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1.
BMC Infect Dis ; 20(1): 685, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948127

RESUMO

BACKGROUND: Recombinant fusion protein ESAT6-CFP10 (EC) is a newly developed skin test reagent for detecting Mycobacterium tuberculosis (M. tuberculosis) infection. In this study, we evaluated whether induration and erythema could be used as diagnostic indicators for EC skin test to detect M. tuberculosis infection. METHODS: A total of 743 tuberculosis patients and 1514 healthy volunteers underwent an EC skin test. The diameters of induration and erythema were measured with Vernier caliper, 24 h, 48 h, and 72 h after skin testing. Related indicators of EC reagent diagnostic test were tested, and the diagnostic effects of the four diagnostic indicators for EC skin test were compared. RESULTS: The sensitivity of induration / erythema measurement was lower at 24 h after EC skin test than at 48 h or 72 h (P<0.01). There was no difference in consistency (P = 0.16) between induration with clinical diagnosis, and erythema with clinical diagnosis at 48 h (88.88 and 90.16%, Kappa value was 0.75 and 0.78, respectively). In patients, the sensitivity of erythema measurement was higher than induration measurement (P<0.01). In healthy volunteers, the specificity of erythema measurement was lower than induration at 24 h after skin test, but there was no difference at 48 h after skin test (P = 0.22). In BCG vaccination volunteers, the specificity of induration and erythema were higher than 90%. In addition, there was a high consistency of induration and erythema. When induration or erythema was used as a positive diagnostic indicator, the sensitivity of the EC skin test was improved, and was no different from the other three indicators in terms of specificity and consistency with clinical diagnosis. CONCLUSIONS: Induration or erythema diameter not less than 5 mm could be used as a diagnostic indicator for detecting M. tuberculosis infection. TRIAL REGISTRATION: Phase III clinical trial of recombinant Mycobacterium tuberculosis ESAT6-CFP10 allergen; CTR20150695 ; registered in December 16, 2015.


Assuntos
Proteínas Recombinantes de Fusão , Teste Tuberculínico/métodos , Tuberculose/diagnóstico , Adulto , Alérgenos , Eritema/etiologia , Eritema/patologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/patogenicidade , Sensibilidade e Especificidade , Fatores de Tempo , Teste Tuberculínico/efeitos adversos , Tuberculose/microbiologia , Adulto Jovem
2.
Nat Commun ; 11(1): 4870, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978384

RESUMO

Little is known about the physiology of latent Mycobacterium tuberculosis infection. We studied the mutational rates of 24 index tuberculosis (TB) cases and their latently infected household contacts who developed active TB up to 5.25 years later, as an indication of bacterial physiological state and possible generation times during latent TB infection in humans. Here we report that the rate of new mutations in the M. tuberculosis genome decline dramatically after two years of latent infection (two-sided p < 0.001, assuming an 18 h generation time equal to log phase M. tuberculosis, with latency period modeled as a continuous variable). Alternatively, assuming a fixed mutation rate, the generation time increases over the latency duration. Mutations indicative of oxidative stress do not increase with increasing latency duration suggesting a lack of host or bacterial derived mutational stress. These results suggest that M. tuberculosis enters a quiescent state during latency, decreasing the risk for mutational drug resistance and increasing generation time, but potentially increasing bacterial tolerance to drugs that target actively growing bacteria.


Assuntos
Tuberculose Latente/microbiologia , Taxa de Mutação , Mycobacterium tuberculosis/genética , Tuberculose/microbiologia , Adulto , Brasil , DNA Bacteriano/isolamento & purificação , Feminino , Genoma Bacteriano , Humanos , Masculino , Mutação , Mycobacterium tuberculosis/patogenicidade , Estresse Oxidativo , Filogenia , Polimorfismo de Nucleotídeo Único , Fatores de Tempo , Adulto Jovem
3.
BMC Infect Dis ; 20(1): 556, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32736602

RESUMO

BACKGROUND: There is a general dearth of information on extrapulmonary tuberculosis (EPTB). Here, we investigated Mycobacterium tuberculosis (Mtb) drug resistance and transmission patterns in EPTB patients treated in the Tshwane metropolitan area, in South Africa. METHODS: Consecutive Mtb culture-positive non-pulmonary samples from unique EPTB patients underwent mycobacterial genotyping and were assigned to phylogenetic lineages and transmission clusters based on spoligotypes. MTBDRplus assay was used to search mutations for isoniazid and rifampin resistance. Machine learning algorithms were used to identify clinically meaningful patterns in data. We computed odds ratio (OR), attributable risk (AR) and corresponding 95% confidence intervals (CI). RESULTS: Of the 70 isolates examined, the largest cluster comprised 25 (36%) Mtb strains that belonged to the East Asian lineage. East Asian lineage was significantly more likely to occur within chains of transmission when compared to the Euro-American and East-African Indian lineages: OR = 10.11 (95% CI: 1.56-116). Lymphadenitis, meningitis and cutaneous TB, were significantly more likely to be associated with drug resistance: OR = 12.69 (95% CI: 1.82-141.60) and AR = 0.25 (95% CI: 0.06-0.43) when compared with other EPTB sites, which suggests that poor rifampin penetration might be a contributing factor. CONCLUSIONS: The majority of Mtb strains circulating in the Tshwane metropolis belongs to East Asian, Euro-American and East-African Indian lineages. Each of these are likely to be clustered, suggesting on-going EPTB transmission. Since 25% of the drug resistance was attributable to sanctuary EPTB sites notorious for poor rifampin penetration, we hypothesize that poor anti-tuberculosis drug dosing might have a role in the development of resistance.


Assuntos
Farmacorresistência Bacteriana/genética , Mycobacterium tuberculosis/genética , Tuberculose/transmissão , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Isoniazida/uso terapêutico , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade , Filogenia , Rifampina/uso terapêutico , África do Sul , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Tuberculose Pulmonar/microbiologia , Adulto Jovem
4.
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
5.
PLoS One ; 15(8): e0236362, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32797053

RESUMO

BACKGROUND: Tuberculosis (TB) is among the top 10 causes of mortality and the first killer among infectious diseases worldwide. One of the factors fuelling the TB epidemic is the global rise of multidrug resistant TB (MDR-TB). The aim of this study was to determine the magnitude and factors associated with MDR-TB in the Tigray Region, Ethiopia. METHOD: This study employed a facility-based cross-sectional study design, which was conducted between July 2018 and August 2019. The inclusion criteria for the study participants were GeneXpert-positive who were not under treatment for TB, PTB patients' ≥15 years of age and who provided written informed consent. A total of 300 participants were enrolled in the study, with a structured questionnaire used to collect data on clinical, sociodemographic and behavioral factors. Sputum samples were collected and processed for acid-fast bacilli staining, culture and drug susceptibility testing. Drug susceptibility testing was performed using a line probe assay. Logistic regression was used to analyze associations between outcome and predictor variables. RESULTS: The overall proportion of MDR-TB was 16.7% (11.6% and 32.7% for new and previously treated patients, respectively). Of the total MDR-TB isolates, 5.3% were pre-XDR-TB. The proportion of MDR-TB/HIV co-infection was 21.1%. A previous history of TB treatment AOR 3.75; 95% CI (0.7-2.24), cigarette smoking AOR 6.09; CI (1.65-2.50) and patients who had an intermittent fever (AOR = 2.54, 95% CI = 1.21-5.4) were strongly associated with MDR-TB development. CONCLUSIONS: The magnitude of MDR-TB observed among new and previously treated patients is very alarming, which calls for an urgent need for intervention. The high proportion of MDR-TB among newly diagnosed cases indicates ongoing transmission, which suggests the need for enhanced TB control program performance to interrupt transmission. The increased proportion of MDR-TB among previously treated cases indicates a need for better patient management to prevent the evolution of drug resistance. Assessing the TB control program performance gaps and an optimal implementation of the WHO recommended priority actions for the management of drug-resistant TB, is imperative to help reduce the current high MDR-TB burden in the study region.


Assuntos
Infecções por HIV/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/uso terapêutico , Estudos Transversais , Etiópia/epidemiologia , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/microbiologia , Infecções por HIV/patologia , Humanos , Isoniazida/uso terapêutico , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mycobacterium tuberculosis/patogenicidade , Rifampina/uso terapêutico , Fatores de Risco , Escarro/efeitos dos fármacos , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/patologia , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Adulto Jovem
6.
PLoS One ; 15(8): e0237345, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32813724

RESUMO

BACKGROUND: Mixed/polyclonal infections due to different genotypes are reported in Tuberculosis. The current study was designed to understand the fate of mixed infections during the course of treatment and follow-up and its role in disease pathogenesis. METHODS: Sputum samples were collected on 0,1,2,3,6,12 and 24 months from 157 treatment-naïve patients, cultures subjected to Drug-Susceptibility-testing (MGIT 960), spoligotyping, MIRU-VNTR and SNP genotyping. All isolated colonies on thin layer agar (7H11) were subjected to spoligotyping. FINDINGS: One thirty three baseline cultures were positive (133/157, 84.7%), 43(32.3%) had mixture of genotypes. Twenty-four of these patients (55.8%) showed change in genotype while six showed different drug-susceptibility patterns while on treatment. Twenty-three (53.5%) patients with polyclonal infections showed resistance to at least one drug compared to 10/90 (11.1%) monoclonal infections (P<0.0001). Eight patients had recurrent TB, two with a new genotype and two with altered phenotypic DST. CONCLUSIONS: The coexistence of different genotypes and change of genotypes during the same disease episode, while on treatment, confirms constancy of polyclonal infections. The composition of the mixture of genotypes and the relative predominance may be missed by culture due to its limit of detection. Polyclonal infections in TB could be a rule rather than exception and challenges the age-old dogma of reactivation/reinfection.


Assuntos
Antituberculosos/farmacologia , Coinfecção/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla/genética , Mycobacterium tuberculosis/genética , Tuberculose Pulmonar/microbiologia , Adolescente , Adulto , Antituberculosos/uso terapêutico , Técnicas de Tipagem Bacteriana , Evolução Clonal , Coinfecção/epidemiologia , Coinfecção/microbiologia , DNA Bacteriano/genética , DNA Bacteriano/isolamento & purificação , Feminino , Seguimentos , Técnicas de Genotipagem , Humanos , Limite de Detecção , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/patogenicidade , Filogenia , Polimorfismo de Nucleotídeo Único , Prevalência , Recidiva , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/epidemiologia , Adulto Jovem
7.
PLoS One ; 15(7): e0236496, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32702008

RESUMO

BACKGROUND: To improve the quality of diagnosing pulmonary tuberculosis (TB), WHO recommends the use of rapid molecular testing as an alternative to conventional microscopic methods. Loop-mediated isothermal amplification assay (LAMP test) is a practical and cost-effective nucleic amplification technique. We evaluated the pragmatic accuracy of an in-house LAMP assay for the diagnosis of TB in a remote health care setting where an advanced rapid molecular test is not available. METHODS: A prospective diagnostic accuracy study was conducted. Patients with clinical symptoms suggestive of TB were consecutively enrolled from April to August 2016. Sputum samples were collected from each patient and were sent for microscopic examination (both acid-fast stain and fluorescence stain), in-house LAMP test, and TB culture. RESULTS: One hundred and seven patients with TB symptoms were used in the final analysis. This included 50 (46.7%) culture-positive TB patients and 57 (53.3%) culture-negative patients. The overall sensitivity of the in-house LAMP based on culture positivity was 88.8% (95/107) with a 95%CI of 81.2-94.1. The sensitivity was 90.9% (40/44) with a 95%CI of 78.3-97.5 for smear-positive, culture-positive patients, and was 16.7% (1/6) with a 95%CI of 0.4-64.1 for smear-negative, culture-positive patients. The overall sensitivity of the in-house LAMP test compared to smear microscopy methods were not significantly different (p = 0.375). The specificity of the in-house LAMP based on non-TB patients (smear-negative, culture-negative) was 94.7% (54/57) with a 95%CI of 85.4-98.9. CONCLUSIONS: The diagnostic accuracy of the in-house LAMP test in a community hospital was comparable to other previous reports in terms of specificity. The sensitivity of the in-house assay could be improved with better sputum processing and DNA extraction method.


Assuntos
Técnicas de Diagnóstico Molecular/normas , Técnicas de Amplificação de Ácido Nucleico/normas , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/genética , Testes Diagnósticos de Rotina/efeitos adversos , Testes Diagnósticos de Rotina/normas , Feminino , Hospitais Comunitários , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/patogenicidade , Estudos Prospectivos , Escarro/metabolismo , Tailândia/epidemiologia , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/patologia
8.
Adv Exp Med Biol ; 1207: 413-423, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671764

RESUMO

Bacterial infection is a common clinical disease that can affect a variety of organs and tissues. Autophagy, as an important part of the innate immune response and adaptive immune response, plays an important role in the defense against bacterial infection. Bacteria can also evade autophagy by destroying or utilizing autophagy virulence proteins or related molecules. Studying the mechanism of autophagy in bacteria and its interaction with cells help to discover new pathogenic mechanisms of bacterial infection. This chapter introduces the possible mechanisms of autophagy during bacterial infections such as Salmonella and Mycobacterium tuberculosis, in order to discover new ways to prevent and control infectious diseases.


Assuntos
Autofagia , Infecções Bacterianas , Autofagia/imunologia , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Humanos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Salmonella/imunologia , Salmonella/patogenicidade , Virulência
9.
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
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 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
12.
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
13.
Cancer Invest ; 38(6): 356-364, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32468861

RESUMO

Pleural effusion adenosine deaminase (ADA) levels are elevated in various diseases. We investigated whether pleural effusion ADA levels differ among patients with malignant pleural mesothelioma (MPM), lung cancer (LC), and benign diseases, including tuberculous pleurisy. We examined 329 patients from February 2002 to July 2013. There were 131 MPM cases with ADA levels of 32.29 IU/L; 117 LC cases with ADA levels of 21.12 IU/L; 54 benign disease cases with ADA levels of 20.98 IU/L. A significant difference existed in pleural effusion ADA levels between MPM and benign disease patients. Pleural effusion ADA levels were significantly higher in MPM patients.


Assuntos
Adenosina Desaminase/genética , Neoplasias Pulmonares/diagnóstico , Mesotelioma/diagnóstico , Neoplasias/diagnóstico , Neoplasias Pleurais/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/diagnóstico por imagem , Mesotelioma/genética , Mesotelioma/patologia , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/patogenicidade , Neoplasias/diagnóstico por imagem , Neoplasias/genética , Neoplasias/patologia , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/diagnóstico por imagem , Derrame Pleural Maligno/genética , Derrame Pleural Maligno/patologia , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Toracoscopia , Tuberculose Pleural/diagnóstico , Tuberculose Pleural/genética , Tuberculose Pleural/microbiologia , Tuberculose Pleural/patologia
14.
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
15.
PLoS One ; 15(5): e0229700, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379829

RESUMO

One of the most important and exclusive characteristics of mycobacteria is their cell wall. Amongst its constituent components are two related families of glycosylated lipids, diphthioceranates and phthiocerol dimycocerosate (PDIM) and its variant phenolic glycolipids (PGL). PGL have been associated with cell wall impermeability, phagocytosis, defence against nitrosative and oxidative stress and, intriguingly, biofilm formation. In bacteria from the Mycobacterium tuberculosis complex (MTBC), the biosynthetic pathway of the phenolphthiocerol moiety of PGL depends upon the expression of several genes encoding type I polyketide synthases (PKS), namely ppsA-E and pks15/1 which constitute the PDIM + PGL locus, and that are highly conserved in PDIM/PGL-producing strains. Consensus has not been achieved regarding the genetic organization of pks15/1 locus and knowledge is lacking on its transcriptional signature. Here we explore publicly available datasets of transcriptome data (RNA-seq) from more than 100 MTBC experiments in 40 growth conditions to outline the transcriptional structure and signature of pks15/1, using a differential expression approach to infer the regulatory patterns involving these and related genes. We show that pks1 expression is highly correlated with fadD22, Rv2949c, lppX, fadD29 and, also, pks6 and pks12, with the first three putatively integrating into a polycistronic structure. We evidence dynamic transcriptional heterogeneity within the genes involved in phenolphtiocerol and phenolic glycolipid production, most exhibiting up-regulation upon acidic pH and antibiotic exposure and down-regulation under hypoxia, dormancy, and low/high iron concentration. We finally propose a model based on transcriptome data in which σD positively regulates pks1, pks15 and fadD22, while σB and σE factors exert negative regulation at an upper level.


Assuntos
Antígenos de Bactérias/biossíntese , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica , Glicolipídeos/biossíntese , Glicolipídeos/genética , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidade , Policetídeo Sintases/genética , Transcriptoma , Parede Celular/metabolismo , Simulação por Computador , Redes Reguladoras de Genes , Loci Gênicos , Genoma Bacteriano/genética , Ligases/genética , RNA-Seq , Virulência/genética
16.
PLoS One ; 15(4): e0232142, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32324806

RESUMO

INTRODUCTION: Tuberculosis (TB) remains a significant cause of morbidity and mortality in Vietnam. The current TB burden is unknown as not all individuals with TB are diagnosed, recorded and notified. The second national TB prevalence survey was conducted in 2017-2018 to assess the current burden of TB disease in the country. METHOD: Eighty-two clusters were selected using a multistage cluster sampling design. Adult (≥15 years of age) residents having lived for 2 weeks or more in the households of the selected clusters were invited to participate in the survey. The survey participants were screened for TB by a questionnaire and digital chest X-ray after providing written informed consent. Individuals with a positive symptom screen and/or chest X-ray suggestive of TB were asked to provide sputum samples to test for Mycobacterium tuberculosis by Ziehl-Neelsen direct light microscopy, Xpert MTB/RIF G4, BACTEC MGIT960 liquid culture and Löwenstein-Jensen solid culture. Bacteriologically confirmed TB cases were defined by an expert panel following a standard decision tree. RESULT: Of 87,207 eligible residents, 61,763 (70.8%) participated, and 4,738 (7.7%) screened positive for TB. Among these, 221 participants were defined as bacteriologically confirmed TB cases. The estimated prevalence of bacteriologically confirmed adult pulmonary TB was 322 (95% CI: 260-399) per 100,000, and the male-to-female ratio was 4.0 (2.8-5.8, p<0.001). In-depth interviews with the participants with TB disease showed that only 57.9% (95% CI: 51.3-64.3%) reported cough for 2 weeks or more and 32.1% (26.3-38.6%) did not report any symptom consistent with TB, while their chest X-ray results showed that 97.7% (95% CI: 94.6-99.1) had abnormal chest X-ray images suggesting TB. CONCLUSION: With highly sensitive diagnostics applied, this survey showed that the TB burden in Vietnam remains high. Half of the TB cases were not picked up by general symptom-based screening and were identified by chest X-ray only. Our results indicate that improving TB diagnostic capacity and access to care, along with reducing TB stigma, need to be top priorities for TB control and elimination in Vietnam.


Assuntos
Tuberculose Pulmonar/epidemiologia , Adolescente , Adulto , Idoso , Tosse/microbiologia , Estudos Transversais , Testes Diagnósticos de Rotina/métodos , Feminino , Humanos , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Mycobacterium tuberculosis/patogenicidade , Prevalência , Escarro/microbiologia , Inquéritos e Questionários , Tórax/microbiologia , Vietnã/epidemiologia , Adulto Jovem
17.
Int J Nanomedicine ; 15: 2231-2258, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32280217

RESUMO

Rapid emergence of aggressive, multidrug-resistant Mycobacteria strain represents the main cause of the current antimycobacterial-drug crisis and status of tuberculosis (TB) as a major global health problem. The relatively low-output of newly approved antibiotics contributes to the current orientation of research towards alternative antibacterial molecules such as advanced materials. Nanotechnology and nanoparticle research offers several exciting new-concepts and strategies which may prove to be valuable tools in improving the TB therapy. A new paradigm in antituberculous therapy using silver nanoparticles has the potential to overcome the medical limitations imposed in TB treatment by the drug resistance which is commonly reported for most of the current organic antibiotics. There is no doubt that AgNPs are promising future therapeutics for the medication of mycobacterial-induced diseases but the viability of this complementary strategy depends on overcoming several critical therapeutic issues as, poor delivery, variable intramacrophagic antimycobacterial efficiency, and residual toxicity. In this paper, we provide an overview of the pathology of mycobacterial-induced diseases, andhighlight the advantages and limitations of silver nanoparticles (AgNPs) in TB treatment.


Assuntos
Antituberculosos/farmacologia , Nanopartículas Metálicas/uso terapêutico , Prata/farmacologia , Tuberculose/tratamento farmacológico , Antituberculosos/química , Humanos , Nanopartículas Metálicas/química , Infecções por Mycobacterium/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade , Prata/química , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
18.
Nat Commun ; 11(1): 1949, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327653

RESUMO

Genetic diversity of Mycobacterium tuberculosis affects immune responses and clinical outcomes of tuberculosis (TB). However, how bacterial diversity orchestrates immune responses to direct distinct TB severities is unknown. Here we study 681 patients with pulmonary TB and show that M. tuberculosis isolates from cases with mild disease consistently induce robust cytokine responses in macrophages across multiple donors. By contrast, bacteria from patients with severe TB do not do so. Secretion of IL-1ß is a good surrogate of the differences observed, and thus to classify strains as probable drivers of different TB severities. Furthermore, we demonstrate that M. tuberculosis isolates that induce low levels of IL-1ß production can evade macrophage cytosolic surveillance systems, including cGAS and the inflammasome. Isolates exhibiting this evasion strategy carry candidate mutations, generating sigA recognition boxes or affecting components of the ESX-1 secretion system. Therefore, we provide evidence that M. tuberculosis strains manipulate host-pathogen interactions to drive variable TB severities.


Assuntos
Citosol/imunologia , Interleucina-1beta/metabolismo , Mycobacterium tuberculosis/patogenicidade , Transdução de Sinais/imunologia , Tuberculose Pulmonar/imunologia , Animais , Proteínas de Bactérias/genética , Células Cultivadas , Citocinas/metabolismo , Feminino , Genoma Bacteriano/genética , Humanos , Evasão da Resposta Imune , Imunomodulação , Inflamassomos/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Mutação , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Filogenia , Polimorfismo de Nucleotídeo Único , Tuberculose Pulmonar/microbiologia , Virulência/genética
19.
Nat Commun ; 11(1): 1960, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327655

RESUMO

Gene rv3722c of Mycobacterium tuberculosis is essential for in vitro growth, and encodes a putative pyridoxal phosphate-binding protein of unknown function. Here we use metabolomic, genetic and structural approaches to show that Rv3722c is the primary aspartate aminotransferase of M. tuberculosis, and mediates an essential but underrecognized role in metabolism: nitrogen distribution. Rv3722c deficiency leads to virulence attenuation in macrophages and mice. Our results identify aspartate biosynthesis and nitrogen distribution as potential species-selective drug targets in M. tuberculosis.


Assuntos
Aspartato Aminotransferases/metabolismo , Ácido Aspártico/metabolismo , Proteínas de Bactérias/metabolismo , Mycobacterium tuberculosis/enzimologia , Nitrogênio/metabolismo , Animais , Aspartato Aminotransferases/química , Aspartato Aminotransferases/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Células Cultivadas , Feminino , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/patogenicidade , Ligação Proteica , Conformação Proteica , Virulência/genética
20.
PLoS One ; 15(4): e0231637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315335

RESUMO

INTRODUCTION: The contribution of high tuberculosis (TB) transmission pockets in propagating area-wide transmission has not been adequately described in Zimbabwe. This study aimed to describe the presence of hotspot transmission of TB cases in Harare city from 2011 to 2012 using geospatial techniques. METHODS: Anonymised TB patient data stored in an electronic database at Harare City Health department was analysed using geospatial methods. Confirmed TB cases were mapped using geographic information system (GIS). Global Moran's I and Anselin Local Moran's I (LISA) were used to assess clustering and the local Getis-Ord Gi* was used to estimate hotspot phenomenon of TB cases in Harare City for the period between 2011 and 2012. RESULTS: A total of 12,702 TB cases were accessed and mapped on the Harare City map. In both 2011 and 2012, ninety (90%) of cases were new and had a high human immunodeficiency virus (HIV)/TB co-infection rate of 72% across all suburbs. Tuberculosis prevalence was highest in the Southern district in both 2011 and 2012. There were pockets of spatial distribution of TB prevalence across West South West, Southern, Western, South Western and Eastern health districts. TB hot spot occurrence was restricted to the West South West, parts of South Western, Western health districts. West South West district had an increased peri-urban population with inadequate social services including health facilities. These conditions were conducive for increased intensity of TB occurrence, a probable indication of high transmission especially in the presence of high HIV co-infection. CONCLUSIONS AND RECOMMENDATIONS: Increased TB transmission was limited to a health district with high informal internal migrants with limited health services in Harare City. To minimise spread of TB into greater Harare, there is need to improve access to TB services in the peri-urban areas.


Assuntos
Transmissão de Doença Infecciosa , Infecções por HIV/epidemiologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Sistemas de Informação Geográfica , HIV/patogenicidade , Infecções por HIV/complicações , Infecções por HIV/microbiologia , Infecções por HIV/virologia , Acesso aos Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Análise Espacial , Tuberculose/complicações , Tuberculose/microbiologia , Tuberculose/virologia , População Urbana , Adulto Jovem , Zimbábue/epidemiologia
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