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1.
BMC Infect Dis ; 20(1): 831, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33176701

RESUMO

BACKGROUND: The discovery of antibiotics in the mid-twentieth century marked a major transition in tuberculosis (TB) treatment and control. There are few studies describing the duration of TB disease and its treatment from the pre-chemotherapy era and little data on how these treatments changed in response to the development of effective antibiotics. The goal of this research is to understand how inpatient treatment for high incidence populations, the First Nations peoples of Saskatchewan, Canada, changed in response to increasing availability of antibiotics effective against TB. We expected that as treatment regimens transitioned from convalescence-only to triple antibiotic therapy, the length of inpatient treatment would shorten. METHODS: Analyses were performed on records of sanatoria admissions and discharges occurring between 1933 and 1959 in Saskatchewan, Canada. Year of antibiotic discovery was taken as a proxy for treatment regimen: no chemotherapy (pre-1944), mono-therapy (Streptomycin, 1944-1946), dual-therapy (Streptomycin and PAS, 1946-1952), and triple-therapy (Streptomycin, PAS, and INH 1952-). A pooled linear regression of log-transformed length of first admission as predicted by year of admission was modeled to assess the relationship between admission length and year of admission, corrected for clinical and demographic variables. RESULTS: First admission length increased 19% in the triple-therapy era as compared to the pre-chemotherapy era, from 316 days (10.4 months) to 377 days (12.4 months). After the discovery of INH (1952), we find statistically significant increases in the proportion of successfully completed therapies (0.55 versus 0.60, p = 0.035), but also in patients who left hospital against medical advice (0.19 versus 0.29, p < 0.0001), indicating that as hospitalizations lengthened, more patients chose to discharge without the sanction of their physician. The readmission rate increased from 10 to 50% of all admissions while the province-level TB-specific death rate fell from 63.1 per 10,000 in 1933 to 4.7 per 10,000 in 1958. CONCLUSION: Counterintuitively, we find that the length of first admissions increased with the discovery of TB-treating antibiotics. Increasing admission volume and readmission rate indicate an intensification of inpatient TB treatment during this era. These analyses provide a novel estimate of the effect of changing treatment policy on sanatorium admissions in this population.


Assuntos
Antibacterianos/uso terapêutico , Tempo de Internação/tendências , Readmissão do Paciente/tendências , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá/epidemiologia , Criança , Pré-Escolar , Feminino , Hospitais , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Alta do Paciente , Estudos Retrospectivos , Resultado do Tratamento , Tuberculose/microbiologia , Adulto Jovem
2.
J Oleo Sci ; 69(11): 1481-1486, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33132280

RESUMO

Via utilizing the mixed-ligand method, a novel coordination polymer (CP) containing Cu(II) has been prepared by self-assembly at the ambient temperature, and its chemical formula is {[Cu(BINDI)0.5 (bpe)]·3H2O} n (1, bpe = 1,2-bis(4-pyridyl)ethylene and H4BINDI = N,N'-bis(5-isophthalic acid) naphthalenediimide). For the treatment of the tuberculosis, its biological function was evaluated as well. The CFU assay was performed to determine the bacterial numbers of the Mycobacterium in alveolar macrophages. In addition to this, the ropA gene of the Mycobacterium in alveolar macrophages was also detected through the real time RT-PCR method. Only the oxygen atoms on the metal complex are identified to be able to interact with the probe protein by molecular docking simulation.


Assuntos
Cobre/farmacologia , Macrófagos Alveolares/microbiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Polímeros/farmacologia , Proteínas de Bactérias/análise , Proteínas de Bactérias/genética , Contagem de Colônia Microbiana , Cobre/química , Cobre/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/genética , Oxigênio , Polímeros/química , Polímeros/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
3.
Nat Commun ; 11(1): 5225, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067434

RESUMO

Patients with type 2 diabetes (T2D) have a lower risk of Mycobacterium tuberculosis infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence, when being treated with metformin. However, a detailed mechanistic understanding of these protective effects is lacking. Here, we use mass cytometry to show that metformin treatment expands a population of memory-like antigen-inexperienced CD8+CXCR3+ T cells in naive mice, and in healthy individuals and patients with T2D. Metformin-educated CD8+ T cells have increased (i) mitochondrial mass, oxidative phosphorylation, and fatty acid oxidation; (ii) survival capacity; and (iii) anti-mycobacterial properties. CD8+ T cells from Cxcr3-/- mice do not exhibit this metformin-mediated metabolic programming. In BCG-vaccinated mice and guinea pigs, metformin enhances immunogenicity and protective efficacy against M. tuberculosis challenge. Collectively, these results demonstrate an important function of CD8+ T cells in metformin-derived host metabolic-fitness towards M. tuberculosis infection.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Animais , Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Cobaias , Humanos , Masculino , Camundongos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/fisiologia , Tuberculose/etiologia , Tuberculose/imunologia , Tuberculose/microbiologia , Tuberculose/prevenção & controle
4.
PLoS One ; 15(10): e0240203, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33027297

RESUMO

The COVID-19 pandemic, caused by type 2 Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), puts all of us to the test. Epidemiologic observations could critically aid the development of protective measures to combat this devastating viral outbreak. Recent observations, linked nation based universal Bacillus Calmette-Guerin (BCG) vaccination to potential protection against morbidity and mortality from SARS-CoV-2, and received much attention in public media. We wished to validate the findings by examining the country based association between COVID-19 mortality per million population, or daily rates of COVID-19 case fatality (i.e. Death Per Case/Days of the endemic [dpc/d]) and the presence of universal BCG vaccination before 1980, or the year of the establishment of universal BCG vaccination. These associations were examined in multiple regression modeling based on publicly available databases on both April 3rd and May 15th of 2020. COVID-19 deaths per million negatively associated with universal BCG vaccination in a country before 1980 based on May 15th data, but this was not true for COVID-19 dpc/d on either of days of inquiry. We also demonstrate possible arbitrary selection bias in such analyses. Consequently, caution should be exercised amidst the publication surge on COVID-19, due to political/economical-, arbitrary selection-, and fear/anxiety related biases, which may obscure scientific rigor. We argue that global COVID-19 epidemiologic data is unreliable and therefore should be critically scrutinized before using it as a nidus for subsequent hypothesis driven scientific discovery.


Assuntos
Vacina BCG , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/mortalidade , Pneumonia Viral/epidemiologia , Pneumonia Viral/mortalidade , Vacinação , Adulto , Idoso , Animais , Criança , Pré-Escolar , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Humanos , Lactente , Recém-Nascido , Mycobacterium tuberculosis/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Saúde da População , Tuberculose/microbiologia , Tuberculose/prevenção & controle , Adulto Jovem
5.
BMC Infect Dis ; 20(1): 766, 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33069210

RESUMO

BACKGROUND: Evaluating the completeness of tuberculosis (TB) notification data is important for monitoring of TB surveillance systems. We conducted an inventory study to calculate TB underreporting in Germany in 2013-2017. METHODS: Acquisition of two pseudonymized case-based data sources (national TB notification data and antibiotic resistance surveillance data) was followed by two-source Capture-recapture (CRC) analysis, as case-based data from a third source was unavailable. Aggregated data on consumption of a key anti-TB drug (pyrazinamide [PZA]) was compared to an estimated need for PZA based on TB notification data to obtain an independent underreporting estimation. Additionally, notified TB incidence was compared to TB rate in an aggregated health insurance fund dataset. RESULTS: CRC and PZA-based approaches indicated that between 93 and 97% (CRC) and between 91 and 95% (PZA) of estimated cases were captured in the national TB notification data in the years 2013-2017. Insurance fund dataset did not indicate TB underreporting on the national level in 2017. CONCLUSIONS: Our results suggest that more than 90% of estimated TB cases are captured within the German TB surveillance system, and accordingly the TB notification rate is likely a good proxy of the diagnosed TB incidence rate. An increase in underreporting and discrepancies however should be further investigated.


Assuntos
Antituberculosos/uso terapêutico , Mycobacterium tuberculosis , Pirazinamida/uso terapêutico , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Bases de Dados Factuais , Notificação de Doenças/métodos , Alemanha , Humanos , Incidência , Armazenamento e Recuperação da Informação , Tempo de Internação , Tuberculose/microbiologia
6.
Int J Nanomedicine ; 15: 5901-5909, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32884258

RESUMO

Background: Tuberculosis (TB) has always been recognized as one of the fatal infectious diseases, which is caused by Mycobacterium tuberculosis (M.tb). Isonicotinic acid hydrazide or isoniazid (INH) is one of the most commonly utilized drugs in the treatment of TB. Patients need to take 300 mg daily of INH for 6 months in combination with another anti-TB drug and tolerate several side effects of INH. On the other hand, the emergence of resistant strains of anti-TB antibiotics is one of the major problems in the treatment of this disease. So, antimicrobial drug delivery by nanofluids could improve the efficacy, and reduce the adverse effects of antimicrobial drugs. The purpose of this study was to perform a novel method to synthesize INH-conjugated multi-wall carbon nanotubes (MWCNTs) for more effective drug delivery, as well as, TB treatment. Methods: INH-conjugated functionalized MWCNTs were prepared, using a reflux system. The characterization of the obtained nano-drug was performed by the elemental analyses of total nitrogen, hydrogen, carbon and sulfur (CHNS), Raman spectroscopy, Fourier transform infrared (FTIR), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) methods. The nanofluid of nano-drug was prepared by the ultrasonic method, and the related antibacterial effect studies were carried out on the two strains of M.tb. Results: The antimicrobial effect of INH-conjugated MWCNTs was found to be much better at low concentrations than the pure drug in all of the strains. Conclusion: Since one of the main antimicrobial mechanisms of MWCNTs is through the destruction of the bacterial cell wall, in addition to its antimicrobial effects, it increased the drug delivery of INH at lower doses compared to drug alone. So, the nanofluid, containing INH-conjugated MWCNTs, had a better lethal effect on a variety of M.tb strains than that of the drug alone.


Assuntos
Antituberculosos/farmacologia , Isoniazida/administração & dosagem , Isoniazida/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Nanoestruturas/química , Antituberculosos/administração & dosagem , Antituberculosos/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Isoniazida/química , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Nanoestruturas/administração & dosagem , Nanotubos de Carbono/química , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Tuberculose/microbiologia
7.
PLoS One ; 15(9): e0238193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881875

RESUMO

INTRODUCTION: Detection of Mycobacterium tuberculosis (Mtb) in patient-derived bioaerosol is a potential tool to measure source case infectiousness. However, current bioaerosol sampling approaches have reported low detection yields in sputum-positive TB cases. To increase the utility of bioaerosol sampling, we present advances in bioaerosol collection and Mtb identification that improve detection yields. METHODS: A previously described Respiratory Aerosol Sampling Chamber (RASC) protocol, or "RASC-1", was modified to incorporate liquid collection of bioaerosol using a high-flow wet-walled cyclone (RASC-2). Individuals with GeneXpert-positive pulmonary TB were sampled pre-treatment over 60-minutes. Putative Mtb bacilli were detected in collected fluid by fluorescence microscopy utilising DMN-Trehalose. Exhaled air and bioaerosol volumes were estimated using continuous CO2 monitoring and airborne particle counting, respectively. Mtb capture was calculated per exhaled air volume sampled and bioaerosol volume for RASC-1 (n = 35) and for RASC-2 (n = 21). Empty chamber samples were collected between patients as controls. RESULTS: The optimised RASC-2 protocol sampled a median of 258.4L (IQR: 226.9-273.6) of exhaled air per patient compared with 27.5L (IQR: 23.6-30.3) for RASC-1 (p<0.0001). Bioaerosol volume collection was estimated at 2.3nL (IQR: 1.1-3.6) for RASC-2 compared with 0.08nL (IQR: 0.05-0.10) for RASC-1 (p<0.0001). The detection yield of viable Mtb improved from 43% (median 2 CFU, range: 1-14) to 95% (median 20.5 DMN-Trehalose positive bacilli, range: 2-155). These improvements represent a lowering of the limit of detection in the RASC-2 platform to 0.9 Mtb bacilli per 100L of exhaled air from 3.3 Mtb bacilli per 100L (RASC-1). CONCLUSION: This study demonstrates that technical improvements in particle collection together with sensitive detection enable rapid quantitation of viable Mtb in bioaerosols of sputum positive TB cases. Increased sampling sensitivity may allow future TB transmission studies to be extended to sputum-negative and subclinical individuals, and suggests the potential utility of bioaerosol measurement for rapid intervention in other airborne infectious diseases.


Assuntos
Aerossóis/análise , Manejo de Espécimes/métodos , Tuberculose/diagnóstico , Adulto , Dióxido de Carbono/química , Expiração , Feminino , Humanos , Masculino , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose/microbiologia
8.
PLoS One ; 15(9): e0239289, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32936814

RESUMO

Mycobacterium tuberculosis (Mtb) is the causative agent for tuberculosis, the most extended infectious disease around the world. When Mtb enters inside the pulmonary alveolus it is rapidly phagocytosed by the alveolar macrophage. Although this controls the majority of inhaled microorganisms, in this case, Mtb survives inside the macrophage and multiplies. A posterior chemokine and cytokine cascade generated by the irruption of monocytes, neutrophils and posteriorly, by T-cells, does not necessarily stop the growth of the granuloma. Interestingly, the encapsulation process built by fibroblasts is able to surround the lesion and stop its growing. The success of this last process determines if the host enters in an asymptomatic latent state or continues into a life-threatening and infective active tuberculosis disease (TB). Understanding such dichotomic process is challenging, and computational modeling can bring new ideas. Thus, we have modeled the different stages of the infection, first in a single alveolus (a sac with a radius of 0.15 millimeters) and, second, inside a secondary lobule (a compartment of the lungs of around 3 cm3). We have employed stochastic reaction-diffusion equations to model the interactions among the cells and the diffusive transport to neighboring alveolus. The whole set of equations have successfully described the encapsulation process and determine that the size of the lesions depends on its position on the secondary lobule. We conclude that size and shape of the secondary lobule are the relevant variables to control the lesions, and, therefore, to avoid the evolution towards TB development. As lesions appear near to interlobular connective tissue they are easily controlled and their growth is drastically stopped, in this sense secondary lobules with a more flattened shape could control better the lesion.


Assuntos
Simulação por Computador , Granuloma/patologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose/imunologia , Quimiocinas/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Difusão , Granuloma/imunologia , Granuloma/microbiologia , Humanos , Tuberculose Latente/imunologia , Tuberculose Latente/microbiologia , Tuberculose Latente/patologia , Pulmão/imunologia , Pulmão/metabolismo , Macrófagos Alveolares/enzimologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Mycobacterium tuberculosis/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Fagocitose/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Tuberculose/microbiologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
9.
BMC Infect Dis ; 20(1): 711, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32993535

RESUMO

BACKGROUND: Mycobacterium bovis could infect patients with immunodeficiency or immunosuppressive conditions via Bacillus Calmette-Guérin (BCG) vaccination. Tuberculosis-related hemophagocytic syndrome (HPS) is reported, but not HPS caused by Mycobacterium bovis in children. CASE PRESENTATION: A 4-month Chinese boy presented fever and cough. The initial laboratory investigation showed the lymphocyte count of 0.97 × 109/L, which decreased gradually. HPS was diagnosed based on the test results that fulfilled the HLH-2004 criteria. In addition, Mycobacterium tuberculosis complex was detected from his peripheral blood via metagenomic next-generation sequencing (mNGS) and M. bovis was identified by polymerase chain reaction-reverse dot blot (PCR-RDB). Thus, the patient was treated with Isoniazid, Rifampin, and Pyrazinamide, but not improved. However, parents refused to accept further therapy, and was discharged on the day 12 of admission. To confirm the pathogenesis, genetic analysis was performed. Mutation in the interleukin-2 receptor subunit gamma gene: Exon 6: c.854G > A; p. Arg285Gln was detected in the patient and the mother, which could underlie X-linked severe combined immunodeficiency. CONCLUSIONS: A boy with X-SCID was diagnosed with M. bovis-associated HPS, emphasizing that X-SCID should be considered when M. bovis is detected in a male infant with low lymphocyte counts.


Assuntos
Linfo-Histiocitose Hemofagocítica/complicações , Mycobacterium bovis/genética , Mycobacterium tuberculosis/genética , Tuberculose/complicações , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/complicações , Antibióticos Antituberculose/uso terapêutico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Subunidade gama Comum de Receptores de Interleucina/genética , Isoniazida/uso terapêutico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/microbiologia , Masculino , Mutação , Alta do Paciente , Reação em Cadeia da Polimerase , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , Resultado do Tratamento , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
10.
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
11.
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
12.
Mol Immunol ; 126: 101-109, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32795663

RESUMO

Autophagy is considered as an effective strategy for host cells to eliminate intracellular Mycobacterium tuberculosis (Mtb). Dual-specificity phosphatase 5 (DUSP5) is an endogenous phosphatase of ERK1/2, and plays an important role in host innate immune responses, its function in autophagy regulation however remains unexplored. In the present study, the function of DUSP5 in autophagy in Mycobacterium bovis Bacillus Calmette-Guerin (BCG)-infected RAW264.7 cells, a murine macrophage-like cell line, was examined by assessing the alteration of the cell morphology, expression of autophagy markers, and ERK1/2 signaling activation. The results demonstrated that the BCG infection could induce DUSP5 expression and activate ERK1/2 signaling in RAW264.7 cells; an activation of ERK1/2 signaling contributed to autophagic process in RAW264.7 cells. Moreover, DUSP5 knockdown increased the expression of autophagy-related proteins (Atgs), including LC3-II, Beclin1, Atg5 and Atg7. However, an overexpression of DUSP5 exhibited an opposite effect. Mechanistically, DUSP5 could inhibit the formation of autophagosome by suppressing the phosphorylation of signaling molecules in ERK1/2 signaling cascade. This study thus demonstrated a novel role of DUSP5 in modulating autophagy inRAW264.7 cells in response to BCG infection in particular, and autophagy macrophage to Mtb in general.


Assuntos
Autofagia/imunologia , Fosfatases de Especificidade Dupla/metabolismo , Sistema de Sinalização das MAP Quinases/imunologia , Mycobacterium bovis/imunologia , Tuberculose/imunologia , Animais , Autofagossomos/imunologia , Autofagossomos/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Modelos Animais de Doenças , Fosfatases de Especificidade Dupla/genética , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Fosforilação/genética , Fosforilação/imunologia , Células RAW 264.7 , RNA Interferente Pequeno/metabolismo , Tuberculose/microbiologia
13.
BMC Infect Dis ; 20(1): 609, 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811463

RESUMO

BACKGROUND: Ratios of different immune cell populations (i.e., monocyte-to-lymphocyte, neutrophil-to-lymphocyte, and platelet-to-lymphocyte ratios) have been studied as a means of predicting future tuberculosis (TB) disease risk or to assist in the diagnosis of incident TB disease. No studies to-date, however, have evaluated the potential of these ratios to predict or assist in the diagnosis of incident TB infection - the first step in the natural history of TB disease. METHODS: In this prospective study, we evaluated the complete blood count (CBC)-derived metrics of monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) as predictors of future TB infection risk or aids in the diagnosis of TB infection among 145 Tanzanian adolescents enrolled in the DAR-901 vaccine trial, using paired CBCs and interferon-gamma release assays (IGRAs) obtained at 0, 60 and 720 days after study enrollment. RESULTS: At baseline, there were no significant differences between study participants who remained persistently IGRA negative throughout the study period and those who subsequently converted to IGRA positive with respect to MLR (0.18 vs 0.17, p = 0.10), NLR (0.88 vs 1.02, p = 0.08), or PLR (115 vs 120, p = 0.28). Similarly, no significant differences were noted with respect to MLR, NLR, and PLR between IGRA converters and time-matched negative controls at the time of IGRA conversion. With respect to other blood cell measures, however, there were modest but significant differences between IGRA negatives and IGRA converters with respect to red blood cell count (4.8 vs 4.6 ×  106 cells/mcL, p = 0.008), hemoglobin (12.6 vs 12.3 g/dL, p = 0.01), and hematocrit (38.8 vs 37.8%, p = 0.005). CONCLUSIONS: In contrast to prior studies that have suggested that the ratios of different immune cell populations are associated with development of TB disease, our present findings do not demonstrate an association between these ratios and the development of TB infection. However, decreased red blood cell measures were associated with the subsequent development of TB infection, suggesting either that dysregulation of iron metabolism may play a role in TB pathogenesis or that following TB infection, iron dysregulation may precede IGRA positivity. TRIAL REGISTRATION: Clinicaltrials.gov NCT02712424 . Date of registration: March 14, 2016.


Assuntos
Contagem de Células Sanguíneas/métodos , Plaquetas , Linfócitos , Monócitos , Neutrófilos , Tuberculose/diagnóstico , Tuberculose/epidemiologia , Adolescente , Feminino , Humanos , Incidência , Testes de Liberação de Interferon-gama , Masculino , Estudos Prospectivos , Tanzânia/epidemiologia , Tuberculose/sangue , Tuberculose/microbiologia
14.
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
16.
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
17.
Int J Infect Dis ; 98: 447-453, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32619758

RESUMO

OBJECTIVES: Tuberculosis (TB) is an infectious and contagious disease that has been very influential in human history and presents high rates of mortality. The objective of this study was to investigate the association of VDR, IL10, and SLC11A1 gene polymorphisms with susceptibility to the presence of Mycobacterium tuberculosis infection. METHODS: A total of 135 patients with confirmed TB and 141 healthy individuals were included in the analysis. Blood samples were collected for DNA extraction. Genotyping of the polymorphisms in the VDR and IL10 genes was performed by real-time PCR, and genotyping of the polymorphisms in the SLC11A1 gene by conventional PCR, followed by visualization in polyacrylamide gel. The genomic ancestry was obtained using an autosomal panel with 48 insertion/deletion ancestry-informative markers. RESULTS: Polymorphisms TaqI (TT, p=0.004), FokI (CC and CC+CT, p=0.012 and p=0.003, respectively), and BsmI (GG, p=0.008) in the VDR gene, as well as A-592C (GC+AG, p=0.001) in the IL10 gene, were significantly associated with susceptibility to TB In addition, high production of VDR combined with low production of IL10 showed protection for the TB group (p=0.035). CONCLUSIONS: The VDR polymorphisms may confer an increased risk and the IL10 haplotype may be a protection factor for the presence of M. tuberculosis infection in the Brazilian population.


Assuntos
Interleucina-10/genética , Receptores de Calcitriol/genética , Tuberculose/genética , Adulto , Brasil/epidemiologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Mycobacterium tuberculosis/fisiologia , Polimorfismo Genético , Tuberculose/epidemiologia , Tuberculose/microbiologia , Adulto Jovem
18.
BMC Public Health ; 20(1): 1021, 2020 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-32600287

RESUMO

BACKGROUND: Ethiopia has shown significant efforts to address the burden of TB/HIV comorbidity through the TB/HIV collaborative program. However, these diseases are still the highest cause of death in the country. Therefore, this systematic review and meta-analysis evaluated this program by investigating the overall proportion of unknown HIV status among TB patients using published studies in Ethiopia. METHODS: We conducted a systematic review and meta-analysis of published studies in Ethiopia. We identified the original studies using the databases MEDLINE/PubMed, and Google Scholar. The heterogeneity across studies was assessed using Cochran's Q test and I 2 statistics. The Begg's rank correlation and the Egger weighted regression tests were assessed for the publication bias. We estimated the pooled proportion of unknown HIV status among TB patients using the random-effects model. RESULTS: Overall, we included 47 studies with 347,896 TB patients eligible for HIV test. The pooled proportion of unknown HIV status among TB patients was 27%(95% CI; 21-34%) and with a substantial heterogeneity (I2 = 99.9%). In the subgroup analysis, the pooled proportion of unknown HIV status was 39% (95% CI; 25-54%) among children and 20% (95% CI; 11-30%) among adults. In the region based analysis, the highest pooled proportion of unknown HIV status was in Gambella, 38% (95% CI; 16-60%) followed by Addis Ababa, 34%(95% CI; 12-55%), Amhara,30%(95% CI; 21-40%),and Oromia, 23%(95% CI; 9-38%). Regarding the study facilities, the pooled proportion of unknown HIV status was 33% (95% CI; 23-43%) in the health centers and 26%(95% CI; 17-35%) in the hospitals. We could not identify the high heterogeneity observed in this review and readers should interpret the results of the pooled proportion analysis with caution. CONCLUSION: In Ethiopia, about one-third of tuberculosis patients had unknown HIV status. This showed a gap to achieve the currently implemented 90-90-90 HIV/AIDS strategic plan in Ethiopia, by 2020. Therefore, Ethiopia should strengthen TB/HIV collaborative activities to mitigate the double burden of diseases.


Assuntos
Coinfecção/epidemiologia , Infecções por HIV/epidemiologia , Serviços Preventivos de Saúde/estatística & dados numéricos , Tuberculose/epidemiologia , Adolescente , Adulto , Criança , Coinfecção/microbiologia , Coinfecção/prevenção & controle , Etiópia/epidemiologia , Infecções por HIV/microbiologia , Infecções por HIV/prevenção & controle , Nível de Saúde , Humanos , Avaliação de Programas e Projetos de Saúde , Tuberculose/microbiologia , Tuberculose/prevenção & controle , Adulto Jovem
19.
Mikrobiyol Bul ; 54(2): 211-222, 2020 Apr.
Artigo em Turco | MEDLINE | ID: mdl-32723277

RESUMO

Members of the Mycobacterium tuberculosis complex (MTBC) are the causative agents of tuberculosis (TB). Rifampin resistance in the clinical isolates of MTBC is an important indicator for multidrug resistant-TB (MDR-TB) cases. In this study, it was aimed to evaluate whether the Sensititre MycoTB plaque method is suitable for the routine use in determining drug susceptibility of rifampin resistant MTBC strains. Xpert MTBC/ RIF positive rifampin resistant 100 MTBC isolates were included in the study. Xpert MTBC/RIF (Cepheid, USA) test were performed after the samples were processed by homogenization and decontamination and acid-fast staining. Rifampin resistant clinical samples were cultured in automated MGIT/BACTEC 960 (Becton Dickinson, USA) system and acid fast bacteria (AFB) were investigated. The anti-TB drug susceptibility tests of all culture positive AFB and cord factor identified as MTBC by using a cart test (MPB64, Capilla TB-Neo, Tauns Laboratories, Inc., Numazu, Japan) were performed with the Löwenstein-Jensen proportion method (LJPM) and Sensititre MycoTB (Trek Diagnostic Systems, Cleveland, OH, USA) methods. For the comparison of the methods used, the tests were performed simultaneously. The standard LJPM was performed according to the previously described procedures by World Health Organization and the Sensititre MycoTB plate method was performed as defined by the manufacturer. The final concentrations of isoniazide, rifampin, rifabutin, ethambutol, ofloxacin, moxifloxacin amikacin, kanamycin, cycloserine, ethionamide and p-aminosalicylic acid in Löwenstein-Jensen media for LJPM were 0.2 µg/ml, 40.0 µg/ml, 20.0 µg/ml, 2.0 µg/ml, 2.0 µg/ml, 1.0 µg/ml, 4.0 µg/ml, 30.0 µg/ml, 30.0 µg/ml, 40.0 µg/ml, 40.0 µg/ml and 1.0 µg/ ml, respectively. The results were obtained in 14 days for all of the drugs in the Sensititre MycoTB plate method and in 28-42 days in the LJPM. In this study, the sensitivity and specificity percentages of the Sensititre MycoTB method and the categorical agreement between the two methods were calculated. The sensitivity and specificity percentages of the Sensititre MycoTB plate method were between 84.4-100% and 95.6- 100%, respectively. The categorical agreements between the two methods were 92-100% for the drugs tested in the study. Ethambutol was found to have the lowest sensitivity (84.4%) and specificity (95.6%). The sensitivities of isoniazide, ofloxacin, streptomycin, kanamycin, ethionamide and p-aminosalicylic acid were 98.8%, 90.0%, 94.3%, 87.5%, 91.7% and 95.6%, respectively, while rifampicin, rifabutin, moxifloxacin, amikacin, cycloserine were calculated as 100%. The specificities of isoniazid, rifampicin, rifabutin, ofloxacin, moxifloxacin, amikacin, kanamycin, and cycloserine were found to be 100%, streptomycin, ethionamide and p-aminosalicylic specificity were 96.9%, 97.4% and 98.9% respectively. The categorical agreement was 96-100% in all tested drugs except ethambutol (92%). As a result, although the cost is high, owing to the short incubation period, easy to perform, the possibility for evaluating both first and second line anti-TB drugs simultaneously, determination of minimum inhibitory concentration values of the drugs, long shelf life, high sensitivity, specificity and the categorical agreement values, the Sensititre MycoTB method was determined as an effective method that can be used especially in laboratories where the workload and the MDR-TB cases are high.


Assuntos
Antituberculosos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis , Rifampina , Tuberculose , Antituberculosos/farmacologia , Etambutol/farmacologia , Testes de Sensibilidade Microbiana/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/farmacologia , Tuberculose/microbiologia
20.
PLoS One ; 15(7): e0236109, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692774

RESUMO

BACKGROUND: Pyrazinamide (PZA) is a common drug that causes serious adverse events (SAEs). The aim of this study was to determine the incidence of and risk factors for SAEs due to PZA during first-line anti-tuberculosis treatment. METHODS: The medical records of patients with tuberculosis (TB) treated with PZA-containing regimens including first-line drugs-ethambutol, rifampicin, and isoniazid-from January 2003 to June 2016 were reviewed. SAEs were defined as side effects that led to drug discontinuation. The causative drug was determined based on the disappearance of the SAEs upon drug withdrawal and/or the recurrence of the same SAEs with re-challenge. RESULTS: Of 2,478 patients with TB, 16.4% experienced SAEs. The incidence of SAEs increased significantly as age increased, except with rifampin. PZA accounted for most SAEs (55.8%). Hepatotoxicity was the most common SAE due to PZA (44.5%), followed by gastrointestinal (GI) intolerance (23.8%). The risk of SAEs due to PZA increased significantly as age increased, when sex and comorbidities were adjusted (odds ratio, 1.013; 95% confidence interval, 1.004-1.023; P = 0.007). In the subgroup analysis, older age was an independent risk factor for GI intolerance but not for hepatotoxicity. CONCLUSION: PZA was the most common drug associated with SAEs among the first-line anti-TB drugs, and old age was an independent factor for SAE occurrence. This study suggests that the early recognition of whether the causative agent is PZA may improve effective treatment compliance, particularly in elderly patients.


Assuntos
Antituberculosos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinamida/efeitos adversos , Tuberculose/tratamento farmacológico , Idoso , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Tuberculose/microbiologia
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