Introduction: Mycobacterium tuberculosis produces several proteins that have been associated with... more Introduction: Mycobacterium tuberculosis produces several proteins that have been associated with its virulence and therefore intensively studied as target for subunit vaccine against tuberculosis. Ag85C, MPT51 and HspX were shown to be immunogenic and antigenic proteins. Also, a fusion protein (rCMX) developed using part of these individual molecules induced specific Th1 and Th17 and poly functional Th cells, that were related to tuberculosis protection. Objectives: This study aimed to understand how this immune response was induced . Methodology: Pulmonary, peritoneal, alveolar, and bone marrow derived macrophages from BALB/c mice were stimulated with the recombinant antigens: Ag85C, MPT51, HspX, CMX or with BCG or rBCG CMX vaccines. Results: All macrophage types responded to Ag85C and CMX with elevated NO production when compared with unstimulated macrophages, while the response to MPT51 and CMX produced urea at similar levels as M2 derived macrophages. HspX did not stimulate mac...
Objetivo: Ressaltar o monitoramento da HPN por imunofenotipagem por citometria de fluxo (CMF) e a... more Objetivo: Ressaltar o monitoramento da HPN por imunofenotipagem por citometria de fluxo (CMF) e avaliar a eficácia do tratamento com o anticorpo monoclonal eculizumab. Metodologia: O trabalho é uma análise retrospectiva de dados de prontuários dos pacientes encaminhados a um Instituto de referência em doenças hematológicas no Estado de Goiás para diagnóstico e monitoramento da HPN no período de janeiro de 2010 a dezembro de 2017. Resultados: Dos 31 pacientes diagnosticados com HPN, 5 foram selecionados com dados completos nos prontuários. No paciente 1, houve uma melhora significativa com o tratamento, com um aumento do número relativo para os marcadores dos eritrócitos (CD55 e CD59) de 22,7% para 71,7%. Para o paciente 3, a variação média de marcadores foi de 0,5% para 5,2%. No paciente 5 a variação média ficou entre 12,6% e 36,9%. O eculizumab reduziu o quadro hemolítico, melhorando os sintomas e estabilizando os resultados dos testes de hemólise. Conclusão: A imunofenotipagem por...
complex has been characterized in the last decade as part of a cluster of mycobacteria that evolv... more complex has been characterized in the last decade as part of a cluster of mycobacteria that evolved from an opportunistic to true human pathogen; however, the factors responsible for pathogenicity are still undefined. It appears that the success of mycobacterial infection is intrinsically related with the capacity of the bacteria to regulate intracellular iron levels, mostly using iron storage proteins. This study evaluated two potential subsp. genes involved in iron storage. Unlike other opportunist or pathogenic mycobacteria studied, complex has two genes similar to ferritins from (Rv3841), and in subsp. , those genes are annotated as and . Molecular dynamic analysis of the predicted expressed proteins showed that they have a ferroxidase center. The expressions of and genes were modulated by the iron levels in both cultures as well as infected macrophages. Structural studies using size-exclusion chromatography, circular dichroism spectroscopy and dynamic light scattering showed th...
is a rapid growing, multidrug-resistant, non-tuberculous mycobacteria that is responsible for a w... more is a rapid growing, multidrug-resistant, non-tuberculous mycobacteria that is responsible for a wide spectrum of skin and soft tissue infections, as well as other organs, such as the lungs. Antimicrobial peptides had been described as broad-spectrum antimicrobial, chemotactic, and immunomodulator molecules. In this study we evaluated an antimicrobial peptide derived from scorpion as an anti-mycobacterial agent in vitro and in vivo. Bioinformatics analyses demonstrated that the peptide ToAP2 have a conserved region similar to several membrane proteins, as well as mouse cathelicidin. ToAP2 inhibited the growth of four strains (GO01, GO06, GO08, and CRM0020) at a minimal bactericidal concentration (MBC) of 200 µM. MBC concentration used to treat infected macrophages was able to inhibit 50% of the bacterial growth of all strains. ToAP2 treatment of infected mice with bacilli reduced the bacterial load in the liver, lung, and spleen, similarly to clarithromycin levels (90%). ToAP2 alone ...
Expert review of clinical immunology, Aug 30, 2017
Development of new tools for rapid and accurate diagnosis of tuberculosis (TB) is considered a st... more Development of new tools for rapid and accurate diagnosis of tuberculosis (TB) is considered a strategy for controlling the disease. The recombinant CMX fusion protein is composed of immunodominant epitopes of the Ag85C (Rv0129c), MPT51 (Rv3803c) and the entire HspX (Rv2031c) proteins from Mycobacterium tuberculosis H37Rv (Mtb). The aim of this study was to evaluate the applicability of a test using the CMX protein in individuals suspected of TB. Indirect ELISA was used to measure serum anti-CMX IgM and IgG in individuals with pulmonary TB. Patients with pulmonary TB had higher titers of IgM (OD = 0.502 ± 0.281) than healthy controls (OD = 0.200 ± 0.125). The cutoff for IgM-ELISA was determined using ROC curve analyzes (AUC = 0.868) with a sensitivity of 80.1% and a specificity of 78.2%. Patients with pulmonary TB also had higher titers of IgG (OD = 0.525 ± 0.391) than healthy controls (OD = 0.215 ± 0.077). The cutoff for IgG-ELISA was determined using ROC curve analyzes (AUC = 0.86...
Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a vaccine used to prevent tuberculosis (TB)... more Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a vaccine used to prevent tuberculosis (TB). Due to the poor protection conferred by BCG in adults, new, more effective formulations have been developed. A recombinant BCG vaccine expressing the CMX fusion protein Ag85c_MPT51_HspX (rBCG-CMX) induced Th1 and Th17 responses and provided better protection than BCG. It has been shown that Mycobacterium smegmatis expressing CMX also induces better protection than BCG and is a strong macrophage activator. The aim of the present study was to evaluate macrophage activation by the recombinant CMX fusion protein and by rBCG-CMX and to evaluate their ability to generate vaccine-specific immune responses. The results demonstrate that rCMX protein expressed by BCG (rBCG-CMX) activates pulmonary macrophages; increases the expression of activation molecules, cytokines, and MHC-II. The interaction with rCMX activates the transcription factor NF-κB and induces the production of the cytokines TGF-...
A tuberculose (TB) é a segunda principal causa de morte por doença infecciosa em todo o mundo e c... more A tuberculose (TB) é a segunda principal causa de morte por doença infecciosa em todo o mundo e constitui um contínuo problema de saúde global. A ocorrência da TB ativa em indivíduos privados de liberdade (PL) é superior aos níveis médios relatados para a população geral. A descoberta tardia dos casos de TB, associada ao atraso no tratamento, agrava o problema da TB nas penitenciárias. Embora estas instituições sejam fechadas, a movimentação de prisioneiros entre diferentes ambientes da prisão, unidades prisionais ou instituições como tribunais transforma estes locais em verdadeiros reservatórios da TB. Este trabalho teve como objetivo fazer a triagem de voluntários PL para submetê-los à prova tuberculínica (PT). Os resultados desta primeira avaliação da PT em uma unidade prisional de Goiás evidenciaram positividade em 50,3% dos homens e 38,1% das mulheres. O acompanhamento dos dados destes indivíduos revelou que após um ano do recrutamento, 1,7% (n=9) dos voluntários apresentaram T...
International journal of chronic obstructive pulmonary disease, 2015
The diagnosis of chronic obstructive pulmonary disease (COPD) is often delayed until later stages... more The diagnosis of chronic obstructive pulmonary disease (COPD) is often delayed until later stages of the disease. The purpose of the present study was to determine the prevalence of COPD among adults on treatment for systemic arterial hypertension independently of the presence of respiratory symptoms. This cross-sectional study included adults aged ≥40 years with tobacco/occupational exposure and systemic arterial hypertension diagnosed at three Primary Health Care facilities in Goiania, Brazil. Patients were evaluated using a standardized respiratory questionnaire and spirometry. COPD prevalence was measured considering the value of forced vital capacity and/or forced expiratory volume in 1 second <0.70. Of a total of 570 subjects, 316 (55%) met inclusion criteria and were invited to participate. Two hundred and thirty-three (73.7%) patients with arterial hypertension reported at least one respiratory symptom, while 83 (26.3%) reported no respiratory symptoms; 41 (17.6%) patient...
Tuberculosis is an infectious disease that affects millions of people worldwide with an annual mo... more Tuberculosis is an infectious disease that affects millions of people worldwide with an annual mortality rate of 1.3 million. The mechanisms contributing to the loss of balance of immune responses and progression to active tuberculosis disease are unknown. Although CD4+ and CD8+ T cells and the cytokines they produce are crucial for protection against tuberculosis they have different roles in tuberculosis immunology. The function of CD4+ T cells has been extensively studied; however, less is known about the phenotype and function of CD8+ T cells. This study evaluated the specific expression of IFN-γ, IL-17, IL-10, and TGF-β and ex vivo expression of perforin and granzyme-B by CD8+ T cells from active tuberculosis individuals compared with latent infected individuals and non-latent infected individuals. Tuberculosis responses were correlated with the baciloscopy score. We observed that the presence of IL-10 and TGF-β expression and down-expression of granzyme-B in CD8+ T cells correlated with increased sputum bacillary load in active tuberculosis individuals. These findings provide new insights into the role of CD8+ T cells in Mycobacterium tuberculosis disease.
Introduction: Mycobacterium tuberculosis produces several proteins that have been associated with... more Introduction: Mycobacterium tuberculosis produces several proteins that have been associated with its virulence and therefore intensively studied as target for subunit vaccine against tuberculosis. Ag85C, MPT51 and HspX were shown to be immunogenic and antigenic proteins. Also, a fusion protein (rCMX) developed using part of these individual molecules induced specific Th1 and Th17 and poly functional Th cells, that were related to tuberculosis protection. Objectives: This study aimed to understand how this immune response was induced . Methodology: Pulmonary, peritoneal, alveolar, and bone marrow derived macrophages from BALB/c mice were stimulated with the recombinant antigens: Ag85C, MPT51, HspX, CMX or with BCG or rBCG CMX vaccines. Results: All macrophage types responded to Ag85C and CMX with elevated NO production when compared with unstimulated macrophages, while the response to MPT51 and CMX produced urea at similar levels as M2 derived macrophages. HspX did not stimulate mac...
Objetivo: Ressaltar o monitoramento da HPN por imunofenotipagem por citometria de fluxo (CMF) e a... more Objetivo: Ressaltar o monitoramento da HPN por imunofenotipagem por citometria de fluxo (CMF) e avaliar a eficácia do tratamento com o anticorpo monoclonal eculizumab. Metodologia: O trabalho é uma análise retrospectiva de dados de prontuários dos pacientes encaminhados a um Instituto de referência em doenças hematológicas no Estado de Goiás para diagnóstico e monitoramento da HPN no período de janeiro de 2010 a dezembro de 2017. Resultados: Dos 31 pacientes diagnosticados com HPN, 5 foram selecionados com dados completos nos prontuários. No paciente 1, houve uma melhora significativa com o tratamento, com um aumento do número relativo para os marcadores dos eritrócitos (CD55 e CD59) de 22,7% para 71,7%. Para o paciente 3, a variação média de marcadores foi de 0,5% para 5,2%. No paciente 5 a variação média ficou entre 12,6% e 36,9%. O eculizumab reduziu o quadro hemolítico, melhorando os sintomas e estabilizando os resultados dos testes de hemólise. Conclusão: A imunofenotipagem por...
complex has been characterized in the last decade as part of a cluster of mycobacteria that evolv... more complex has been characterized in the last decade as part of a cluster of mycobacteria that evolved from an opportunistic to true human pathogen; however, the factors responsible for pathogenicity are still undefined. It appears that the success of mycobacterial infection is intrinsically related with the capacity of the bacteria to regulate intracellular iron levels, mostly using iron storage proteins. This study evaluated two potential subsp. genes involved in iron storage. Unlike other opportunist or pathogenic mycobacteria studied, complex has two genes similar to ferritins from (Rv3841), and in subsp. , those genes are annotated as and . Molecular dynamic analysis of the predicted expressed proteins showed that they have a ferroxidase center. The expressions of and genes were modulated by the iron levels in both cultures as well as infected macrophages. Structural studies using size-exclusion chromatography, circular dichroism spectroscopy and dynamic light scattering showed th...
is a rapid growing, multidrug-resistant, non-tuberculous mycobacteria that is responsible for a w... more is a rapid growing, multidrug-resistant, non-tuberculous mycobacteria that is responsible for a wide spectrum of skin and soft tissue infections, as well as other organs, such as the lungs. Antimicrobial peptides had been described as broad-spectrum antimicrobial, chemotactic, and immunomodulator molecules. In this study we evaluated an antimicrobial peptide derived from scorpion as an anti-mycobacterial agent in vitro and in vivo. Bioinformatics analyses demonstrated that the peptide ToAP2 have a conserved region similar to several membrane proteins, as well as mouse cathelicidin. ToAP2 inhibited the growth of four strains (GO01, GO06, GO08, and CRM0020) at a minimal bactericidal concentration (MBC) of 200 µM. MBC concentration used to treat infected macrophages was able to inhibit 50% of the bacterial growth of all strains. ToAP2 treatment of infected mice with bacilli reduced the bacterial load in the liver, lung, and spleen, similarly to clarithromycin levels (90%). ToAP2 alone ...
Expert review of clinical immunology, Aug 30, 2017
Development of new tools for rapid and accurate diagnosis of tuberculosis (TB) is considered a st... more Development of new tools for rapid and accurate diagnosis of tuberculosis (TB) is considered a strategy for controlling the disease. The recombinant CMX fusion protein is composed of immunodominant epitopes of the Ag85C (Rv0129c), MPT51 (Rv3803c) and the entire HspX (Rv2031c) proteins from Mycobacterium tuberculosis H37Rv (Mtb). The aim of this study was to evaluate the applicability of a test using the CMX protein in individuals suspected of TB. Indirect ELISA was used to measure serum anti-CMX IgM and IgG in individuals with pulmonary TB. Patients with pulmonary TB had higher titers of IgM (OD = 0.502 ± 0.281) than healthy controls (OD = 0.200 ± 0.125). The cutoff for IgM-ELISA was determined using ROC curve analyzes (AUC = 0.868) with a sensitivity of 80.1% and a specificity of 78.2%. Patients with pulmonary TB also had higher titers of IgG (OD = 0.525 ± 0.391) than healthy controls (OD = 0.215 ± 0.077). The cutoff for IgG-ELISA was determined using ROC curve analyzes (AUC = 0.86...
Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a vaccine used to prevent tuberculosis (TB)... more Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a vaccine used to prevent tuberculosis (TB). Due to the poor protection conferred by BCG in adults, new, more effective formulations have been developed. A recombinant BCG vaccine expressing the CMX fusion protein Ag85c_MPT51_HspX (rBCG-CMX) induced Th1 and Th17 responses and provided better protection than BCG. It has been shown that Mycobacterium smegmatis expressing CMX also induces better protection than BCG and is a strong macrophage activator. The aim of the present study was to evaluate macrophage activation by the recombinant CMX fusion protein and by rBCG-CMX and to evaluate their ability to generate vaccine-specific immune responses. The results demonstrate that rCMX protein expressed by BCG (rBCG-CMX) activates pulmonary macrophages; increases the expression of activation molecules, cytokines, and MHC-II. The interaction with rCMX activates the transcription factor NF-κB and induces the production of the cytokines TGF-...
A tuberculose (TB) é a segunda principal causa de morte por doença infecciosa em todo o mundo e c... more A tuberculose (TB) é a segunda principal causa de morte por doença infecciosa em todo o mundo e constitui um contínuo problema de saúde global. A ocorrência da TB ativa em indivíduos privados de liberdade (PL) é superior aos níveis médios relatados para a população geral. A descoberta tardia dos casos de TB, associada ao atraso no tratamento, agrava o problema da TB nas penitenciárias. Embora estas instituições sejam fechadas, a movimentação de prisioneiros entre diferentes ambientes da prisão, unidades prisionais ou instituições como tribunais transforma estes locais em verdadeiros reservatórios da TB. Este trabalho teve como objetivo fazer a triagem de voluntários PL para submetê-los à prova tuberculínica (PT). Os resultados desta primeira avaliação da PT em uma unidade prisional de Goiás evidenciaram positividade em 50,3% dos homens e 38,1% das mulheres. O acompanhamento dos dados destes indivíduos revelou que após um ano do recrutamento, 1,7% (n=9) dos voluntários apresentaram T...
International journal of chronic obstructive pulmonary disease, 2015
The diagnosis of chronic obstructive pulmonary disease (COPD) is often delayed until later stages... more The diagnosis of chronic obstructive pulmonary disease (COPD) is often delayed until later stages of the disease. The purpose of the present study was to determine the prevalence of COPD among adults on treatment for systemic arterial hypertension independently of the presence of respiratory symptoms. This cross-sectional study included adults aged ≥40 years with tobacco/occupational exposure and systemic arterial hypertension diagnosed at three Primary Health Care facilities in Goiania, Brazil. Patients were evaluated using a standardized respiratory questionnaire and spirometry. COPD prevalence was measured considering the value of forced vital capacity and/or forced expiratory volume in 1 second <0.70. Of a total of 570 subjects, 316 (55%) met inclusion criteria and were invited to participate. Two hundred and thirty-three (73.7%) patients with arterial hypertension reported at least one respiratory symptom, while 83 (26.3%) reported no respiratory symptoms; 41 (17.6%) patient...
Tuberculosis is an infectious disease that affects millions of people worldwide with an annual mo... more Tuberculosis is an infectious disease that affects millions of people worldwide with an annual mortality rate of 1.3 million. The mechanisms contributing to the loss of balance of immune responses and progression to active tuberculosis disease are unknown. Although CD4+ and CD8+ T cells and the cytokines they produce are crucial for protection against tuberculosis they have different roles in tuberculosis immunology. The function of CD4+ T cells has been extensively studied; however, less is known about the phenotype and function of CD8+ T cells. This study evaluated the specific expression of IFN-γ, IL-17, IL-10, and TGF-β and ex vivo expression of perforin and granzyme-B by CD8+ T cells from active tuberculosis individuals compared with latent infected individuals and non-latent infected individuals. Tuberculosis responses were correlated with the baciloscopy score. We observed that the presence of IL-10 and TGF-β expression and down-expression of granzyme-B in CD8+ T cells correlated with increased sputum bacillary load in active tuberculosis individuals. These findings provide new insights into the role of CD8+ T cells in Mycobacterium tuberculosis disease.
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