RESUMEN
Tuberculous meningitis, a severe form of tuberculosis caused by Mycobacterium tuberculosis (BK), remains a major public health challenge worldwide. In addition to the complex mechanisms of the innate and adaptive immune response against Mycobacterium tuberculosis, there is a crucial genetic dimension to consider. Individuals with specific genetic variations may have altered immune responses that make them more susceptible to this form of tuberculosis. Genetic mutations in genes encoding surface receptors, adaptor proteins, kinases, transcription factors, nucleic receptors and other molecules involved in cellular interactions and molecular mechanisms have been associated with susceptibility to TB. Understanding the molecular mechanisms of immune interactions in host response to Mycobacterium tuberculosis is crucial to understanding the genetic dimension in susceptibility to tuberculosis, particularly its dreaded form of tuberculous meningitis. The aim of this update is to explore in details the key interactions between the main players in innate and adaptive immunity during infection with Mycobacterium tuberculosis, with particular emphasis on the genetic factors associated with susceptibility to tuberculosis, especially its dreaded form of tuberculous meningitis.
Asunto(s)
Predisposición Genética a la Enfermedad , Mycobacterium tuberculosis , Tuberculosis Meníngea , Humanos , Tuberculosis Meníngea/genética , Tuberculosis Meníngea/inmunología , Mycobacterium tuberculosis/inmunología , Inmunidad Innata/genética , Inmunidad Adaptativa/genéticaRESUMEN
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.
Asunto(s)
MicroARNs , Mycobacterium tuberculosis , Tuberculosis Meníngea , Humanos , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 3 de la Matriz/genética , Tuberculosis Meníngea/genética , Enfermedades Neuroinflamatorias , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismoRESUMEN
BACKGROUND: Tuberculous meningitis (TBM) is difficult to diagnose. We investigated whether a 3-gene host response signature in blood can distinguish TBM from other brain infections. METHODS: The expression of 3 genes (dual specificity phosphatase 3 [DUSP3], guanylate-binding protein [GBP5], krupple-like factor 2 [KLF2]) was analyzed by RNA sequencing of archived whole blood from 4 cohorts of Vietnamese adults: 281 with TBM, 279 with pulmonary tuberculosis, 50 with other brain infections, and 30 healthy controls. Tuberculosis scores (combined 3-gene expression) were calculated following published methodology and discriminatory performance compared using area under a receiver operator characteristic curve (AUC). RESULTS: GBP5 was upregulated in TBM compared to other brain infections (P < .001), with no difference in DUSP3 and KLF2 expression. The diagnostic performance of GBP5 alone (AUC, 0.74; 95% confidence interval [CI], .67-.81) was slightly better than the 3-gene tuberculosis score (AUC, 0.66; 95% CI, .58-.73) in TBM. Both GBP5 expression and tuberculosis score were higher in participants with human immunodeficiency virus (HIV; P < .001), with good diagnostic performance of GBP5 alone (AUC, 0.86; 95% CI, .80-.93). CONCLUSIONS: The 3-gene host signature in whole blood has the ability to discriminate TBM from other brain infections, including in individuals with HIV. Validation in large prospective diagnostic study is now required.
Asunto(s)
Tuberculosis Meníngea , Humanos , Tuberculosis Meníngea/diagnóstico , Tuberculosis Meníngea/sangre , Tuberculosis Meníngea/genética , Masculino , Femenino , Adulto , Persona de Mediana Edad , Proteínas de Unión al GTP/genética , Factores de Transcripción de Tipo Kruppel/genética , Diagnóstico Diferencial , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/genética , Tuberculosis Pulmonar/sangre , Biomarcadores/sangre , Adulto Joven , Vietnam , Curva ROCRESUMEN
Paradoxical reaction (PR) in tuberculous meningitis (TBM) is a major management issue. We report mRNA profiling of cytokines to understand PR in HIV-uninfected TBM patients. 72 patients with TBM were included, and their clinical, MRI, and mRNA profiling of tumor necrosis factor (TNF) α, interleukin (IL) 6, IL10 and interferon (IFN) γ genes in the peripheral blood mononuclear cells were done at admission and 6 weeks of antitubercular treatment. Cytokine profiling was done using reverse transcriptase polymerase chain reaction. PR was defined if repeat MRI at 6 weeks revealed new or increase in exudates, tuberculoma, hydrocephalus or infarctions. Outcome was defined at 6 months using modified Rankin Scale (mRS), and categorized as death, poor and good. 44 (61.1 %) patients had PR, and 28 (38.9 %) had paradoxical tuberculoma (PT). The expression of IL6 and TNFα genes were higher in PR and PT groups. Stage of meningitis and hydrocephalus at admission predicted PR. Patients with PR and PT had more frequently poor outcome. About three-fifth HIV-uninfected TBM patients have PR and two-fifth have PT. Paradoxical reaction is associated with higher expression of IL6 and TNFα. Patients with severe meningitis with hydrocephalus develop PR more frequently.
Asunto(s)
Infecciones por VIH , Hidrocefalia , Mycobacterium tuberculosis , Tuberculoma , Tuberculosis Meníngea , Humanos , Tuberculosis Meníngea/diagnóstico , Tuberculosis Meníngea/tratamiento farmacológico , Tuberculosis Meníngea/genética , Citocinas/genética , Mycobacterium tuberculosis/genética , Interleucina-6/genética , Factor de Necrosis Tumoral alfa/genética , Leucocitos Mononucleares , Hidrocefalia/complicaciones , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genéticaRESUMEN
BACKGROUND: Our previous study revealed the transcriptome atlas of specific cell types in tuberculous meningitis (TBM) model mice injected with the BCG vaccine via scRNA sequencing. However, the activities of miRNAs in TBM at single-cell resolution remain to be explored. METHOD: Cell type-specific miRNA activities were investigated by using motif enrichment analyses (miReact) on the transcriptome data of 15 cell types. The target mRNAs of miRNAs were predicted and subjected to enrichment analysis. Furthermore, miRNAs and their target mRNAs with opposite expression trends were chosen to construct functional networks. Besides, qRT-PCR and RNA scope were performed to verify the expression level of representative miRNA. RESULTS: The tSNE dimensionality reduction presented 15 cell types in TBM model mice, in which microglia and endothelial cells accounted for the majority. Target mRNAs of each cell type were predicted for verification or network construction. The immune and inflammation-related miRNA-mRNA networks of macrophages and microglia, oxidative phosphorylation-related miRNA-mRNA networks of neurons, ion and protein transport-related networks of epididymal cells, and angiogenesis-related miRNA-mRNA networks of VSMCs were constructed. The miRNA activity analysis revealed that miR-21a-3p activity was increased in microglia, macrophages, neurons and epididymal cells. The result of qRT-PCR and RNA scope indicate that miR-21a-3p was significantly higher-expressed in TBM brain tissue compared with normal brain tissue. CONCLUSION: In our study, an in-depth exploration of the mRNA expression and miRNA activity of macrophages, microglia, epididymal cells, neurons and vascular smooth muscle cells during TBM progression was conducted using scRNA-Seq, which provided novel insights into the immune cell engagement in TBM patients.
Asunto(s)
MicroARNs , Tuberculosis Meníngea , Humanos , Animales , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Vacuna BCG , Tuberculosis Meníngea/genética , Células Endoteliales/metabolismo , ARN Mensajero/metabolismo , Análisis de la Célula Individual , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: The purpose of this study was to assess if single nucleotide polymorphisms (SNPs) in lung mucins MUC5B and MUC5AC are associated with Mycobacterium tuberculosis outcomes. METHODS: Independent SNPs in MUC5B and MUC5AC (genotyped by Illumina HumanOmniExpress array) were assessed for associations with tumor necrosis factor (TNF) concentrations (measured by immunoassay) in cerebral spinal fluid (CSF) from tuberculous meningitis (TBM) patients. SNPs associated with CSF TNF concentrations were carried forward for analyses of pulmonary and meningeal tuberculosis susceptibility and TBM mortality. RESULTS: MUC5AC SNP rs28737416 T allele was associated with lower CSF concentrations of TNF (P = 1.8 × 10-8) and IFN-γ (P = 2.3 × 10-6). In an additive genetic model, rs28737416 T/T genotype was associated with higher susceptibility to TBM (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.03-1.49; P = .02), but not pulmonary tuberculosis (OR, 1.11, 95% CI, .98-1.25; P = .10). TBM mortality was higher among participants with the rs28737416 T/T and T/C genotypes (35/119, 30.4%) versus the C/C genotype (11/89, 12.4%; log-rank P = .005) in a Vietnam discovery cohort (n = 210), an independent Vietnam validation cohort (n = 87; 9/87, 19.1% vs 1/20, 2.5%; log-rank P = .02), and an Indonesia validation cohort (n = 468, 127/287, 44.3% vs 65/181, 35.9%; log-rank P = .06). CONCLUSIONS: MUC5AC variants may contribute to immune changes that influence TBM outcomes.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis Meníngea , Humanos , Tuberculosis Meníngea/genética , Tuberculosis Meníngea/complicaciones , Citocinas/genética , Genotipo , Factor de Necrosis Tumoral alfa/genética , Polimorfismo de Nucleótido Simple , Mucina 5AC/genéticaRESUMEN
Tuberculous Meningitis (TBM) diagnosis remains a grave challenge. We evaluated the utility of extracellular vesicles (EVs) as a source of cell-free transrenal-mycobacterial DNA (cf-Tr-MTB DNA) for TBM diagnosis from urine samples. We developed a qPCR-assay targeting a highly repetitive 36-bp sequence specific to Mycobacterium tuberculosis complex. EVs were isolated from urine samples of suspected TBM groups (n = 44) [categorized using composite reference standard as 'Definite' TBM (n = 8), 'Probable' TBM (n = 15), 'Possible' TBM (n = 21)] and 'Non-TBM' group (n = 26). cf-Tr-MTB DNA-based qPCR assay was applied to DNA isolated from EVs (EV-DNA) and EV-free-fraction (EV-free DNA). ROC-curves were generated using qPCR results of 'Definite' TBM and 'Non-TBM' category in both EV-DNA and EV-free DNA samples and cut-off values were selected to provide 100% (95%CI:69.1-100) specificity. The cf-Tr-MTB DNA assay gave a sensitivity of 54.5% (95%CI:38.8-69.6) for EV-DNA and 77.3% (95%CI:62.1-88.5) for EV-free DNA in the TBM group (n = 44). The combination of EV-DNA and EV-free DNA results (corresponding to performance cf-Tr MTB DNA assay in urine), gave an overall sensitivity of 81.8% (95%CI:67.2-91.8) in the TBM group. Our results confirmed EVs as one of the sources of cf-Tr-MTB DNA and we believe the cf-Tr-MTB DNA-based qPCR assay has a potential application for TBM diagnosis.
Asunto(s)
Ácidos Nucleicos Libres de Células , Mycobacterium tuberculosis , Tuberculosis Meníngea , Ácidos Nucleicos Libres de Células/genética , Humanos , Técnicas de Diagnóstico Molecular/métodos , Mycobacterium tuberculosis/genética , Sensibilidad y Especificidad , Tuberculosis Meníngea/diagnóstico , Tuberculosis Meníngea/genética , Tuberculosis Meníngea/microbiologíaRESUMEN
The development of tuberculoma is a process of inflammation, necrosis, and apoptosis. Therefore, the pro-inflammatory cytokines and apoptosis biomarkers are likely to play an important role. In this study, we report the expression of TNFα, IL6, and caspase-3 at the mRNA level in the patients with tuberculous meningitis (TBM) and compare these biomarkers in the patients with and without tuberculoma. A total of 134 patients with TBM and 35 matched healthy controls were included. The clinical, cerebrospinal fluid (CSF), and cranial magnetic resonance imaging (MRI) findings were noted. The mRNA expression of TNFα, IL6, and caspase-3 in peripheral blood mononuclear cells was evaluated by reverse transcriptase polymerase chain reaction. On cranial MRI, 89 (64.2%) patients had tuberculoma, and their level of consciousness, severity of meningitis, CSF findings, and blood counts were not significantly different from those without tuberculoma. Patients with tuberculoma had a higher expression of TNFα and IL6 compared to the controls, but had lower expression compared to the patients without tuberculoma. TNFα expression positively correlated with the expression of caspase-3, but not with IL6. Twenty-five (18.6%) patients died: 12 (13.5%) in tuberculoma and 13 (28.9%) in the non-tuberculoma group. Death was related to higher expression of TNFα and caspase-3. The lower expression of TNFα and IL6 in intracranial tuberculoma suggests that these patients are unlikely to be benefited with TNFα blockers.
Asunto(s)
Tuberculoma Intracraneal , Tuberculosis Meníngea , Biomarcadores , Caspasa 3 , Humanos , Interleucina-6/genética , Leucocitos Mononucleares , ARN Mensajero/análisis , ARN Mensajero/genética , Tuberculoma Intracraneal/líquido cefalorraquídeo , Tuberculosis Meníngea/líquido cefalorraquídeo , Tuberculosis Meníngea/genética , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
The epidemiology of infectious causes of meningitis in sub-Saharan Africa is not well understood, and a common cause of meningitis in this region, Mycobacterium tuberculosis (TB), is notoriously hard to diagnose. Here we show that integrating cerebrospinal fluid (CSF) metagenomic next-generation sequencing (mNGS) with a host gene expression-based machine learning classifier (MLC) enhances diagnostic accuracy for TB meningitis (TBM) and its mimics. 368 HIV-infected Ugandan adults with subacute meningitis were prospectively enrolled. Total RNA and DNA CSF mNGS libraries were sequenced to identify meningitis pathogens. In parallel, a CSF host transcriptomic MLC to distinguish between TBM and other infections was trained and then evaluated in a blinded fashion on an independent dataset. mNGS identifies an array of infectious TBM mimics (and co-infections), including emerging, treatable, and vaccine-preventable pathogens including Wesselsbron virus, Toxoplasma gondii, Streptococcus pneumoniae, Nocardia brasiliensis, measles virus and cytomegalovirus. By leveraging the specificity of mNGS and the sensitivity of an MLC created from CSF host transcriptomes, the combined assay has high sensitivity (88.9%) and specificity (86.7%) for the detection of TBM and its many mimics. Furthermore, we achieve comparable combined assay performance at sequencing depths more amenable to performing diagnostic mNGS in low resource settings.
Asunto(s)
Meningitis , Mycobacterium tuberculosis , Tuberculosis Meníngea , Sistema Nervioso Central , Humanos , Meningitis/microbiología , Metagenómica , Mycobacterium tuberculosis/genética , Tuberculosis Meníngea/líquido cefalorraquídeo , Tuberculosis Meníngea/diagnóstico , Tuberculosis Meníngea/genéticaRESUMEN
BACKGROUND: Central nervous system (CNS) has a different immune surveillance system; therefore, fever at admission and timeline of fever response after antitubercular treatment (ATT) may follow a different course in CNS infection. We report the predictors of fever response in tuberculous meningitis (TBM) including the effect of tumour necrosis factor-α (TNF-α) in cerebrospinal fluid (CSF) and its gene expression at mRNA of peripheral blood mononuclear cells (PBMCs). METHODS: Fifty-seven patients with TBM were prospectively evaluated. Their clinical findings and severity of meningitis were recorded. The expression of TNF-α gene in PBMCs was quantified by real-time polymerase chain reaction and TNF-α concentration in CSF by cytokine bead array both in the patients and 14 matched controls. RESULTS: All the patients had history of fever for a median duration of 75 days. The admission temperature ranged between 37.2°C and 40°C and correlated with CSF cell counts (p < 0.05). Cranial MRI was abnormal in 54 (94.7%) and revealed exudates in 33(57.9%), hydrocephalus in 27(47.4%), infarction in 27(47.4%) and tuberculoma in 33(57.9%) patients. Fever subsided after a median duration of 18 (2 60) days of treatment. Twelve (21.8%) patients only became afebrile within 10 days. The expression of TNF-α gene correlated with CSF concentration of TNF-α (p = 0.02) and independently predicted duration of defervescence [adjusted hazard ratio 1.02 (95% CI 1.00-1.04; p = 0.01). CONCLUSION: In the patients with TBM, defervescence takes longer time, and TNF-α gene expression predicts the duration of defervescence. Future studies are needed to evaluate the role of TNF-α-modifying drugs in TBM.
Asunto(s)
Fiebre/etiología , Imagen por Resonancia Magnética , Tuberculosis Meníngea/complicaciones , Tuberculosis Meníngea/diagnóstico por imagen , Adolescente , Adulto , Anciano , Biomarcadores , Niño , Femenino , Expresión Génica , Humanos , Leucocitos Mononucleares , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tuberculosis Meníngea/líquido cefalorraquídeo , Tuberculosis Meníngea/genética , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/genética , Adulto JovenRESUMEN
We conducted a prospective cohort study to determine the prevalence of leukotriene A4 hydrolase (LTA4H) polymorphisms in Zambian adults with tuberculous meningitis (TBM) and its association with mortality. We completed genotype testing on 101 definite cases of TBM and 119 consecutive non-TBM controls. The distribution of genotypes among TBM patients was as follows: C/C (0.83), C/T (0.14), T/T (0.03). There was no significant difference in genotype distribution between TBM and non-TBM patients. We found no relationship between LTA4H polymorphism and survival. Prospective studies are needed to determine the benefit of adjuvant steroids in TBM based upon population LTA4H genotype. ANN NEUROL 2021;90:994-998.
Asunto(s)
Epóxido Hidrolasas/genética , Genotipo , Tuberculosis Meníngea/genética , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Prevalencia , Tasa de Supervivencia , Tuberculosis Meníngea/mortalidad , Adulto Joven , Zambia/epidemiologíaRESUMEN
OBJECTIVES: Tuberculous meningitis (TBM) is the most severe form of infection caused by Mycobacterium tuberculosis (Mtb). Smurf1 represents a key component in anti-Mtb autophagic targeting in macrophages and in anti-TB host defense in vivo. We hypothesized that genetic variants in the Smurf1 gene region influence susceptibility to TBM. METHODS: Using a case-control study design (235 TBM cases, 239 pulmonary TB cases and 478 healthy controls), we evaluated whether 8 haplotype-tagging single nucleotide polymorphisms (SNPs) in the Smurf1 gene are associated with the development of TBM. RESULTS: Even with the most conservative correction, the polymorphism rs6956450 was associated with TBM under a dominant model (odds ratio [OR], 1.653; 95% confidence interval [CI], 1.192-2.294; P = 0.021), the CG haplotype consisting of rs3294 and rs6956450 was positively associated with TBM (P = 0.013) and another haplotype GC remained negatively associated with TBM in Tibetan subgroup (P < 0.001). No correlation was found between rs6956450 and TBM clinical characteristics or prognosis. CONCLUSIONS: These results firstly link the variants in the Smurf1 gene region with TBM risk, indicating an important role for Smurf1 in the immunopathogenesis of TBM. Future studies will dissect the mechanism, which may help identify targets or genetic markers to guide diagnosis or host-directed therapy in patients with TBM.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Variación Genética , Tuberculosis Meníngea/diagnóstico , Tuberculosis Meníngea/genética , Ubiquitina-Proteína Ligasas/genética , Estudios de Casos y Controles , Femenino , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
Adjunctive treatment with antiinflammatory corticosteroids like dexamethasone increases survival in tuberculosis meningitis. Dexamethasone responsiveness associates with a C/T variant in Leukotriene A4 Hydrolase (LTA4H), which regulates expression of the proinflammatory mediator leukotriene B4 (LTB4). TT homozygotes, with increased expression of LTA4H, have the highest survival when treated with dexamethasone and the lowest survival without. While the T allele is present in only a minority of the world's population, corticosteroids confer modest survival benefit worldwide. Using Bayesian methods, we examined how pretreatment levels of cerebrospinal fluid proinflammatory cytokines affect survival in dexamethasone-treated tuberculous meningitis. LTA4H TT homozygosity was associated with global cytokine increases, including tumor necrosis factor. Association between higher cytokine levels and survival extended to non-TT patients, suggesting that other genetic variants may also induce dexamethasone-responsive pathological inflammation. These findings warrant studies that tailor dexamethasone therapy to pretreatment cerebrospinal fluid cytokine concentrations, while searching for additional genetic loci shaping the inflammatory milieu.
Asunto(s)
Citocinas/líquido cefalorraquídeo , Dexametasona/administración & dosificación , Epóxido Hidrolasas/genética , Variación Genética , Tuberculosis Meníngea , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Tasa de Supervivencia , Tuberculosis Meníngea/líquido cefalorraquídeo , Tuberculosis Meníngea/tratamiento farmacológico , Tuberculosis Meníngea/genética , Tuberculosis Meníngea/mortalidadRESUMEN
Metagenomic next-generation sequencing (mNGS) is an emerging sequence-based method that detects genomic information of pathogenic microorganisms from a wide range of clinical specimens. The mNGS has moderate sensitivity and very high specificity for tuberculous meningitis, and the validity of mNGS was higher than that of Xpert MTB/RIF.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Metagenómica/métodos , Técnicas de Diagnóstico Molecular/métodos , Mycobacterium tuberculosis/genética , Tuberculosis Meníngea/diagnóstico , Tuberculosis Meníngea/genética , Técnicas Bacteriológicas/métodos , Humanos , Metagenoma , Mycobacterium tuberculosis/aislamiento & purificación , Sensibilidad y Especificidad , Tuberculosis Meníngea/microbiologíaRESUMEN
Tubercular meningitis (TBM) continues to be a common cause of neuromorbidity in children. There is no single diagnostic method that can rapidly detect Mycobacterium tuberculosis (M.tb) in TBM patients with high sensitivity and specificity. Newer diagnostic modalities like Xpert/RIF assay and Loop mediated isothermal amplification assay (LAMP) have gained an essential stand in molecular diagnostics due to their high specificity, modest sensitivity in cerebrospinal fluid (CSF) and quick availability of results. Intensified drug regimens using high dose rifampicin, fluoroquinolone and aspirin appear to be useful adjunct therapy but more pediatric clinical trials on large scale are needed to determine their appropriate place in pediatric TBM. The emergence of multi and extreme drug resistant M.tb strains further challenges the standard therapy. In this review authors summarize challenges of the currently used diagnostic methods and treatment for TBM and discuss the recent advances.
Asunto(s)
Técnicas de Diagnóstico Molecular/métodos , Mycobacterium tuberculosis/genética , Técnicas de Amplificación de Ácido Nucleico/métodos , Tuberculosis Meníngea/diagnóstico , Tuberculosis Meníngea/tratamiento farmacológico , Antituberculosos/administración & dosificación , Antituberculosos/efectos adversos , Antituberculosos/uso terapéutico , Aspirina/administración & dosificación , Aspirina/uso terapéutico , Niño , Farmacorresistencia Bacteriana/efectos de los fármacos , Fluoroquinolonas/administración & dosificación , Fluoroquinolonas/uso terapéutico , Humanos , Mycobacterium tuberculosis/aislamiento & purificación , Rifampin/administración & dosificación , Rifampin/uso terapéutico , Sensibilidad y Especificidad , Tuberculosis Meníngea/genéticaRESUMEN
Tuberculous meningitis (TBM) is a commonly encountered central nervous system infection. Characteristic clinical, imaging and cerebrospinal fluid parameters help clinicians to make a prompt presumptive diagnosis that enables them to start empirical anti-tuberculosis treatment. There are several close mimic to TBM, such as partially treated pyogenic meningitis, fungal meningitis, sarcoidosis, meningeal metastases and meningeal lymphomatosis. Microbiological confirmation instils a sense of confidence amongst treating physicians. With conventional phenotypic methods (cerebrospinal fluid microscopy and culture), in more than 50 per cent patients, microbiological confirmation is not achieved. Moreover, these methods take a long time before providing conclusive results. Negative result does not rule out Mycobacterium tuberculosis infection of the brain. Genotypic methods, such as IS 6110 polymerase chain reaction and automated Xpert M. tuberculosis/rifampicin (MTB/RIF) assay system improved the TBM diagnostics, as results are rapidly available. Xpert MTB/RIF assay, in addition, detects rifampicin resistance. Xpert MTB/RIF Ultra is advanced technology which has higher (60-70%) sensitivity and is being considered a game-changer in the diagnostics of TBM. A large number of TBM cases remain unconfirmed. The situation of TBM diagnostics will remain grim, if low-cost technologies are not widely available. Till then, physicians continue to rely on their clinical acumen to start empirical anti-tuberculosis treatment.
Asunto(s)
Pruebas Diagnósticas de Rutina , Mycobacterium tuberculosis/aislamiento & purificación , Tuberculosis Meníngea/diagnóstico , Tuberculosis Meníngea/tratamiento farmacológico , Antibióticos Antituberculosos/uso terapéutico , Genotipo , Humanos , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/patogenicidad , Fenotipo , Rifampin/uso terapéutico , Tuberculosis Meníngea/genética , Tuberculosis Meníngea/microbiologíaRESUMEN
Tuberculous meningitis (TBM) is a severe form of tuberculosis with a high mortality rate. The factors associated with TBM pathogenesis are still unclear. Using comparative whole-genome sequence analysis we compared Mycobacterium tuberculosis (Mtb) isolates from cerebrospinal fluid of TBM cases (n = 73) with those from sputum of pulmonary tuberculosis (PulTB) patients (n = 220) from Thailand. The aim of this study was to seek genetic variants of Mtb associated with TBM. Regardless of Mtb lineage, we found 242 variants that were common to all TBM isolates. Among these variants, 28 were missense SNPs occurring mainly in the pks genes (involving polyketide synthesis) and the PE/PPE gene. Six lineage-independent SNPs were commonly found in TBM isolates, two of which were missense SNPs in Rv0532 (PE_PGRS6). Structural variant analysis revealed that PulTB isolates had 14 genomic regions containing 2-3-fold greater read depth, indicating higher copy number variants and half of these genes belonged to the PE/PPE gene family. Phylogenetic analysis revealed only two small clusters of TBM clonal isolates without support from epidemiological data. This study reported genetic variants of Mtb commonly found in TBM patients compared to PulTB patients. Variants associated with TBM disease warrant further investigation.
Asunto(s)
Proteínas Bacterianas/genética , Genotipo , Mycobacterium tuberculosis/genética , Tuberculosis Meníngea/microbiología , Tuberculosis Pulmonar/microbiología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Filogenia , Sintasas Poliquetidas/genética , Polimorfismo de Nucleótido Simple , Tuberculosis Meníngea/genética , Tuberculosis Pulmonar/genética , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
Humans exposed to Mycobacterium tuberculosis (Mtb) have variable susceptibility to tuberculosis (TB) and its outcomes. Siglec-5 and Siglec-14 are members of the sialic-acid binding lectin family that regulate immune responses to pathogens through inhibitory (Siglec-5) and activating (Siglec-14) domains. The SIGLEC14 coding sequence is deleted in a high proportion of individuals, placing a SIGLEC5-like gene under the expression of the SIGLEC14 promoter (the SIGLEC14 null allele) and causing expression of a Siglec-5 like protein in monocytes and macrophages. We hypothesized that the SIGLEC14 null allele was associated with Mtb replication in monocytes, T-cell responses to the BCG vaccine, and clinical susceptibility to TB. The SIGLEC14 null allele was associated with protection from TB meningitis in Vietnamese adults but not with pediatric TB in South Africa. The null allele was associated with increased IL-2 and IL-17 production following ex-vivo BCG stimulation of blood from 10 week-old South African infants vaccinated with BCG at birth. Mtb replication was increased in THP-1 cells overexpressing either Siglec-5 or Siglec-14 relative to controls. To our knowledge, this is the first study to demonstrate an association between SIGLEC expression and clinical TB, Mtb replication, or BCG-specific T-cell cytokines.
Asunto(s)
Vacuna BCG/administración & dosificación , Lectinas/genética , Mycobacterium tuberculosis/inmunología , Receptores de Superficie Celular/genética , Tuberculosis Meníngea/genética , Tuberculosis Meníngea/prevención & control , Tuberculosis Pulmonar/genética , Tuberculosis Pulmonar/prevención & control , Vacunación , Inmunidad Adaptativa , Adolescente , Adulto , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación Mielomonocítica/genética , Antígenos de Diferenciación Mielomonocítica/inmunología , Vacuna BCG/inmunología , Estudios de Casos y Controles , Preescolar , Citocinas/inmunología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Interacciones Huésped-Patógeno , Humanos , Lactante , Recién Nacido , Lectinas/inmunología , Masculino , Monocitos/inmunología , Monocitos/microbiología , Mycobacterium tuberculosis/crecimiento & desarrollo , Fenotipo , Estudios Prospectivos , Receptores de Superficie Celular/inmunología , Sudáfrica , Linfocitos T/inmunología , Linfocitos T/microbiología , Células THP-1 , Factores de Tiempo , Resultado del Tratamiento , Tuberculosis Meníngea/inmunología , Tuberculosis Meníngea/microbiología , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , VietnamRESUMEN
Background: Damaging inflammation is thought to contribute to the high morbidity and mortality of tuberculous meningitis (TBM), but the link between inflammation and outcome remains unclear. Methods: We performed prospective clinical and routine laboratory analyses of a cohort of adult patients with TBM in Indonesia. We also examined the LTA4H promoter polymorphism, which predicted cerebrospinal fluid (CSF) leukocyte count and survival of Vietnamese patients with TBM. Patients were followed for >1 year. Results: We included 608 patients with TBM, of whom 67.1% had bacteriological confirmation of disease and 88.2% had severe (ie, grade II or III) disease. One-year mortality was 43.7% and strongly associated with decreased consciousness, fever, and focal neurological signs. Human immunodeficiency virus (HIV) infection, present in 15.3% of patients, was associated with higher mortality and different CSF characteristics, compared with absence of HIV infection. Among HIV-uninfected patients, mortality was associated with higher CSF neutrophil counts (hazard ratio [HR], 1.10 per 10% increase; 95% confidence interval [CI], 1.04-1.16), low CSF to blood glucose ratio (HR, 1.16 per 0.10 decrease; 95% CI, 1.04-1.30), CSF culture positivity (HR, 1.37; 95% CI, 1.02-1.84), and blood neutrophilia (HR, 1.06 per 109 neutrophils/L increase; 95% CI, 1.03-1.10). The LTA4H promoter polymorphism correlated with CSF mononuclear cell count but not with mortality (P = .915). Conclusions: A strong neutrophil response and fever may contribute to or be a result of (immuno)pathology in TBM. Aggressive fever control might improve outcome, and more-precise characterization of CSF leukocytes could guide possible host-directed therapeutic strategies in TBM.
Asunto(s)
Epóxido Hidrolasas/genética , Inflamación/microbiología , Tuberculosis Meníngea/mortalidad , Adulto , Líquido Cefalorraquídeo/citología , Femenino , Genotipo , Infecciones por VIH/complicaciones , Infecciones por VIH/microbiología , Humanos , Indonesia , Inflamación/virología , Estimación de Kaplan-Meier , Recuento de Leucocitos , Masculino , Análisis Multivariante , Mycobacterium tuberculosis , Neutrófilos/inmunología , Regiones Promotoras Genéticas , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Tuberculosis Meníngea/complicaciones , Tuberculosis Meníngea/genética , Adulto JovenRESUMEN
Background: Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM. Methods: We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM. All were genotyped for single-nucleotide polymorphism rs17525495, and inflammatory phenotype was defined by cerebrospinal fluid (CSF) leukocyte and cytokine concentrations. Results: LTA4H genotype predicted survival of human immunodeficiency virus (HIV)-uninfected patients, with TT-genotype patients significantly more likely to survive TBM than CC-genotype patients, according to Cox regression analysis (univariate P = .040 and multivariable P = .037). HIV-uninfected, TT-genotype patients had high CSF proinflammatory cytokine concentrations, with intermediate and lower concentrations in those with CT and CC genotypes. Increased CSF cytokine concentrations correlated with more-severe disease, but patients with low CSF leukocytes and cytokine concentrations were more likely to die from TBM. HIV infection independently predicted death due to TBM (hazard ratio, 3.94; 95% confidence interval, 2.79-5.56) and was associated with globally increased CSF cytokine concentrations, independent of LTA4H genotype. Conclusions: LTA4H genotype and HIV infection influence pretreatment inflammatory phenotype and survival from TBM. LTA4H genotype may predict adjunctive corticosteroid responsiveness in HIV-uninfected individuals.