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1.
Nat Commun ; 14(1): 188, 2023 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635274

RESUMO

Few studies from Africa have described the clinical impact of co-infections on SARS-CoV-2 infection. Here, we investigate the presentation and outcome of SARS-CoV-2 infection in an African setting of high HIV-1 and tuberculosis prevalence by an observational case cohort of SARS-CoV-2 patients. A comparator group of non SARS-CoV-2 participants is included. The study includes 104 adults with SARS-CoV-2 infection of whom 29.8% are HIV-1 co-infected. Two or more co-morbidities are present in 57.7% of participants, including HIV-1 (30%) and active tuberculosis (14%). Amongst patients dually infected by tuberculosis and SARS-CoV-2, clinical features can be typical of either SARS-CoV-2 or tuberculosis: lymphopenia is exacerbated, and some markers of inflammation (D-dimer and ferritin) are further elevated (p < 0.05). Amongst HIV-1 co-infected participants those with low CD4 percentage strata exhibit reduced total, but not neutralising, anti-SARS-CoV-2 antibodies. SARS-CoV-2 specific CD8 T cell responses are present in 35.8% participants overall but undetectable in combined HIV-1 and tuberculosis. Death occurred in 30/104 (29%) of all COVID-19 patients and in 6/15 (40%) of patients with coincident SARS-CoV-2 and tuberculosis. This shows that in a high incidence setting, tuberculosis is a common co-morbidity in patients admitted to hospital with COVID-19. The immune response to SARS-CoV-2 is adversely affected by co-existent HIV-1 and tuberculosis.


Assuntos
COVID-19 , Infecções por HIV , Tuberculose , Adulto , Humanos , África/epidemiologia , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/imunologia , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , HIV-1 , Imunidade , SARS-CoV-2 , Tuberculose/complicações , Tuberculose/epidemiologia
2.
Clin Infect Dis ; 76(8): 1412-1422, 2023 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-36482216

RESUMO

BACKGROUND: Drug regimens that include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in tuberculous meningitis (TBM). Safety data on their use in combination and in the context of human immunodeficiency virus (HIV) are needed to inform clinical trial design. METHODS: We conducted a phase 2, open-label, parallel-design, randomized, controlled trial to assess the safety of high-dose rifampicin, linezolid, and high-dose aspirin in HIV-associated TBM. Participants were randomized (1.4:1:1) to 3 treatment arms (1, standard of care [SOC]; 2, SOC + additional rifampicin [up to 35 mg/kg/d] + linezolid 1200 mg/d reducing after 28 days to 600 mg/d; 3, as per arm 2 + aspirin 1000 mg/d) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed. RESULTS: A total of 52 participants with HIV-associated TBM were randomized; 59% had mild disease (British Medical Research Council (MRC) grade 1) vs 39% (grade 2) vs 2% (grade 3). AESI or death occurred in 10 of 16 (63%; arm 3) vs 4 of 14 (29%; arm 2) vs 6 of 20 (30%; arm 1; P = .083). The cumulative proportion of AESI or death (Kaplan-Meier) demonstrated worse outcomes in arm 3 vs arm 1 (P = .04); however, only 1 event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (modified Rankin scale) between arms. CONCLUSIONS: High-dose rifampicin and adjunctive linezolid can safely be added to the standard of care in HIV-associated TBM. Larger studies are required to determine whether potential toxicity associated with these interventions, particularly high-dose aspirin, is outweighed by mortality or morbidity benefit. CLINICAL TRIALS REGISTRATION: NCT03927313.


Assuntos
Infecções por HIV , Tuberculose Meníngea , Humanos , Rifampina/efeitos adversos , Antituberculosos/efeitos adversos , Aspirina/efeitos adversos , Tuberculose Meníngea/complicações , Tuberculose Meníngea/tratamento farmacológico , Linezolida/efeitos adversos , HIV , Resultado do Tratamento , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico
3.
BMC Bioinformatics ; 23(1): 481, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376837

RESUMO

BACKGROUND: Single sample pathway analysis (ssPA) transforms molecular level omics data to the pathway level, enabling the discovery of patient-specific pathway signatures. Compared to conventional pathway analysis, ssPA overcomes the limitations by enabling multi-group comparisons, alongside facilitating numerous downstream analyses such as pathway-based machine learning. While in transcriptomics ssPA is a widely used technique, there is little literature evaluating its suitability for metabolomics. Here we provide a benchmark of established ssPA methods (ssGSEA, GSVA, SVD (PLAGE), and z-score) alongside the evaluation of two novel methods we propose: ssClustPA and kPCA, using semi-synthetic metabolomics data. We then demonstrate how ssPA can facilitate pathway-based interpretation of metabolomics data by performing a case-study on inflammatory bowel disease mass spectrometry data, using clustering to determine subtype-specific pathway signatures. RESULTS: While GSEA-based and z-score methods outperformed the others in terms of recall, clustering/dimensionality reduction-based methods provided higher precision at moderate-to-high effect sizes. A case study applying ssPA to inflammatory bowel disease data demonstrates how these methods yield a much richer depth of interpretation than conventional approaches, for example by clustering pathway scores to visualise a pathway-based patient subtype-specific correlation network. We also developed the sspa python package (freely available at https://pypi.org/project/sspa/ ), providing implementations of all the methods benchmarked in this study. CONCLUSION: This work underscores the value ssPA methods can add to metabolomic studies and provides a useful reference for those wishing to apply ssPA methods to metabolomics data.


Assuntos
Doenças Inflamatórias Intestinais , Metabolômica , Humanos , Metabolômica/métodos , Transcriptoma , Análise por Conglomerados , Espectrometria de Massas
5.
Eur J Immunol ; 52(7): 1112-1119, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35398886

RESUMO

Immune reconstitution inflammatory syndrome (IRIS) can be a complication of antiretroviral therapy (ART) in patients with advanced HIV, but its pathogenesis is uncertain. In tuberculosis (TB) endemic countries, IRIS is often associated with mycobacterial infections or Bacille-Calmette-Guerin (BCG) vaccination in children. With no predictive or confirmatory tests at present, IRIS remains a diagnosis of exclusion. We tested whether RISK6 and Sweeney3, validated immune-based blood transcriptomic signatures for TB, could predict or diagnose IRIS in HIV+ children and adults. Transcripts were measured by RT-qPCR in BCG-vaccinated children and by microarray in HIV+ adults with TB including TB meningitis (TBM). Signature scores before ART initiation and up to IRIS diagnosis were compared between participants who did or did not develop IRIS. In children, RISK6 and Sweeney3 discriminated IRIS cases from non-IRIS controls before ART, and at diagnosis. In adults with TB, RISK6 discriminated IRIS cases from controls after half-week on ART and at TB-IRIS onset. In adults with TBM, only Sweeney3 discriminated IRIS cases from controls before ART, while both signatures distinguished cases from controls at TB-IRIS onset. Parsimonious whole blood transcriptomic signatures for TB showed potential to predict and diagnose IRIS in HIV+ children and adults.


Assuntos
Infecções por HIV , Síndrome Inflamatória da Reconstituição Imune , Tuberculose , Adulto , Vacina BCG , Criança , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Síndrome Inflamatória da Reconstituição Imune/complicações , Síndrome Inflamatória da Reconstituição Imune/diagnóstico , Transcriptoma , Tuberculose/diagnóstico
6.
mBio ; 12(6): e0176621, 2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-34872348

RESUMO

The crucial transmission phase of tuberculosis (TB) relies on infectious sputum and yet cannot easily be modeled. We applied one-step RNA sequencing (RNA-Seq) to sputum from infectious TB patients to investigate the host and microbial environments underlying transmission of Mycobacterium tuberculosis. In such TB sputa, compared to non-TB controls, transcriptional upregulation of inflammatory responses, including an interferon-driven proinflammatory response and a metabolic shift toward glycolysis, was observed in the host. Among all bacterial sequences in the sputum, approximately 1.5% originated from M. tuberculosis, and its transcript abundance was lower in HIV-1-coinfected patients. Commensal bacterial abundance was reduced in the presence of M. tuberculosis infection. Direct alignment to the genomes of the predominant microbiota species also reveals differential adaptation, whereby firmicutes (e.g., streptococci) displayed a nonreplicating phenotype with reduced transcription of ribosomal proteins and reduced activities of ATP synthases, while Neisseria and Prevotella spp. were less affected. The transcriptome of sputum M. tuberculosis more closely resembled aerobic replication and shared similarity in carbon metabolism to in vitro and in vivo models with significant upregulation of genes associated with cholesterol metabolism and downstream propionate detoxification pathways. In addition, and counter to previous reports on intracellular M. tuberculosis infection in vitro, M. tuberculosis in sputum was zinc, but not iron, deprived, and the phoP loci were also significantly downregulated, suggesting that the pathogen is likely extracellular in location. IMPORTANCE Although a few studies have described the microbiome composition of TB sputa based on 16S ribosomal DNA, these studies did not compare to non-TB samples and the nature of the method does not allow any functional inference. This is the first study to apply such technology using clinical specimens and obtained functional transcriptional data on all three aspects simultaneously. We anticipate that an improved understanding on the biological interactions in the respiratory tract may also allow novel interventions, such as those involving microbiome manipulation or inhibitor targeting disease-specific metabolic pathways.


Assuntos
Bactérias/genética , Colesterol/metabolismo , Microbiota , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Escarro/microbiologia , Tuberculose Pulmonar/microbiologia , Bactérias/classificação , Bactérias/isolamento & purificação , Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Humanos , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/isolamento & purificação , Escarro/química , Transcriptoma
7.
Wellcome Open Res ; 6: 136, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34286103

RESUMO

Background: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis with a mortality of ~50% in those co-infected with HIV-1. Current antibiotic regimens are based on those known to be effective in pulmonary TB and do not account for the differing ability of the drugs to penetrate the central nervous system (CNS). The host immune response drives pathology in TBM, yet effective host-directed therapies are scarce. There is sufficient data to suggest that higher doses of rifampicin (RIF), additional linezolid (LZD) and adjunctive aspirin (ASA) will be beneficial in TBM yet rigorous investigation of the safety of these interventions in the context of HIV associated TBM is required. We hypothesise that increased dose RIF, LZD and ASA used in combination and in addition to standard of care for the first 56 days of treatment with be safe and tolerated in HIV-1 infected people with TBM. Methods: In an open-label randomised parallel study, up to 100 participants will receive either; i) standard of care (n=40, control arm), ii) standard of care plus increased dose RIF (35mg/kg) and LZD (1200mg OD for 28 days, 600mg OD for 28 days) (n=30, experimental arm 1), or iii) as per experimental arm 1 plus additional ASA 1000mg OD (n=30, experimental arm 2). After 56 days participants will continue standard treatment as per national guidelines. The primary endpoint is death and the occurrence of solicited treatment-related adverse events at 56 days. In a planned pharmacokinetic (PK) sub-study we aim to assess PK/pharmacodynamic (PD) of oral vs IV rifampicin, describe LZD and RIF PK and cerebrospinal fluid concentrations, explore PK/PD relationships, and investigate drug-drug interactions between LZD and RIF. Safety and pharmacokinetic data from this study will inform a planned phase III study of intensified therapy in TBM. Clinicaltrials.gov registration: NCT03927313 (25/04/2019).

8.
Front Immunol ; 12: 763364, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35003075

RESUMO

Mycobacterium tuberculosis (Mtb) genes encoding proteins targeted by vaccines and drugs should be expressed in the lung, the main organ affected by Mtb, for these to be effective. However, the pulmonary expression of most Mtb genes and their proteins remains poorly characterized. The aim of this study is to fill this knowledge gap. We analyzed large scale transcriptomic datasets from specimens of Mtb-infected humans, TB-hypersusceptible (C3H/FeJ) and TB-resistant (C57BL/6J) mice and compared data to in vitro cultured Mtb gene-expression profiles. Results revealed high concordance in the most abundantly in vivo expressed genes between pulmonary Mtb transcriptomes from different datasets and different species. As expected, this contrasted with a lower correlation found with the highest expressed Mtb genes from in vitro datasets. Among the most consistently and highly in vivo expressed genes, 35 have not yet been explored as targets for vaccination or treatment. More than half of these genes are involved in protein synthesis or metabolic pathways. This first lung-oriented multi-study analysis of the in vivo expressed Mtb-transcriptome provides essential data that considerably increase our understanding of pulmonary TB infection biology, and identifies novel molecules for target-based TB-vaccine and drug development.


Assuntos
Pulmão/metabolismo , Mycobacterium tuberculosis/genética , Transcriptoma , Animais , Antígenos de Bactérias/genética , Humanos , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose
9.
JCI Insight ; 5(10)2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32369443

RESUMO

The ability of Mycobacterium tuberculosis to form serpentine cords is intrinsically related to its virulence, but specifically how M. tuberculosis cording contributes to pathogenesis remains obscure. Here, we show that several M. tuberculosis clinical isolates form intracellular cords in primary human lymphatic endothelial cells (hLECs) in vitro and in the lymph nodes of patients with tuberculosis. We identified via RNA-Seq a transcriptional program that activated, in infected-hLECs, cell survival and cytosolic surveillance of pathogens pathways. Consistent with this, cytosolic access was required for intracellular M. tuberculosis cording. Mycobacteria lacking ESX-1 type VII secretion system or phthiocerol dimycocerosates expression, which failed to access the cytosol, were indeed unable to form cords within hLECs. Finally, we show that M. tuberculosis cording is a size-dependent mechanism used by the pathogen to avoid its recognition by cytosolic sensors and evade either resting or IFN-γ-induced hLEC immunity. These results explain the long-standing association between M. tuberculosis cording and virulence and how virulent mycobacteria use intracellular cording as strategy to successfully adapt and persist in the lymphatic tracts.


Assuntos
Antígenos de Bactérias , Proteínas de Bactérias , Células Endoteliais , Evasão da Resposta Imune , Mycobacterium tuberculosis , Tuberculose , Fatores de Virulência , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Células Cultivadas , Células Endoteliais/imunologia , Células Endoteliais/microbiologia , Células Endoteliais/patologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , RNA-Seq , Tuberculose/genética , Tuberculose/imunologia , Tuberculose/patologia , Fatores de Virulência/genética , Fatores de Virulência/imunologia
10.
Wellcome Open Res ; 5: 292, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-35118196

RESUMO

A dysregulated host immune response significantly contributes to morbidity and mortality in tuberculous meningitis (TBM). Effective host directed therapies (HDTs) are critical to improve survival and clinical outcomes. Currently only one HDT, dexamethasone, is proven to improve mortality. However, there is no evidence dexamethasone reduces morbidity, how it reduces mortality is uncertain, and it has no proven benefit in HIV co-infected individuals. Further research on these aspects of its use, as well as alternative HDTs such as aspirin, thalidomide and other immunomodulatory drugs is needed. Based on new knowledge from pathogenesis studies, repurposed therapeutics which act upon small molecule drug targets may also have a role in TBM. Here we review existing literature investigating HDTs in TBM, and propose new rationale for the use of novel and repurposed drugs. We also discuss host variable responses and evidence to support a personalised approach to HDTs in TBM.

11.
Nat Commun ; 10(1): 3767, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434901

RESUMO

Tuberculous meningitis (TBM) is the most severe form of TB with high rates of mortality and morbidity. Here we conduct RNA-sequencing on whole blood as well as on ventricular and lumbar cerebrospinal fluid (CSF) of pediatric patients treated for TBM. Differential transcript expression of TBM cases are compared with healthy controls in whole blood and with non-TB cerebral infection controls in CSF. Whole blood RNA-Seq analysis demonstrates a distinct immune response pattern in TBM, with significant increase in both canonical and non-canonical inflammasome activation and decrease in T-cell activation. In ventricular CSF, a significant enrichment associated with neuronal excitotoxicity and cerebral damage is detected in TBM. Finally, compartmental comparison in TBM indicates that the ventricular profile represents brain injury whereas the lumbar profile represents protein translation and cytokine signaling. Together, transcriptomic analysis shows that disease processes differ between the periphery and the central nervous system, and within brain compartments.


Assuntos
Sistema Nervoso/imunologia , Tuberculose Meníngea/líquido cefalorraquidiano , Tuberculose Meníngea/imunologia , Criança , Pré-Escolar , Citocinas , Feminino , Humanos , Lactente , Masculino , Mycobacterium tuberculosis , Sistema Nervoso/microbiologia , Análise de Sequência de RNA , Transcriptoma , Tuberculose Meníngea/sangue
12.
Expert Rev Respir Med ; 12(10): 881-891, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30138039

RESUMO

INTRODUCTION: Inflammation, or the prolonged resolution of inflammation, contributes to death from tuberculosis. Interest in inflammatory mechanisms and the prospect of beneficial immune modulation as an adjunct to antibacterial therapy has revived and the concept of host directed therapies has been advanced. Such renewed attention has however, overlooked the experience of such therapy with corticosteroids. Areas covered: The authors conducted literature searches and evaluated randomized clinical trials, systematic reviews and current guidelines and summarize these findings. They found evidence of benefit in meningeal and pericardial tuberculosis in HIV-1 uninfected persons, but less so in those HIV-1 coinfected and evidence of harm in the form of opportunist malignancy in those not prescribed antiretroviral therapy. Adjunctive corticosteroids are however of benefit in the treatment and prevention of paradoxical HIV-tuberculosis immune reconstitution inflammatory syndrome. Expert commentary: Further high-quality clinical trials and experimental medicine studies are warranted and analysis of materials arising from such studies could illuminate ways to improve corticosteroid efficacy or identify novel pathways for more specific intervention.


Assuntos
Antituberculosos/uso terapêutico , Glucocorticoides/uso terapêutico , Tuberculose/tratamento farmacológico , Quimioterapia Combinada , Humanos
13.
Int J Cardiol Heart Vasc ; 18: 104-108, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29750184

RESUMO

BACKGROUND: Pericardial disorders are a common cause of heart disease, and the most common cause of pericarditis in developing countries is tuberculous (TB) pericarditis. It has been shown that prednisolone added to standard anti-TB therapy leads to a lower rate of constrictive pericarditis. We conducted a pilot study to evaluate the effect of adjunctive prednisolone treatment on the concentration of inflammatory markers in pericardial tuberculosis, in order to inform immunological mechanisms at the disease site. METHODS: Pericardial fluid, plasma and saliva samples were collected from fourteen patients with pericardial tuberculosis, at multiple time points. Inflammatory markers were measured using multiplex luminex analysis and ELISA. RESULTS: In samples from 14 patients we confirmed a strongly compartmentalized immune response at the disease site and found that prednisolone significantly reduced IL-6 concentrations in plasma by 8 hours of treatment, IL-1beta concentrations in saliva, as well as IL-8 concentrations in both pericardial fluid and saliva by 24 hours. CONCLUSION: Monitoring the early effect of adjunctive immunotherapy in plasma or saliva is a possibility in pericarditis.

14.
Proc Natl Acad Sci U S A ; 115(5): E964-E973, 2018 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-29339504

RESUMO

The transition between latent and active tuberculosis (TB) occurs before symptom onset. Better understanding of the early events in subclinical disease will facilitate the development of diagnostics and interventions that improve TB control. This is particularly relevant in the context of HIV-1 coinfection where progression of TB is more likely. In a recent study using [18F]-fluoro-2-deoxy-d-glucose positron emission/computed tomography (FDG-PET/CT) on 35 asymptomatic, HIV-1-infected adults, we identified 10 participants with radiographic evidence of subclinical disease, significantly more likely to progress than the 25 participants without. To gain insight into the biological events in early disease, we performed blood-based whole genome transcriptomic analysis on these participants and 15 active patients with TB. We found transcripts representing the classical complement pathway and Fcγ receptor 1 overabundant from subclinical stages of disease. Levels of circulating immune (antibody/antigen) complexes also increased in subclinical disease and were highly correlated with C1q transcript abundance. To validate our findings, we analyzed transcriptomic data from a publicly available dataset where samples were available in the 2 y before TB disease presentation. Transcripts representing the classical complement pathway and Fcγ receptor 1 were also differentially expressed in the 12 mo before disease presentation. Our results indicate that levels of antibody/antigen complexes increase early in disease, associated with increased gene expression of C1q and Fcγ receptors that bind them. Understanding the role this plays in disease progression may facilitate development of interventions that prevent this, leading to a more favorable outcome and may also be important to diagnostic development.


Assuntos
Complexo Antígeno-Anticorpo/sangue , Proteínas do Sistema Complemento/genética , Infecções por HIV/imunologia , Tuberculose/imunologia , Anticorpos/sangue , Análise por Conglomerados , Coinfecção , Comorbidade , Progressão da Doença , Fluordesoxiglucose F18 , Infecções por HIV/complicações , Humanos , Interferons/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Transdução de Sinais , Transcrição Gênica , Ativação Transcricional , Transcriptoma , Tuberculose/complicações
15.
Cell Host Microbe ; 21(5): 619-628.e5, 2017 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-28494243

RESUMO

The intracellular pathogen Mycobacterium tuberculosis (Mtb) lives within phagosomes and also disrupts these organelles to access the cytosol. The host pathways and mechanisms that contribute to maintaining Mtb phagosome integrity have not been investigated. Here, we examined the spatiotemporal dynamics of Mtb-containing phagosomes and identified an interferon-gamma-stimulated and Rab20-dependent membrane trafficking pathway in macrophages that maintains Mtb in spacious proteolytic phagolysosomes. This pathway functions to promote endosomal membrane influx in infected macrophages, and is required to preserve Mtb phagosome integrity and control Mtb replication. Rab20 is specifically and significantly upregulated in the sputum of human patients with active tuberculosis. Altogether, we uncover an immune-regulated cellular pathway of defense that promotes maintenance of Mtb within intact membrane-bound compartments for efficient elimination.


Assuntos
Interações Hospedeiro-Patógeno/fisiologia , Membranas/metabolismo , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/metabolismo , Fagossomos/metabolismo , Fagossomos/microbiologia , Transporte Proteico/fisiologia , Proteínas rab de Ligação ao GTP/metabolismo , Animais , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Técnicas de Cultura de Células , Modelos Animais de Doenças , Endossomos/metabolismo , Feminino , Humanos , Interferon gama/metabolismo , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Fagossomos/enzimologia , Fagossomos/imunologia , Células RAW 264.7 , Análise de Sequência de RNA , Análise Espaço-Temporal , Escarro
16.
J Infect Dis ; 215(5): 677-686, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-27932622

RESUMO

Tuberculous meningitis (TBM) is a frequent cause of meningitis in individuals with human immunodeficiency virus (HIV) infection, resulting in death in approximately 40% of affected patients. A severe complication of antiretroviral therapy (ART) in these patients is neurological tuberculosis-immune reconstitution inflammatory syndrome (IRIS), but its underlying cause remains poorly understood. To investigate the pathogenesis of TBM-IRIS, we performed longitudinal whole-blood microarray analysis of HIV-infected patients with TBM and reflected the findings at the protein level. Patients in whom TBM-IRIS eventually developed had significantly more abundant neutrophil-associated transcripts, from before development of TBM-IRIS through IRIS symptom onset. After ART initiation, a significantly higher abundance of transcripts associated with canonical and noncanonical inflammasomes was detected in patients with TBM-IRIS than in non-IRIS controls. Whole-blood transcriptome findings complement protein measurement from the site of disease, which together suggest a dominant role for the innate immune system in the pathogenesis of TBM-IRIS.


Assuntos
Sistema Nervoso Central/virologia , Infecções por HIV/imunologia , Síndrome Inflamatória da Reconstituição Imune/imunologia , Inflamassomos/sangue , Tuberculose Meníngea/imunologia , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Caspase 1/sangue , Caspase 1/líquido cefalorraquidiano , Caspase 3/sangue , Caspase 3/líquido cefalorraquidiano , Caspases Iniciadoras/sangue , Caspases Iniciadoras/líquido cefalorraquidiano , Proteínas do Sistema Complemento/metabolismo , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/microbiologia , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Prognóstico , Estudos Prospectivos , Transcriptoma , Tuberculose Meníngea/virologia
17.
Nat Med ; 22(10): 1090-1093, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27595321

RESUMO

Tuberculosis is classically divided into states of latent infection and active disease. Using combined positron emission and computed tomography in 35 asymptomatic, antiretroviral-therapy-naive, HIV-1-infected adults with latent tuberculosis, we identified ten individuals with pulmonary abnormalities suggestive of subclinical, active disease who were substantially more likely to progress to clinical disease. Our findings challenge the conventional two-state paradigm and may aid future identification of biomarkers that are predictive of progression.


Assuntos
Infecções por HIV/complicações , Tuberculose Latente/diagnóstico por imagem , Tuberculose Pulmonar/diagnóstico por imagem , Adulto , Coinfecção/diagnóstico por imagem , Progressão da Doença , Feminino , Fluordesoxiglucose F18 , Humanos , Testes de Liberação de Interferon-gama , Tuberculose Latente/complicações , Masculino , Mycobacterium tuberculosis/isolamento & purificação , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radiografia Torácica , Compostos Radiofarmacêuticos , África do Sul , Escarro/microbiologia , Tuberculose/complicações , Tuberculose/diagnóstico por imagem , Tuberculose Pulmonar/complicações
18.
Semin Immunopathol ; 38(2): 185-98, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26423994

RESUMO

Patients co-infected with HIV-1 and tuberculosis (TB) are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) following commencement of antiretroviral therapy (ART). TB-IRIS is characterized by transient but severe localized or systemic inflammatory reactions against Mycobacterium tuberculosis antigens. Here, we review the risk factors and clinical management of TB-IRIS, as well as the roles played by different aspects of the immune response in contributing to TB-IRIS pathogenesis.


Assuntos
Coinfecção , Infecções por HIV/complicações , Interações Hospedeiro-Patógeno , Síndrome Inflamatória da Reconstituição Imune/etiologia , Tuberculose/complicações , Animais , Gerenciamento Clínico , Modelos Animais de Doenças , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Síndrome Inflamatória da Reconstituição Imune/diagnóstico , Síndrome Inflamatória da Reconstituição Imune/metabolismo , Síndrome Inflamatória da Reconstituição Imune/terapia , Sistema Imunitário/citologia , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Mycobacterium tuberculosis/imunologia , Fatores de Risco , Transdução de Sinais , Tuberculose/tratamento farmacológico , Tuberculose/imunologia , Tuberculose/microbiologia
19.
Nat Commun ; 6: 8451, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-26399326

RESUMO

Patients with HIV-associated tuberculosis (TB) initiating antiretroviral therapy (ART) may develop immune reconstitution inflammatory syndrome (TB-IRIS). No biomarkers for TB-IRIS have been identified and the underlying mechanisms are unclear. Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB. We identify differentially abundant transcripts as early as week 0.5 post ART initiation that predict downstream activation of proinflammatory cytokines in patients who progress to TB-IRIS. At the characteristic time of TB-IRIS onset (week 2), the signature is characterized by over-representation of innate immune mediators including TLR signalling and TREM-1 activation of the inflammasome. In keeping with the transcriptional data, concentrations of plasma cytokines and caspase-1/5 are elevated in TB-IRIS. Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients. These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.


Assuntos
Citocinas/imunologia , Infecções por HIV/imunologia , Síndrome Inflamatória da Reconstituição Imune/imunologia , Inflamassomos/imunologia , Receptores Toll-Like/imunologia , Tuberculose/imunologia , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Caspase 1/genética , Caspase 1/imunologia , Caspases/genética , Caspases/imunologia , Citocinas/genética , Feminino , Perfilação da Expressão Gênica , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Síndrome Inflamatória da Reconstituição Imune/induzido quimicamente , Síndrome Inflamatória da Reconstituição Imune/genética , Imunidade Inata/genética , Imunidade Inata/imunologia , Inflamassomos/genética , Mediadores da Inflamação , Interleucina-1/genética , Interleucina-1/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/imunologia , Receptores Toll-Like/genética , Receptor Gatilho 1 Expresso em Células Mieloides , Tuberculose/complicações , Adulto Jovem
20.
J Exp Med ; 212(9): 1449-63, 2015 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-26282876

RESUMO

CD4+ T cells mediate protection against Mycobacterium tuberculosis (Mtb); however, the phenotype of protective T cells is undefined, thereby confounding vaccination efforts. IL-27 is highly expressed during human tuberculosis (TB), and absence of IL-27R (Il27ra) specifically on T cells results in increased protection. IL-27R deficiency during chronic Mtb infection does not impact antigen-specific CD4+ T cell number but maintains programmed death-1 (PD-1), CD69, and CD127 expression while reducing T-bet and killer cell lectin-like receptor G1 (KLRG1) expression. Furthermore, T-bet haploinsufficiency results in failure to generate KLRG1+, antigen-specific CD4+ T cells, and in improved protection. T cells in Il27ra(-/-) mice accumulate preferentially in the lung parenchyma within close proximity to Mtb, and antigen-specific CD4+ T cells lacking IL-27R are intrinsically more fit than intact T cells and maintain IL-2 production. Improved fitness of IL-27R-deficient T cells is not associated with increased proliferation but with decreased expression of cell death-associated markers. Therefore, during Mtb infection, IL-27R acts intrinsically on T cells to limit protection and reduce fitness, whereas the IL-27R-deficient environment alters the phenotype and location of T cells. The significant expression of IL-27 in TB and the negative influence of IL-27R on T cell function demonstrate the pathway by which this cytokine/receptor pair is detrimental in TB.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Mycobacterium tuberculosis/imunologia , Receptores de Citocinas/imunologia , Receptores de Interleucina/imunologia , Tuberculose/imunologia , Adulto , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD4-Positivos/patologia , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-7/genética , Subunidade alfa de Receptor de Interleucina-7/imunologia , Interleucinas/genética , Interleucinas/imunologia , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Masculino , Camundongos , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores de Citocinas/genética , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptores de Interleucina/genética , Transativadores/genética , Transativadores/imunologia , Tuberculose/genética , Tuberculose/patologia
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