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1.
Nat Commun ; 12(1): 394, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452244

RESUMO

Mycobacterium tuberculosis secretes the tuberculosis necrotizing toxin (TNT) to kill host cells. Here, we show that the WXG100 proteins EsxE and EsxF are essential for TNT secretion. EsxE and EsxF form a water-soluble heterodimer (EsxEF) that assembles into oligomers and long filaments, binds to membranes, and forms stable membrane-spanning channels. Electron microscopy of EsxEF reveals mainly pentameric structures with a central pore. Mutations of both WXG motifs and of a GXW motif do not affect dimerization, but abolish pore formation, membrane deformation and TNT secretion. The WXG/GXW mutants are locked in conformations with altered thermostability and solvent exposure, indicating that the WXG/GXW motifs are molecular switches controlling membrane interaction and pore formation. EsxF is accessible on the bacterial cell surface, suggesting that EsxEF form an outer membrane channel for toxin export. Thus, our study reveals a protein secretion mechanism in bacteria that relies on pore formation by small WXG proteins.


Assuntos
Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/metabolismo , Mycobacterium tuberculosis/patogenicidade , Porinas/metabolismo , Sistemas de Secreção Tipo VII/metabolismo , Motivos de Aminoácidos/genética , Proteínas de Bactérias/genética , Toxinas Bacterianas/toxicidade , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Humanos , Bicamadas Lipídicas/metabolismo , Microscopia Eletrônica , Mutação , Mycobacterium tuberculosis/metabolismo , Porinas/genética , Multimerização Proteica , Células THP-1 , Tuberculose/microbiologia , Tuberculose/patologia , Sistemas de Secreção Tipo VII/genética
2.
PLoS Comput Biol ; 16(12): e1008520, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33370784

RESUMO

Mycobacterium tuberculosis (Mtb) infection causes tuberculosis (TB), a disease characterized by development of granulomas. Granulomas consist of activated immune cells that cluster together to limit bacterial growth and restrict dissemination. Control of the TB epidemic has been limited by lengthy drug regimens, antibiotic resistance, and lack of a robustly efficacious vaccine. Fibrosis commonly occurs during treatment and is associated with both positive and negative disease outcomes in TB but little is known about the processes that initiate fibrosis in granulomas. Human and nonhuman primate granulomas undergoing fibrosis can have spindle-shaped macrophages with fibroblast-like morphologies suggesting a relationship between macrophages, fibroblasts, and granuloma fibrosis. This relationship has been difficult to investigate because of the limited availability of human pathology samples, the time scale involved in human TB, and overlap between fibroblast and myeloid cell markers in tissues. To better understand the origins of fibrosis in TB, we used a computational model of TB granuloma biology to identify factors that drive fibrosis over the course of local disease progression. We validated the model with granulomas from nonhuman primates to delineate myeloid cells and lung-resident fibroblasts. Our results suggest that peripheral granuloma fibrosis, which is commonly observed, can arise through macrophage-to-myofibroblast transformation (MMT). Further, we hypothesize that MMT is induced in M1 macrophages through a sequential combination of inflammatory and anti-inflammatory signaling in granuloma macrophages. We predict that MMT may be a mechanism underlying granuloma-associated fibrosis and warrants further investigation into myeloid cells as drivers of fibrotic disease.


Assuntos
Granuloma/patologia , Macrófagos/patologia , Miofibroblastos/patologia , Biologia de Sistemas , Tuberculose/patologia , Fibrose , Humanos , Mycobacterium tuberculosis/imunologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo
3.
BMC Bioinformatics ; 21(Suppl 17): 449, 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33308156

RESUMO

BACKGROUND: The STriTuVaD project, funded by Horizon 2020, aims to test through a Phase IIb clinical trial one of the most advanced therapeutic vaccines against tuberculosis. As part of this initiative, we have developed a strategy for generating in silico patients consistent with target population characteristics, which can then be used in combination with in vivo data on an augmented clinical trial. RESULTS: One of the most challenging tasks for using virtual patients is developing a methodology to reproduce biological diversity of the target population, ie, providing an appropriate strategy for generating libraries of digital patients. This has been achieved through the creation of the initial immune system repertoire in a stochastic way, and through the identification of a vector of features that combines both biological and pathophysiological parameters that personalise the digital patient to reproduce the physiology and the pathophysiology of the subject. CONCLUSIONS: We propose a sequential approach to sampling from the joint features population distribution in order to create a cohort of virtual patients with some specific characteristics, resembling the recruitment process for the target clinical trial, which then can be used for augmenting the information from the physical the trial to help reduce its size and duration.


Assuntos
Biologia Computacional/métodos , Tuberculose/imunologia , Interface Usuário-Computador , Anticorpos Antibacterianos/metabolismo , Sistema Imunitário/fisiologia , Tuberculose/metabolismo , Tuberculose/patologia , Tuberculose/prevenção & controle
4.
PLoS One ; 15(10): e0240090, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33031403

RESUMO

OBJECTIVES: This study aimed to analyze the factors associated with likely TB deaths, likely TB-related deaths and deaths from other causes. Understanding the factors associated with mortality could help the strategy to End TB, especially the goal of reducing TB deaths by 95% between 2015 and 2035. METHODS: A retrospective, population-based cohort study of the causes of death was performed using a competing risk model in patients receiving treatment for TB. Patients had started TB treatment in Brazil 2008-2013 with any death certificates dated in the same period. We used three categories of deaths, according to ICD-10 codes: i) probable TB deaths; ii) TB-related deaths; iii) deaths from other causes. RESULTS: In this cohort, 39,997 individuals (14.1%) died, out of a total of 283,508 individuals. Of these, 8,936 were probable TB deaths (22.4%) and 3,365 TB-related deaths (8.4%), illustrating high mortality rates. 27,696 deaths (69.2%) were from other causes. From our analysis, factors strongly associated with probable TB deaths were male gender (sHR = 1.33, 95% CI: 1.26-1.40), age over 60 years (sHR = 9.29, 95% CI: 8.15-10.60), illiterate schooling (sHR = 2.33, 95% CI: 2.09-2.59), black (sHR = 1.33, 95% CI: 1.26-1.40) and brown (sHR = 13, 95% CI: 1.07-1.19) color/race, from the Southern region (sHR = 1.19, 95% CI: 1.10-1.28), clinical mixed forms (sHR = 1.91, 95% CI: 1.73-2.11) and alcoholism (sHR = 1.90, 95% CI: 1.81-2.00). Also, HIV positive serology was strongly associated with probable TB deaths (sHR = 62.78; 95% CI: 55.01-71.63). CONCLUSIONS: In conclusion, specific strategies for active surveillance and early case detection can reduce mortality among patients with tuberculosis, leading to more timely detection and treatment.


Assuntos
Risco , Tuberculose/patologia , Adolescente , Adulto , Alcoolismo/complicações , Brasil , Criança , Pré-Escolar , Grupos Étnicos , Feminino , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Humanos , Lactente , Recém-Nascido , Alfabetização , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores Sexuais , Análise de Sobrevida , Tuberculose/complicações , Tuberculose/mortalidade , Adulto Jovem
6.
PLoS One ; 15(8): e0238119, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32845896

RESUMO

Abdominal tuberculosis (ATB) continues to pose a major diagnostic challenge for clinicians due to its nonspecific clinical presentation, variable anatomical location and lack of sensitive diagnostic tools. In spite of the development of several assays till date; no single test has proved to be adequate for ATB diagnosis. In this study, we for the first time report the detection of circulating cell-free Mycobacterium tuberculosis (M. tuberculosis) DNA (cfMTB-DNA) in ascitic fluid (AF) samples and its utility in ATB diagnosis. Sixty-five AF samples were included in the study and processed for liquid culture, cytological, biochemical and molecular assays. A composite reference standard (CRS) was formulated to categorize the patients into 'Definite ATB' (M. tuberculosis culture positive, n = 2), 'Probable ATB' (n = 16), 'Possible ATB' (n = 13) and 'Non-TB' category (n = 34). Two molecular assays were performed, namely, the novel cfMTB-DNA qPCR assay targeting M. tuberculosis devR gene and Xpert MTB/RIF assay (Xpert), and their diagnostic accuracy was assessed using CRS as reference standard. Clinical features such as fever, loss of weight, abdominal distension and positive Mantoux were found to be strongly associated with ATB disease (p<0.05). cfMTB-DNA qPCR had a sensitivity of 66.7% (95% CI:40.9,86.7) with 97.1% specificity (95% CI:84.7,99.9) in 'Definite ATB' and 'Probable ATB' group collectively. The sensitivity increased to 70.9% (95% CI:51.9,85.8) in the combined 'Definite', 'Probable' and 'Possible' ATB group with similar specificity. The cfMTB-DNA qPCR assay performed significantly better than the Xpert assay which demonstrated a poor sensitivity of ≤16.7% with 100% (95% CI:89.7,100) specificity (p<0.001). We conclude that cfMTB-DNA qPCR assay is an accurate molecular test that can provide direct evidence of M. tuberculosis etiology and has promise to pave the way for improving ATB diagnosis.


Assuntos
Líquido Ascítico/química , Ácidos Nucleicos Livres/análise , DNA Bacteriano/análise , Técnicas de Diagnóstico Molecular/métodos , Mycobacterium tuberculosis/genética , Tuberculose/diagnóstico , Abdome/microbiologia , Abdome/patologia , Adolescente , Adulto , Idoso , Proteínas de Bactérias/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Tuberculose/patologia , Adulto Jovem
7.
BMC Bioinformatics ; 21(1): 375, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859148

RESUMO

BACKGROUND: As the barriers to incorporating RNA sequencing (RNA-Seq) into biomedical studies continue to decrease, the complexity and size of RNA-Seq experiments are rapidly growing. Paired, longitudinal, and other correlated designs are becoming commonplace, and these studies offer immense potential for understanding how transcriptional changes within an individual over time differ depending on treatment or environmental conditions. While several methods have been proposed for dealing with repeated measures within RNA-Seq analyses, they are either restricted to handling only paired measurements, can only test for differences between two groups, and/or have issues with maintaining nominal false positive and false discovery rates. In this work, we propose a Bayesian hierarchical negative binomial generalized linear mixed model framework that can flexibly model RNA-Seq counts from studies with arbitrarily many repeated observations, can include covariates, and also maintains nominal false positive and false discovery rates in its posterior inference. RESULTS: In simulation studies, we showed that our proposed method (MCMSeq) best combines high statistical power (i.e. sensitivity or recall) with maintenance of nominal false positive and false discovery rates compared the other available strategies, especially at the smaller sample sizes investigated. This behavior was then replicated in an application to real RNA-Seq data where MCMSeq was able to find previously reported genes associated with tuberculosis infection in a cohort with longitudinal measurements. CONCLUSIONS: Failing to account for repeated measurements when analyzing RNA-Seq experiments can result in significantly inflated false positive and false discovery rates. Of the methods we investigated, whether they model RNA-Seq counts directly or worked on transformed values, the Bayesian hierarchical model implemented in the mcmseq R package (available at https://github.com/stop-pre16/mcmseq ) best combined sensitivity and nominal error rate control.


Assuntos
RNA/química , Análise de Sequência de RNA/métodos , Interface Usuário-Computador , Teorema de Bayes , Humanos , Método de Monte Carlo , RNA/genética , RNA/metabolismo , Tuberculose/genética , Tuberculose/patologia
8.
PLoS Pathog ; 16(8): e1008632, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32790739

RESUMO

Lymph nodes, particularly thoracic lymph nodes, are among the most common sites of extrapulmonary tuberculosis (TB). However, Mycobacterium tuberculosis (Mtb) infection in these organs is understudied. Aside from being sites of initiation of the adaptive immune system, lymph nodes also serve as niches of Mtb growth and persistence. Mtb infection results in granuloma formation that disrupts and-if it becomes large enough-replaces the normal architecture of the lymph node that is vital to its function. In preclinical models, successful TB vaccines appear to prevent spread of Mtb from the lungs to the lymph nodes. Reactivation of latent TB can start in the lymph nodes resulting in dissemination of the bacteria to the lungs and other organs. Involvement of the lymph nodes may improve Bacille Calmette-Guerin (BCG) vaccine efficacy. Lastly, drug penetration to the lymph nodes is poor compared to blood, lung tissue, and lung granulomas. Future studies on evaluating the efficacy of vaccines and anti-TB drug treatments should include consideration of the effects on thoracic lymph nodes and not just the lungs.


Assuntos
Pulmão/imunologia , Linfonodos/imunologia , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Tuberculose/patologia , Animais , Humanos , Pulmão/microbiologia , Linfonodos/microbiologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose/microbiologia , Tuberculose/prevenção & controle
9.
PLoS Pathog ; 16(6): e1008621, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32544188

RESUMO

During tuberculosis, lung myeloid cells have two opposing roles: they are an intracellular niche occupied by Mycobacterium tuberculosis, and they restrict bacterial replication. Lung myeloid cells from mice infected with yellow-fluorescent protein expressing M. tuberculosis were analyzed by flow cytometry and transcriptional profiling to identify the cell types infected and their response to infection. CD14, CD38, and Abca1 were expressed more highly by infected alveolar macrophages and CD11cHi monocyte-derived cells compared to uninfected cells. CD14, CD38, and Abca1 "triple positive" (TP) cells had not only the highest infection rates and bacterial loads, but also a strong interferon-γ signature and nitric oxide synthetase-2 production indicating recognition by T cells. Despite evidence of T cell recognition and appropriate activation, these TP macrophages are a cellular compartment occupied by M. tuberculosis long-term. Defining the niche where M. tuberculosis resists elimination promises to provide insight into why inducing sterilizing immunity is a formidable challenge.


Assuntos
Antígenos CD11/imunologia , Macrófagos Alveolares , Monócitos , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/imunologia , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/imunologia , Animais , Antígenos CD11/genética , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/microbiologia , Macrófagos Alveolares/patologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/microbiologia , Monócitos/patologia , Mycobacterium tuberculosis/genética , Linfócitos T/imunologia , Linfócitos T/microbiologia , Linfócitos T/patologia , Tuberculose/genética , Tuberculose/patologia
10.
Nat Commun ; 11(1): 3062, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546788

RESUMO

Anti-tuberculosis (TB) drugs, while being highly potent in vitro, require prolonged treatment to control Mycobacterium tuberculosis (Mtb) infections in vivo. We report here that mesenchymal stem cells (MSCs) shelter Mtb to help tolerate anti-TB drugs. MSCs readily take up Mtb and allow unabated mycobacterial growth despite having a functional innate pathway of phagosome maturation. Unlike macrophage-resident ones, MSC-resident Mtb tolerates anti-TB drugs remarkably well, a phenomenon requiring proteins ABCC1, ABCG2 and vacuolar-type H+ATPases. Additionally, the classic pro-inflammatory cytokines IFNγ and TNFα aid mycobacterial growth within MSCs. Mechanistically, evading drugs and inflammatory cytokines by MSC-resident Mtb is dependent on elevated PGE2 signaling, which we verify in vivo analyzing sorted CD45-Sca1+CD73+-MSCs from lungs of infected mice. Moreover, MSCs are observed in and around human tuberculosis granulomas, harboring Mtb bacilli. We therefore propose, targeting the unique immune-privileged niche, provided by MSCs to Mtb, can have a major impact on tuberculosis prevention and cure.


Assuntos
Antituberculosos/farmacologia , Células-Tronco Mesenquimais/microbiologia , Mycobacterium tuberculosis/patogenicidade , Nicho de Células-Tronco/imunologia , Tuberculose/microbiologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Células Cultivadas , Dinoprostona/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Interferon gama/farmacologia , Isoniazida/farmacologia , Lisossomos/microbiologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Proteínas de Neoplasias/metabolismo , Fagossomos/microbiologia , Tuberculose/patologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Fator de Necrose Tumoral alfa/farmacologia
11.
PLoS Pathog ; 16(6): e1008567, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32574211

RESUMO

Efforts at host-directed therapy of tuberculosis have produced little control of the disease in experimental animals to date. This is not surprising, given that few specific host targets have been validated, and reciprocally, many of the compounds tested potentially impact multiple targets with both beneficial and detrimental consequences. This puts a premium on identifying appropriate molecular targets and subjecting them to more selective modulation. We discovered an aminopyrimidine small molecule, 2062, that had no direct antimycobacterial activity, but synergized with rifampin to reduce bacterial burden in Mtb infected macrophages and mice and also dampened lung immunopathology. We used 2062 and its inactive congeners as tool compounds to identify host targets. By biochemical, pharmacologic, transcriptomic and genetic approaches, we found that 2062's beneficial effects on Mtb control and clearance in macrophages and in mice are associated with activation of transcription factor EB via an organellar stress response. 2062-dependent TFEB activation led to improved autophagy, lysosomal acidification and lysosomal degradation, promoting bacterial clearance in macrophages. Deletion of TFEB resulted in the loss of IFNγ-dependent control of Mtb replication in macrophages. 2062 also targeted multiple kinases, such as PIKfyve, VPS34, JAKs and Tyk2, whose inhibition likely limited 2062's efficacy in vivo. These findings support a search for selective activators of TFEB for HDT of TB.


Assuntos
Antituberculosos/farmacologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Mycobacterium tuberculosis/metabolismo , Rifampina/farmacologia , Tuberculose , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Mycobacterium tuberculosis/patogenicidade , Tuberculose/tratamento farmacológico , Tuberculose/metabolismo , Tuberculose/patologia
12.
Nat Commun ; 11(1): 2270, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385301

RESUMO

Mycobacterium tuberculosis is a global health problem in part as a result of extensive cytotoxicity caused by the infection. Here, we show how M. tuberculosis causes caspase-1/NLRP3/gasdermin D-mediated pyroptosis of human monocytes and macrophages. A type VII secretion system (ESX-1) mediated, contact-induced plasma membrane damage response occurs during phagocytosis of bacteria. Alternatively, this can occur from the cytosolic side of the plasma membrane after phagosomal rupture in infected macrophages. This damage causes K+ efflux and activation of NLRP3-dependent IL-1ß release and pyroptosis, facilitating the spread of bacteria to neighbouring cells. A dynamic interplay of pyroptosis with ESCRT-mediated plasma membrane repair also occurs. This dual plasma membrane damage seems to be a common mechanism for NLRP3 activators that function through lysosomal damage.


Assuntos
Membrana Celular/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Tuberculose/metabolismo , Tuberculose/patologia , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Catepsinas/metabolismo , Membrana Celular/ultraestrutura , Proteínas de Fluorescência Verde/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Inflamassomos/metabolismo , Inflamassomos/ultraestrutura , Mitocôndrias/metabolismo , Mycobacterium tuberculosis/metabolismo , Fagossomos/metabolismo , Fagossomos/ultraestrutura , Células THP-1
13.
Rev Mal Respir ; 37(5): 399-411, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32386802

RESUMO

A paradoxical reaction is the worsening of prior existing, or the appearance of, new tuberculous lesions, following the initiation of treatment with anti-tuberculous drugs, after the exclusion of poor compliance, malabsorption, drug interaction or multiresistant mycobacteria. Well known and well managed in the context of HIV coinfection, it is not well known outside this context. An increasing number of publications have described this syndrome. This review aims to describe the pathogenic, epidemiological, clinical, prognostic and therapeutic elements of non-HIV-associated paradoxical reactions. It involves a reversal of the Mycobacterium tuberculosis-induced immunodepression along with a heightened detrimental pro-inflammatory profile caused by efficient drug treatment. Extra-thoracic locations, especially lymph nodes and neurological, malnutrition and initial lymphopenia are the principal risk factors. The median delay is 40±20 days after the onset of treatment. Corticosteroids are the mainstay of the management. Anti-TNF-α drugs show good results in corticosteroid refractory cases. The prognosis is good overall except in neurological forms. The place of preventive methods remains to be established.


Assuntos
Antituberculosos/uso terapêutico , Progressão da Doença , Tuberculose/tratamento farmacológico , Tuberculose/patologia , Antituberculosos/efeitos adversos , Humanos , Linfonodos/efeitos dos fármacos , Linfonodos/microbiologia , Linfonodos/patologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/fisiologia , Fatores de Risco , Tuberculose/epidemiologia
14.
PLoS Genet ; 16(5): e1008766, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32365090

RESUMO

Complex traits are known to be influenced by a combination of environmental factors and rare and common genetic variants. However, detection of such multivariate associations can be compromised by low statistical power and confounding by population structure. Linear mixed effects models (LMM) can account for correlations due to relatedness but have not been applicable in high-dimensional (HD) settings where the number of fixed effect predictors greatly exceeds the number of samples. False positives or false negatives can result from two-stage approaches, where the residuals estimated from a null model adjusted for the subjects' relationship structure are subsequently used as the response in a standard penalized regression model. To overcome these challenges, we develop a general penalized LMM with a single random effect called ggmix for simultaneous SNP selection and adjustment for population structure in high dimensional prediction models. We develop a blockwise coordinate descent algorithm with automatic tuning parameter selection which is highly scalable, computationally efficient and has theoretical guarantees of convergence. Through simulations and three real data examples, we show that ggmix leads to more parsimonious models compared to the two-stage approach or principal component adjustment with better prediction accuracy. Our method performs well even in the presence of highly correlated markers, and when the causal SNPs are included in the kinship matrix. ggmix can be used to construct polygenic risk scores and select instrumental variables in Mendelian randomization studies. Our algorithms are available in an R package available on CRAN (https://cran.r-project.org/package=ggmix).


Assuntos
Algoritmos , Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Animais , Simulação por Computador , Cruzamentos Genéticos , Genética Populacional/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Leishmania tropica/genética , Leishmaniose Cutânea/genética , Modelos Lineares , Camundongos , Camundongos Endogâmicos , Herança Multifatorial/genética , Mycobacterium bovis , Dinâmica Populacional , Tamanho da Amostra , Software , Tuberculose/genética , Tuberculose/patologia
15.
PLoS Genet ; 16(4): e1008728, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32352966

RESUMO

Genetic studies of both the human host and Mycobacterium tuberculosis (MTB) demonstrate independent association with tuberculosis (TB) risk. However, neither explains a large portion of disease risk or severity. Based on studies in other infectious diseases and animal models of TB, we hypothesized that the genomes of the two interact to modulate risk of developing active TB or increasing the severity of disease, when present. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which there were 3 MTB lineages of which L4-Ugandan (L4.6) is the most recent. TB severity, measured using the Bandim TBscore, was modeled as a function of host SNP genotype, MTB lineage, and their interaction, within two independent cohorts of TB cases, N = 113 and 121. No association was found between lineage and severity, but association between multiple polymorphisms in IL12B and TBscore was replicated in two independent cohorts (most significant rs3212227, combined p = 0.0006), supporting previous associations of IL12B with TB susceptibility. We also observed significant interaction between a single nucleotide polymorphism (SNP) in SLC11A1 and the L4-Ugandan lineage in both cohorts (rs17235409, meta p = 0.0002). Interestingly, the presence of the L4-Uganda lineage in the presence of the ancestral human allele associated with more severe disease. These findings demonstrate that IL12B is associated with severity of TB in addition to susceptibility, and that the association between TB severity and human genetics can be due to an interaction between genes in the two species, consistent with host-pathogen coevolution in TB.


Assuntos
Coevolução Biológica , Mycobacterium tuberculosis/genética , Polimorfismo de Nucleotídeo Único , Tuberculose/genética , Adolescente , Adulto , Idoso , Proteínas de Transporte de Cátions/genética , Evolução Molecular , Feminino , Genoma Bacteriano , Interações Hospedeiro-Patógeno , Humanos , Subunidade p40 da Interleucina-12/genética , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/patogenicidade , Tuberculose/microbiologia , Tuberculose/patologia
16.
BMC Infect Dis ; 20(1): 325, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32380957

RESUMO

BACKGROUND: Tuberculosis (TB) and HV have been intertwined and makeup a deadly human syndemic worldwide, especially in developing countries like Ethiopia. Previous studies have reported different TB incidences and its association with CD4+ T cell counts among HIV positive patients in Ethiopia. Thus, the goal of this meta-analysis was, first, to determine pooled incident TB among adult HIV positive patients, and second, to assess the association between incident TB and baseline CD4+ T cell count strata's. METHODS: We searched PubMed, Cochrane library, Science Direct and Google scholar databases from June 1 to 30, 2018. The I2 statistics and Egger's regression test was used to determine heterogeneity and publication bias among included studies respectively. A random effects model was used to estimate pooled incident TB and odds ratio with the respective 95% confidence intervals using Stata version 11.0 statistical software. RESULTS: A total of 403 research articles were identified, and 10 studies were included in the meta-analysis. The pooled incident TB among adult HIV infected patients in Ethiopia was 16.58% (95% CI; 13.25-19.91%). Specifically, TB incidence in Pre-ART and ART was 17.16% (95% CI; 7.95-26.37%) and 16.24% (95% CI; 12.63-19.84%) respectively. Moreover, incident TB among ART receiving patients with baseline CD4+ T cell count < and > 200 cells/mm3 was 28.86% (95% CI; 18.73-38.98%) and 13.7% (95% CI; 1.41-25.98%) correspondingly. The odds of getting incident TB was 2.88 (95% CI; 1.55-5.35%) for patients with baseline CD4+ T cell count < 200 cells/mm3 compared to patients with baseline CD4+ T cell count > 200 cells/mm3. CONCLUSION: High incident TB among adult HIV positive patients was estimated, especially in patients with CD4+ T cell count < 200 cells/mm3. Therefore, Early HIV screening and ART initiation, as well as strict compliance with ART and increasing the coverage of TB preventive therapy to more risky groups are important to prevent the problem. TRIAL REGISTRATION: Study protocol registration: CRD42018090802.


Assuntos
Contagem de Linfócito CD4 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/microbiologia , Tuberculose/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Adolescente , Adulto , Etiópia/epidemiologia , Infecções por HIV/epidemiologia , Soropositividade para HIV/complicações , Soropositividade para HIV/tratamento farmacológico , Soropositividade para HIV/microbiologia , Humanos , Incidência , Pessoa de Meia-Idade , Razão de Chances , Cooperação do Paciente , Fatores de Risco , Tuberculose/patologia , Adulto Jovem
17.
Eur J Cancer ; 132: 168-175, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32375103

RESUMO

BACKGROUND: An amassing body of evidence exists to support an association between the use of immune checkpoint inhibitors (ICIs) and the development of tuberculosis (TB). METHODS: We performed a systematic review of the literature to assess the nature of this relationship using PubMed, EMBASE and meeting proceedings. RESULTS: We have identified 16 patients who developed active TB during immunotherapy. Median age was 61 (range: 49-87). Twelve (75%) were male and 4 (25%) were female. Lung cancer was the most common type of cancer (n = 8), followed by melanoma (n = 3) and head and neck cancer (n = 3). Median time to TB reactivation after initiation of ICI therapy was 6.3 months (range: 1-24 months). Two (13%) patients died of complications of TB (spinal cord compression, GI perforation). TB reactivation in organs (pericardium, bone, liver, and GI track; one each) other than the lungs has been documented. We did not find any cases of TB reactivation that occurred during anti-CTLA-4 therapy. CONCLUSION: Findings from our systematic review indicate that PD-(L)1 inhibitors are linked to TB reactivation. TB activation can occur in various organs and TB-related fatalities have been reported. TB screening before starting immunotherapy should be considered in high-risk patient populations. Further research, including prospective studies with patients whose baseline TB status is known, is necessary to better understand the incidence of TB reactivation during ICI therapy and how best to manage TB that develops during immunotherapy.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Neoplasias/tratamento farmacológico , Tuberculose/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Prognóstico , Taxa de Sobrevida , Tuberculose/patologia
18.
PLoS Comput Biol ; 16(5): e1007772, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32433644

RESUMO

Tuberculosis (TB) is an infectious disease that still causes more than 1.5 million deaths annually. The World Health Organization estimates that around 30% of the world's population is latently infected. However, the mechanisms responsible for 10% of this reserve (i.e., of the latently infected population) developing an active disease are not fully understood, yet. The dynamic hypothesis suggests that endogenous reinfection has an important role in maintaining latent infection. In order to examine this hypothesis for falsifiability, an agent-based model of growth, merging, and proliferation of TB lesions was implemented in a computational bronchial tree, built with an iterative algorithm for the generation of bronchial bifurcations and tubes applied inside a virtual 3D pulmonary surface. The computational model was fed and parameterized with computed tomography (CT) experimental data from 5 latently infected minipigs. First, we used CT images to reconstruct the virtual pulmonary surfaces where bronchial trees are built. Then, CT data about TB lesion' size and location to each minipig were used in the parameterization process. The model's outcome provides spatial and size distributions of TB lesions that successfully reproduced experimental data, thus reinforcing the role of the bronchial tree as the spatial structure triggering endogenous reinfection. A sensitivity analysis of the model shows that the final number of lesions is strongly related with the endogenous reinfection frequency and maximum growth rate of the lesions, while their mean diameter mainly depends on the spatial spreading of new lesions and the maximum radius. Finally, the model was used as an in silico experimental platform to explore the transition from latent infection to active disease, identifying two main triggering factors: a high inflammatory response and the combination of a moderate inflammatory response with a small breathing amplitude.


Assuntos
Brônquios/metabolismo , Mycobacterium tuberculosis/crescimento & desenvolvimento , Tuberculose/patologia , Algoritmos , Animais , Antituberculosos/uso terapêutico , Doenças Transmissíveis/tratamento farmacológico , Simulação por Computador , Feminino , Humanos , Pulmão/microbiologia , Pulmão/patologia , Modelos Teóricos , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/patogenicidade , Suínos , Tomografia Computadorizada por Raios X , Tuberculose/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico
19.
PLoS Comput Biol ; 16(5): e1007280, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32433646

RESUMO

Mycobacterium tuberculosis (Mtb), the causative infectious agent of tuberculosis (TB), kills more individuals per year than any other infectious agent. Granulomas, the hallmark of Mtb infection, are complex structures that form in lungs, composed of immune cells surrounding bacteria, infected cells, and a caseous necrotic core. While granulomas serve to physically contain and immunologically restrain bacteria growth, some granulomas are unable to control Mtb growth, leading to bacteria and infected cells leaving the granuloma and disseminating, either resulting in additional granuloma formation (local or non-local) or spread to airways or lymph nodes. Dissemination is associated with development of active TB. It is challenging to experimentally address specific mechanisms driving dissemination from TB lung granulomas. Herein, we develop a novel hybrid multi-scale computational model, MultiGran, that tracks Mtb infection within multiple granulomas in an entire lung. MultiGran follows cells, cytokines, and bacterial populations within each lung granuloma throughout the course of infection and is calibrated to multiple non-human primate (NHP) cellular, granuloma, and whole-lung datasets. We show that MultiGran can recapitulate patterns of in vivo local and non-local dissemination, predict likelihood of dissemination, and predict a crucial role for multifunctional CD8+ T cells and macrophage dynamics for preventing dissemination.


Assuntos
Biologia Computacional/métodos , Previsões/métodos , Tuberculose/patologia , Animais , Linfócitos T CD8-Positivos/imunologia , Simulação por Computador , Citocinas/imunologia , Granuloma/microbiologia , Granuloma do Sistema Respiratório/microbiologia , Granuloma do Sistema Respiratório/fisiopatologia , Humanos , Pulmão/microbiologia , Linfonodos/patologia , Macrófagos/imunologia , Modelos Teóricos , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/microbiologia
20.
Sci Rep ; 10(1): 8603, 2020 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-32451410

RESUMO

The spatial distributions of diverse facilities are often understood in terms of the optimization of the commute distance or the economic profit. Incorporating more general objective functions into such optimization framework may be useful, helping the policy decisions to meet various social and economic demands. As an example, we consider how hospitals should be distributed to minimize the total fatalities of tuberculosis (TB). The empirical data of Korea shows that the fatality rate of TB in a district decreases with the areal density of hospitals, implying their correlation and the possibility of reducing the nationwide fatalities by adjusting the hospital distribution across districts. Approximating the fatality rate by the probability of a patient not to visit a hospital in her/his residential district for the duration period of TB and evaluating the latter probability in the random-walk framework, we obtain the fatality rate as an exponential function of the hospital density with a characteristic constant related to each district's effective lattice constant estimable empirically. This leads us to the optimal hospital distribution which finds the hospital density in a district to be a logarithmic function of the rescaled patient density. The total fatalities is reduced by 13% with this optimum. The current hospital density deviates from the optimized one in different manners from district to district, which is analyzed in the proposed model framework. The assumptions and limitations of our study are also discussed.


Assuntos
Instalações de Saúde/estatística & dados numéricos , Tuberculose/patologia , Bases de Dados Factuais , Instalações de Saúde/tendências , Hospitais , Humanos , Método de Monte Carlo , República da Coreia , Taxa de Sobrevida , Tuberculose/mortalidade
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