that these neural organoids and NPC-based in vitro systems offer a new approach for understanding the pathogenesis of CNS-TB and the associated learning deficiencies. Organoid cultures may offer a new platform for evaluating anti-mycobacterial treatment strategies for human CNS-TB. Topic Categories Immune Mechanisms of Human Disease (HUM)
2024-01-25 | Recent advances in understanding the human host immune response in tuberculous meningitis.
Tuberculous meningitis (TBM), the most severe form of tuberculosis, causes death in approximately 25% cases despite antibiotic therapy, and half of survivors are left with neurological disability. Mortality and morbidity are contributed to by a dysregulated immune response, and adjunctive host-directed therapies are required to modulate this response and improve outcomes. Developing such therapies relies on improved understanding of the host immune response to TBM. The historical challenges in TBM research of limited in vivo and in vitro models have been partially overcome by recent developments in proteomics, transcriptomics, and metabolomics, and the use of these technologies in nested substudies of large clinical trials. We review the current understanding of the human immune response in TBM. We begin with M. tuberculosis entry into the central nervous system (CNS), microglial infection and blood-brain and other CNS barrier dysfunction. We then outline the innate response, including the early cytokine response, role of canonical and non-canonical inflammasomes, eicosanoids and specialised pro-resolving mediators. Next, we review the adaptive response including T cells, microRNAs and B cells, followed by the role of the glutamate-GABA neurotransmitter cycle and the tryptophan pathway. We discuss host genetic immune factors, differences between adults and children, paradoxical reaction, and the impact of HIV-1 co-infection including immune reconstitution inflammatory syndrome. Promising immunomodulatory therapies, research gaps, ongoing challenges and future paths are discussed.
2023-11-28 | Effectiveness of Adjunctive High-Dose Infliximab Therapy to Improve Disability-Free Survival Among Patients With Severe Central Nervous System Tuberculosis: A Matched Retrospective Cohort Study.
Few treatment options exist for patients with severe central nervous system (CNS) tuberculosis (TB) worsening due to inflammatory lesions, despite optimal antitubercular therapy (ATT) and steroids. Data regarding the efficacy and safety of infliximab in these patients are sparse. We performed a matched retrospective cohort study based on Medical Research Council (MRC) grading system and modified Rankin Scale (mRS) scores comparing 2 groups of adults with CNS TB. Cohort A received at least 1 dose of infliximab after optimal ATT and steroids between March 2019 and July 2022. Cohort B received only ATT and steroids. Disability-free survival (mRS score ≤2) at 6 months was the primary outcome. Baseline MRC grades and mRS scores were similar between the cohorts. Median duration before initiation of infliximab therapy from start of ATT and steroids was 6 (IQR: 3.7-13) months and for neurological deficits was 4 (IQR: 2-6.2) months. Indications for infliximab were symptomatic tuberculomas (20/30; 66.7%), spinal cord involvement with paraparesis (8/30; 26.7%), and optochiasmatic arachnoiditis (3/30; 10%), worsening despite adequate ATT and steroids. Severe disability (5/30 [16.7%] and 21/60 [35%]) and all-cause mortality (2/30 [6.7%] and 13/60 [21.7%]) at 6 months were lower in cohort A versus cohort B, respectively. In the combined study population, only exposure to infliximab was positively associated (aRR: 6.2; 95% CI: 2.18-17.83; P = .001) with disability-free survival at 6 months. There were no clear infliximab-related side effects noted. Infliximab may be an effective and safe adjunctive strategy among severely disabled patients with CNS TB not improving despite optimal ATT and steroids. Adequately powered phase 3 clinical trials are required to confirm these early findings.
2021-11-03 | Cerebrospinal fluid IL-1β is elevated in tuberculous meningitis patients but not associated with mortality.
Inflammation contributes to the pathophysiology and high mortality of tuberculous meningitis. The IL-1β pathway has been implicated in immunopathology and could be a target for host-directed therapy. IL-1β was elevated in the cerebrospinal fluid (CSF) of 225 HIV-uninfected tuberculous meningitis patients in Indonesia compared to controls, but did not predict subsequent mortality, nor did IL-6 or IL-1Ra. Furthermore, genetic loci known to regulate IL1B gene expression did not predict mortality in 443 tuberculous meningitis patients, although two of these loci did predict CSF IL-1β concentrations. Collectively, these data argue against a role for IL-1β targeted host-directed therapy in tuberculous meningitis.
2021-09-28 | Infliximab for Paradoxical Reactions in Pediatric Central Nervous System Tuberculosis
Paradoxical reactions in central nervous system tuberculosis (CNS-TB) are associated with significant morbidity and mortality. We describe 4 HIV-uninfected children treated for CNS-TB with severe paradoxical reactions unresponsive to corticosteroids. All made recovery after treatment with infliximab, highlighting the safety and effectiveness of infliximab for this complication, and need for prospective trials.
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2024-09-06 | Development of innovative multi-epitope mRNA vaccine against central nervous system tuberculosis using in silico approaches.
Tuberculosis(TB) of the Central nervous system (CNS) is a rare and highly destructive disease. The emergence of drug resistance has increased treatment difficulty, leaving the Bacillus Calmette-Guérin (BCG) vaccine as the only licensed preventative immunization available. This study focused on identifying the epitopes of PknD (Rv0931c) and Rv0986 from Mycobacterium tuberculosis(Mtb) strain H37Rv using an in silico method. The goal was to develop a therapeutic mRNA vaccine for preventing CNS TB. The vaccine was designed to be non-allergenic, non-toxic, and highly antigenic. Codon optimization was performed to ensure effective translation in the human host. Additionally, the secondary and tertiary structures of the vaccine were predicted, and molecular docking with TLR-4 was carried out. A molecular dynamics simulation confirmed the stability of the complex. The results indicate that the vaccine structure shows effectiveness. Overall, the constructed vaccine exhibits ideal physicochemical properties, immune response, and stability, laying a theoretical foundation for future laboratory experiments.
2024-04-01 | Role of MicroRNAs as post transcription regulators of matrix metalloproteinases and their association in tuberculous meningitis.
Matrix metalloproteinases (MMPs) have a role in driving neuroinflammation in infectious as well as non-infectious diseases; however, recent reports have potentiated the role of microRNAs in regulating MMPs at post-transcriptional levels, leading to dysregulation of crucial MMP functions like tissue remodelling, blood brain barrier integrity, etc. In present study, microRNAs regulating MMPs (MMP2 and MMP3) were selected from database search followed by literature support. Expression of these microRNAs i.e., hsa-miR-495-3p, hsa-miR-132-3p and hsa-miR-21-5p was assessed by RT-PCR and the protein levels of MMPs were assessed by ELISA in the cerebrospinal fluid (CSF) of tuberculous meningitis (TBM) patients, healthy controls (HC) and non-infectious neuroinflammatory disease (NID) patients. The expression of hsa-miR-495-3p and hsa-miR-132-3p showed downregulation in TBM while hsa-miR-21-5p was overexpressed as compared to healthy controls. Moreover, MMP levels were found to be deranged with a significant increase in MMP3 levels in the TBM and NID patients compared to HC group. These observations highlight dysregulated microRNAs (hsa-miR-495-3p, hsa-miR-21-5p and hsa-miR-132-3p) levels might impair the levels of MMPs (MMP2 and MMP3) leading to neuroinflammation in TBM and NID population. These findings can further be applied to target these microRNAs for developing newer treatment modalities for better complication management.
2013-03-13 | Modulation of angiogenic factor VEGF by DNA-hsp65 vaccination in a murine CNS tuberculosis model
Tuberculosis (TB) is a serious public health problem. Development of experimental models and vaccines are essential to elucidate physiopathological mechanisms and to control the disease. Vascular endothelial growth factor (VEGF) is a potent activator of vascular permeability and angiogenesis. VEGF seems to participate in breakdown of the blood brain-barrier (BBB) in tuberculous meningitis (TBM), contributing to worsening of disease. Therefore, the objective here was to extent the characterization of our previously described murine model of central nervous system TB (CNS-TB) by describing the VEGF participation in the CNS disease, and suggesting a vaccination plan in mice. Plasmid encoding DNA protein antigen DNA-hsp65 has been described as a protector against TB infection and was used here to test its effectiveness in the prevention of VEGF production and TB disease. Vaccinated mice and its controls were injected with Mycobacterium bovis bacillus Calmette-Guerin (BCG) in cerebellum. Four weeks after BCG injection, mice were perfused and brains were paraffin-embedded for VEGF expression analysis. We observed VEGF immunohistochemical expression in TBM and granulomas in non-vaccinated mice. The DNA-hsp65 treatment blocked the expression of VEGF in mice TBM. Therefore, our murine model indicated the VEGF participation in the physiopathology of CNS-TB and the potential prevention of the DNA-hsp65 in the disease progression.
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2022-04-08 | Preclinical Safety Evaluation: Acute and Repeated-Dose Toxicity of a New Intranasal Recombinant Vector Vaccine TB/FLU-04L Against Tuberculosis.
Vaccination against tuberculosis is one of the most successful medical measures to reduce morbidity and mortality. The BCG vaccine has been in use for more than 100 years, but its efficacy is still controversial. New vaccine candidates may offer better protection than available BCG vaccine. In this work, we studied the acute and the repeated-dose toxicity study of a new vector vaccine TB/Flu-04L against tuberculosis. The study was conducted on 60 BALB/c mice and 150 Wistar rats. The vaccine was administered intranasally and intravenously for the acute toxicity study. For the repeated-dose toxicity study, rats were intranasally immunized by 6.5 log10 TCID50 or 7.5 log10 TCID50 three times with 21-day intervals. Mortality, temperature, body weight, food and water consumption, hematological and biochemical parameters, urine analysis, as well as cardiovascular, respiratory, and central nervous system parameters were evaluated. A macroscopic examination of internal organs was performed. The TB/FLU-04L vaccine did not cause death among the mice and rats in the acute toxicity study. There were no pathological abnormalities in animal condition, behavior, food and water consumption, temperature, and body weight during the observation period. The results suggest that intranasal repeated-dose administration of the TB/FLU-04L vaccine does not exhibit significant toxicity in rats.Hematological and biochemistry analysis and the histological examination identified no toxicity-associated changes. The toxicity study in mice and rats showed that the intranasal vector vaccine TB/FLU-04L had no toxic effect. The tests confirm no adverse effects for laboratory animals in the studied parameters.
2013-06-11 | Vaccination with Recombinant Mycobacterium tuberculosis PknD Attenuates Bacterial Dissemination to the Brain in Guinea Pigs
We have previously identified Mycobacterium tuberculosis PknD to be an important virulence factor required for the pathogenesis of central nervous system (CNS) tuberculosis (TB). Specifically, PknD mediates bacillary invasion of the blood-brain barrier, which can be neutralized by specific antisera, suggesting its potential role as a therapeutic target against TB meningitis.We utilized an aerosol challenge guinea pig model of CNS TB and compared the protective efficacy of recombinant M. tuberculosis PknD subunit protein with that of M. bovis BCG against bacillary dissemination to the brain. BCG vaccination limited the pulmonary bacillary burden after aerosol challenge with virulent M. tuberculosis in guinea pigs and also reduced bacillary dissemination to the brain (P = 0.01). PknD vaccination also offered significant protection against bacterial dissemination to the brain, which was no different from BCG (P>0.24), even though PknD vaccinated animals had almost 100-fold higher pulmonary bacterial burdens. Higher levels of PknD-specific IgG were noted in animals immunized with PknD, but not in BCG-vaccinated or control animals. Furthermore, pre-incubation of M. tuberculosis with sera from PknD-vaccinated animals, but not with sera from BCG-vaccinated or control animals, significantly reduced bacterial invasion in a human blood-brain barrier model (P<0.01).Current recommendations for administering BCG at birth are based on protection gained against severe disease, such as TB meningitis, during infancy. We demonstrate that vaccination with recombinant M. tuberculosis PknD subunit offers a novel strategy to protect against TB meningitis, which is equivalent to BCG in a guinea pig model. Moreover, since BCG lacks the PknD sensor, BCG could also be boosted to develop a more effective vaccine against TB meningitis, a devastating disease that disproportionately affects young children.
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Drug Discovery Landscape
3 orphan drug designations for Central nervous system tuberculosis.
3 orphan drug designations for Central nervous system tuberculosis.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Aminosalicylic acid [Granupas (previously called Para-aminosalicylic acid Lucane and PAS-GR)] | small molecules | EMA | Eurocept International B.V. | |
Vaccinia virus Ankara expressing tuberculosis antigen 85A | vaccines | EMA | University of Oxford | |
Bedaquiline [Sirturo] | small molecules | EMA | Janssen Cilag International |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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