Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 8.349
Filtrar
1.
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
3.
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
4.
BMC Infect Dis ; 20(1): 746, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046016

RESUMO

BACKGROUND: Effective active case finding (ACF) activities are essential for early identification of new cases of active tuberculosis (TB) and latent TB infection (LTBI). Accurate diagnostics as well as the ability to identify contacts at high risk of infection are essential for ACF, and have not been systematically reported from Central Asia. The objective was to implement a pilot ACF program to determine the prevalence and risk factors for LTBI and active TB among contacts of individuals with TB in Kyrgyz Republic using Quantiferon-TB Gold plus (QuantiFERON). METHODS: An enhanced ACF project in the Kyrgyz Republic was implemented in which close and household (home) contacts of TB patients from the Issyk-Kul Oblast TB Center were visited at home. QuantiFERON and the tuberculin skin test (TST) alongside clinical and bacteriological examination were used to identify LTBI and active TB cases among contacts. The association for QuantiFERON positivity and risk factors were analysed and compared to TST results. RESULTS: Implementation of ACF with QuantiFERON involved close collaboration with the national sanitary and epidemiological services (SES) and laboratories in the Kyrgyz Republic. From 67 index cases, 296 contacts were enrolled of whom 253 had QuantiFERON or TST results; of those 103 contacts had LTBI (positive TST or IGRA), and four (1.4%) active TB cases were detected. Index case smear microscopy (OR 1.76) and high household density (OR 1.97) were significant risk factors for QuantiFERON positivity for all contacts. When stratified by age, association with smear positivity disappeared for children below 15 years. TST was not associated with any risk factor. CONCLUSIONS: This is the first time that ACF activities have been reported for Central Asia, and provide insight for implementation of effective ACF in the region. These ACF activities using QuantiFERON led to increase in the detection of LTBI and active cases, prior to patients seeking treatment. Household density should be taken into consideration as an important risk factor for the stratification of future ACF activities.


Assuntos
Busca de Comunicante/métodos , Testes de Liberação de Interferon-gama/métodos , Tuberculose Latente/diagnóstico , Tuberculose Latente/epidemiologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Testes Diagnósticos de Rotina , Características da Família , Feminino , Humanos , Lactente , Recém-Nascido , Quirguistão/epidemiologia , Tuberculose Latente/microbiologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prevalência , Fatores de Risco , Teste Tuberculínico/métodos , Tuberculose Pulmonar/microbiologia , Adulto Jovem
5.
Medicine (Baltimore) ; 99(36): e22015, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899054

RESUMO

INTRODUCTION: Tuberculosis (TB) is a global infectious disease. In low-incidence countries, paediatric TB affects mostly immigrant children and children of immigrants. We hypothesize that these children are at risk of exposure to Mycobacterium tuberculosis when they travel to the country of origin of their parents to visit friends and relatives (VFR). In this study, we aim to estimate the incidence rate and risk factors associated to latent tuberculosis infection (LTBI) and TB in VFR children. METHODS AND ANALYSIS: A prospective study will be carried out in collaboration with 21 primary health care centres (PCC) and 5 hospitals in Catalonia, Spain. The study participants are children under 15 years of age, either immigrant themselves or born to immigrant parents, who travel to countries with high incidence of TB (≥ 40 cases/100,000 inhabitants). A sample size of 492 children was calculated. Participants will be recruited before traveling, either during a visit to a travel clinic or to their PCC, where a questionnaire including sociodemographic, epidemiological and clinical data will be completed, and a tuberculin skin test (TST) will be performed and read after 48 to 72 hours; patients with a positive TST at baseline will be excluded. A visit will be scheduled eight to twelve-weeks after their return to perform a TST and a QuantiFERON-TB Gold Plus test. The incidence rate of LTBI will be estimated per individual/month and person/year per country visited, and also by age-group. ETHICS AND DISSEMINATION: The study protocol was approved by the Clinical Research Ethics Committee of the Hospital Universitari Mútua Terrassa (code 02/16) and the Clinical Research Ethics Committee of the Fundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (code P16/094). Articles will be published in indexed scientific journals. TRIAL REGISTRATION: Clinical-Trials.gov: NCT04236765.


Assuntos
Tuberculose Latente/epidemiologia , Tuberculose Latente/transmissão , Mycobacterium tuberculosis/isolamento & purificação , Adolescente , Criança , Testes Diagnósticos de Rotina/métodos , Emigrantes e Imigrantes , Família , Feminino , Amigos , Humanos , Incidência , Testes de Liberação de Interferon-gama/métodos , Tuberculose Latente/diagnóstico , Masculino , Mycobacterium tuberculosis/imunologia , Estudos Prospectivos , Fatores de Risco , Espanha/epidemiologia , Viagem/tendências , Teste Tuberculínico/métodos
6.
PLoS Pathog ; 16(9): e1008887, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32956412

RESUMO

Despite the availability of multiple antibiotics, tuberculosis (TB) remains a major health problem worldwide, with one third of the population latently infected and ~2 million deaths annually. The only available vaccine for TB, Bacillus Calmette Guérin (BCG), is ineffective against adult pulmonary TB. Therefore, alternate strategies that enhance vaccine efficacy are urgently needed. Vaccine efficacy and long-term immune memory are critically dependent on central memory T (TCM) cells, whereas effector memory T (TEM) cells are important for clearing acute infections. Recently, it has been shown that inhibition of the Kv1.3 K+ ion channel, which is predominantly expressed on TEM but not TCM cells, profoundly enhances TCM cell differentiation. We exploited this phenomenon to improve TCM:TEM cell ratios and protective immunity against Mycobacterium tuberculosis infection in response to BCG vaccination of mice. We demonstrate that luteolin, a plant-derived Kv1.3 K+ channel inhibitor, profoundly promotes TCM cells by selectively inhibiting TEM cells, and significantly enhances BCG vaccine efficacy. Thus, addition of luteolin to BCG vaccination may provide a sustainable means to improve vaccine efficacy by boosting host immunity via modulation of memory T cell differentiation.


Assuntos
Vacina BCG/imunologia , Memória Imunológica/efeitos dos fármacos , Canal de Potássio Kv1.3 , Luteolina/farmacologia , Mycobacterium tuberculosis/imunologia , Linfócitos T/imunologia , Tuberculose/imunologia , Animais , Canal de Potássio Kv1.3/antagonistas & inibidores , Canal de Potássio Kv1.3/imunologia , Camundongos , Tuberculose/prevenção & controle
7.
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
8.
Yonsei Med J ; 61(9): 789-796, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32882763

RESUMO

PURPOSE: The prevalence of Mycobacterium tuberculosis (M. tb) and the status of M. bovis BCG vaccination may affect host immune responses to M. tb antigens. Understanding of the predominant local M. tb strain and immune signatures induced by its strain-specific antigens may contribute to an improved diagnosis of tuberculosis (TB). The aim of this study was to determine immune responses to M. tb antigen which was identified from the hyper-virulent Beijing/K strain in South Korea. MATERIALS AND METHODS: Pulmonary TB patients (n=52) and healthy subjects (n=92) including individuals with latent TB infection (n=31) were recruited, and QuantiFERON-TB Gold In-Tube tests were performed. The Beijing/K-antigen specific immune signatures were examined by diluted whole blood assays and multiplex bead arrays in a setting where nationwide BCG vaccination is employed. RESULTS: Statistical analyses demonstrated that three [C-X-C motif chemokine (CXCL10), interleukin (IL)-6, interferon (IFN)-α] of 17 cytokines/chemokines distinguished active cases from healthy controls following stimulation with the Beijing/K-specific antigen. IFN-α also differentiated between active diseases and latent TB infection (p<0.01), and the detection rate of TB was dramatically increased in combination with IL-6 and CXCL10 at the highest levels of specificity (95-100%). CONCLUSION: Our data indicate that immune signatures to the M. tb Beijing/K-specific antigen can provide useful information for improved TB diagnostics. The antigen may be developed as a diagnostic marker or a vaccine candidate, particularly in regions where the M. tb Beijing/K strain is endemic.


Assuntos
Tuberculose Latente/diagnóstico , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Pulmonar/diagnóstico , Adolescente , Adulto , Antígenos de Bactérias/sangue , Antígenos de Bactérias/genética , Antígenos de Superfície/sangue , Antígenos de Superfície/genética , Proteínas de Bactérias , Pequim , Estudos de Casos e Controles , Citocinas/sangue , Feminino , Humanos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/metabolismo , República da Coreia , Sensibilidade e Especificidade
9.
BMC Infect Dis ; 20(1): 677, 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32942991

RESUMO

BACKGROUND: Approximately 80% - 90% of individuals infected with latent Mycobacterium tuberculosis (Mtb) remain protected throughout their life-span. The release of unique, latent-phase antigens are known to have a protective role in the immune response against Mtb. Although the BCG vaccine has been administered for nine decades to provide immunity against Mtb, the number of TB cases continues to rise, thereby raising doubts on BCG vaccine efficacy. The shortcomings of BCG have been associated with inadequate processing and presentation of its antigens, an inability to optimally activate T cells against Mtb, and generation of regulatory T cells. Furthermore, BCG vaccination lacks the ability to eliminate latent Mtb infection. With these facts in mind, we selected six immunodominant CD4 and CD8 T cell epitopes of Mtb expressed during latent, acute, and chronic stages of infection and engineered a multi-epitope-based DNA vaccine (C6). RESULT: BALB/c mice vaccinated with the C6 construct along with a BCG vaccine exhibited an expansion of both CD4 and CD8 T cell memory populations and augmented IFN-γ and TNF-α cytokine release. Furthermore, enhancement of dendritic cell and macrophage activation was noted. Consequently, illustrating the elicitation of immunity that helps in the protection against Mtb infection; which was evident by a significant reduction in the Mtb burden in the lungs and spleen of C6 + BCG administered animals. CONCLUSION: Overall, the results suggest that a C6 + BCG vaccination approach may serve as an effective vaccination strategy in future attempts to control TB.


Assuntos
Vacina BCG/imunologia , Epitopos de Linfócito T , Tuberculose/prevenção & controle , Vacinas de DNA/imunologia , Animais , Antígenos de Bactérias/imunologia , Vacina BCG/genética , Vacina BCG/farmacologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/genética , Feminino , Memória Imunológica , Interferon gama/metabolismo , Tuberculose Latente/prevenção & controle , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Vacinas de DNA/farmacologia
10.
BMC Infect Dis ; 20(1): 570, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758165

RESUMO

BACKGROUND: In sub-Saharan Africa (SSA), most prisons are overcrowded with poor ventilation and put prisoners disproportionally at risk of exposure to Mycobacterium tuberculosis (TB) and developing TB infection but are mostly missed due to poor access to healthcare. Active case-finding (ACF) of TB in prisons facilitates early diagnosis and treatment of inmates and prevent the spread. We explored literature and described evidence on TB ACF interventions and approaches for prisoners in SSA prisons. METHODS: Guided by the Arksey and O'Malley framework, we searched PubMed, Google Scholar, SCOPUS, Academic search complete, CINAHL and MEDLINE with full text via EBSCOhost for articles on prisoners and ACF from 2000 to May 2019 with no language restriction. Two investigators independently screened the articles at the abstract and full-text stages in parallel guided by the eligibility criteria as well as performed the methodological quality appraisal of the included studies using the latest mixed-method appraisal tool. We extracted all relevant data, organized them into themes and sub-themes, and presented a narrative summary of the results. RESULTS: Of the 391 eligible articles found, 31 met the inclusion criteria. All 31 articles were published between 2006 and 2019 with the highest six (19.4%) in 2015. We found evidence in 11 countries. That is, Burkina Faso, Cameroon, Coˆte d'Ivoire, the Democratic Republic of the Congo, Ethiopia, Ghana, Malawi, Nigeria, South Africa, Uganda, and Zambia with most 41.9% (13/31) recorded in Ethiopia. These intervention studies were conducted in 134 prisons between 2001 and 2018 using either a single or combination of mass, facility-led, entry, peer educators for routine screening, and exit ACF approaches. The majority (74%) of the studies utilized only a mass screening approach. The most (68%) reported study outcome was smear-positive TB cases only (68%). We found no evidence in 16 SSA countries although they are classified among the three high-burden country lists for TB TB/HIV and Multidrug resistant-TB group. CONCLUSION: Our review highlights a dearth of evidence on TB ACF interventions in most SSA countries prisons. Hence, there is the need to scaling-up ACF interventions in SSA prisons, particularly countries included in the three high-burden country lists for TB, TB/HIV, and MDR-TB.


Assuntos
Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/imunologia , Prisioneiros , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , África ao Sul do Saara/epidemiologia , Antibióticos Antituberculose/uso terapêutico , Farmacorresistência Bacteriana Múltipla , Feminino , Humanos , Masculino , Programas de Rastreamento/métodos , Mycobacterium tuberculosis/isolamento & purificação , Técnicas de Amplificação de Ácido Nucleico , Prevalência , Rifampina/uso terapêutico , Escarro/microbiologia , Teste Tuberculínico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
11.
PLoS One ; 15(8): e0237062, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760105

RESUMO

Nutritional status contributes to the regulation of immune responses against pathogens, and malnutrition has been considered as a risk factor for tuberculosis (TB). Mycobacterium tuberculosis (Mtb), the causative agent of TB, can modulate host lipid metabolism and induce lipid accumulation in macrophages, where the bacilli adopt a dormant phenotype. In addition, serum lipid components play dual roles in the regulation of and protection from Mtb infection. We analyzed the relationship between nutritional status and the humoral immune response in TB patients. We found that serum HDL levels are positively correlated with the serum IgA specific for Mtb antigens. Analysis of the relationship between serum nutritional parameters and clinical parameters in TB patients showed that serum albumin and CRP levels were negatively correlated before treatment. We also observed reduced serum LDL levels in TB patients following treatment. These findings may provide insight into the role of serum lipids in host immune responses against Mtb infection. Furthermore, improving the nutritional status may enhance vaccination efficacy.


Assuntos
Imunidade Humoral , Mycobacterium tuberculosis/imunologia , Estado Nutricional/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Idoso , Anticorpos Antibacterianos/sangue , Proteína C-Reativa/metabolismo , Progressão da Doença , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Albumina Sérica Humana/metabolismo , Vacinas contra a Tuberculose/imunologia , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/tratamento farmacológico
12.
Proc Natl Acad Sci U S A ; 117(34): 20848-20859, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32778586

RESUMO

Tuberculosis (TB) claims 1.5 million lives per year. This situation is largely due to the low efficacy of the only licensed TB vaccine, Bacillus Calmette-Guérin (BCG) against pulmonary TB. The metabolic disease type 2 diabetes (T2D) is a risk factor for TB and the mechanisms underlying increased TB susceptibility in T2D are not well understood. Furthermore, it is unknown if new TB vaccines will provide protection in the context of T2D. Here we used a diet-induced murine model of T2D to investigate the underlying mechanisms of TB/T2D comorbidity and to evaluate the protective capacity of two experimental TB vaccines in comparison to conventional BCG. Our data reveal a distinct immune dysfunction that is associated with diminished recognition of mycobacterial antigens in T2D. More importantly, we provide compelling evidence that mucosal delivery of recombinant BCG strains expressing the Mycobacterium tuberculosis (Mtb) ESX-1 secretion system (BCG::RD1 and BCG::RD1 ESAT-6 ∆92-95) are safe and confer superior immunity against aerosol Mtb infection in the context of T2D. Our findings suggest that the remarkable anti-TB immunity by these recombinant BCG strains is achieved via augmenting the numbers and functional capacity of antigen presenting cells in the lungs of diabetic mice.


Assuntos
Antígenos de Bactérias/farmacologia , Proteínas de Bactérias/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Animais , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Vacina BCG , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/metabolismo , Diabetes Mellitus Experimental , Modelos Animais de Doenças , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membrana Mucosa/imunologia , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Vacinas contra a Tuberculose/imunologia , Vacinação
13.
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
14.
PLoS Pathog ; 16(7): e1008413, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32730321

RESUMO

Human immunodeficiency virus infection is the most common risk factor for severe forms of tuberculosis (TB), regardless of CD4 T cell count. Using a well-characterized cynomolgus macaque model of human TB, we compared radiographic, immunologic and microbiologic characteristics of early (subclinical) reactivation of latent M. tuberculosis (Mtb) infection among animals subsequently infected with simian immunodeficiency virus (SIV) or who underwent anti-CD4 depletion by a depletion antibody. CD4 depleted animals had significantly fewer CD4 T cells within granulomas compared to Mtb/SIV co-infected and Mtb-only control animals. After 2 months of treatment, subclinical reactivation occurred at similar rates among CD4 depleted (5 of 7 animals) and SIV infected animals (4 of 8 animals). However, SIV-induced reactivation was associated with more dissemination of lung granulomas that were permissive to Mtb growth resulting in greater bacterial burden within granulomas compared to CD4 depleted reactivators. Granulomas from Mtb/SIV animals displayed a more robust T cell activation profile (IFN-α, IFN-γ, TNF, IL-17, IL-2, IL-10, IL-4 and granzyme B) compared to CD4 depleted animals and controls though these effectors did not protect against reactivation or dissemination, but instead may be related to increased viral and/or Mtb antigens. SIV replication within the granuloma was associated with reactivation, greater overall Mtb growth and reduced Mtb killing resulting in greater overall Mtb burden. These data support that SIV disrupts protective immune responses against latent Mtb infection beyond the loss of CD4 T cells, and that synergy between SIV and Mtb occurs within granulomas.


Assuntos
Coinfecção/imunologia , Tuberculose Latente/imunologia , Tuberculose Latente/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Ativação Viral/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Granuloma/virologia , Hospedeiro Imunocomprometido/imunologia , Macaca fascicularis , Mycobacterium tuberculosis/imunologia , Vírus da Imunodeficiência Símia/imunologia
15.
Mol Immunol ; 125: 123-130, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32659597

RESUMO

The development of a more efficient vaccine is needed to improve tuberculosis control. One of the current approaches is to identify immunogenic T-cell peptides that can elicit a protective and specific immune response. These peptides come from immunogenic proteins of the pathogen. The PE_PGRS33 protein of Mycobacterium tuberculosis has been proved immunogenic. However, little is known about immunogenic T-cell peptides of PE_PGRS33 and their interactions with MHC-II molecules. Therefore, we used the SYFPHEITHI database to determine the immunogenic PE_PGRS33 T-cell peptides. Next, we built homology models by using MOE v2018.1 software in order to obtain information about the specific interactions between the peptides and I-Ak. The AlgPred server was employed to look for allergenic sites in PE_PGRS33. We developed a sequence alignment between PE_PGRS33 and all the human proteins by using BLAST. Three peptides were commercially synthesized, and their activity was evaluated in vitro by the stimulation of PBMC from household contacts of TB patients. Our in silico results showed five immunogenic T-cell peptides. BLAST analysis showed low homology of PE_PGRS33 with human proteins and AlgPred did not reveal allergenic sites in PE_PGRS33. The three peptides triggered the activation of CD4+ T cells from the households contacts, showed by the production of IFN-γ. We identified three immunogenic peptides of PE_PGRS33 that demonstrated activity in vitro which allows to deepen into the immune response towards mycobacterial antigens, moving forward to the identification of new vaccine candidates.


Assuntos
Antígenos de Bactérias/imunologia , Linfócitos T CD4-Positivos/imunologia , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/imunologia , Humanos , Ativação Linfocitária/imunologia , Peptídeos/imunologia , Vacinas de Subunidades/imunologia
16.
BMC Infect Dis ; 20(1): 469, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32615981

RESUMO

BACKGROUND: Interferon-γ release assays (IGRA) with Resuscitation promoting factor (Rpf) proteins enhanced tuberculosis (TB) screening and diagnosis in adults but have not been evaluated in children. Children often develop paucibacillary TB and their immune response differs from that of adults, which together affect TB disease diagnostics and immunodiagnostics. We assessed the ability of Rpf to identify infection among household TB-exposed children in The Gambia and investigated their ability to discriminate Mycobacterium tuberculosis complex (MTBC) infection from active TB disease in children. METHODS: Detailed clinical investigations were done on 93 household TB-exposed Gambian children and a tuberculin skin test (TST) was administered to asymptomatic children. Venous blood was collected for overnight stimulation with ESAT-6/CFP-10-fusion protein (EC), purified protein derivative and RpfA, B, C, D and E. Interferon gamma (IFN-γ) production was measured by ELISA in supernatants and corrected for the background level. Infection status was defined by IGRA with EC and TB disease by mycobacterial confirmation and/or clinical diagnosis. We compared IFN-γ levels between infected and uninfected children and between infected and TB diseased children using a binomial logistic regression model while correcting for age and sex. A Receiver Operating Characteristics analysis was done to find the best cut-off for IFN-γ level and calculate sensitivity and specificity. RESULTS: Interferon gamma production was significantly higher in infected (IGRA+, n = 45) than in uninfected (IGRA-, n = 20) children after stimulation with RpfA, B, C, and D (P = 0.03; 0.007; 0.03 and 0.003, respectively). Using RpfB and D-specific IFN-γ cut-offs (33.9 pg/mL and 67.0 pg/mL), infection was classified with a sensitivity-specificity combination of 73-92% and 77-72% respectively, which was similar to and better than 65-75% for TST. Moreover, IFN-γ production was higher in infected than in TB diseased children (n = 28, 5 bacteriologically confirmed, 23 clinically diagnosed), following RpfB and D stimulation (P = 0.02 and 0.03, respectively). CONCLUSION: RpfB and RpfD show promising results for childhood MTBC infection screening, and both performed similar to and better than the TST in our study population. Additionally, both antigens appear to discriminate between infection and disease in children and thus warrant further investigation as screening and diagnostic antigens for childhood TB.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Citocinas/imunologia , Testes de Liberação de Interferon-gama/métodos , Tuberculose Latente/diagnóstico , Tuberculose Latente/epidemiologia , Programas de Rastreamento/métodos , Mycobacterium tuberculosis/imunologia , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Características da Família , Feminino , Gâmbia/epidemiologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Tuberculose Latente/microbiologia , Masculino , Sensibilidade e Especificidade , Teste Tuberculínico
17.
BMC Infect Dis ; 20(1): 459, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32611401

RESUMO

BACKGROUND: Extra pulmonary manifestation of tuberculosis (TB) accounts for approximately one-half of TB cases in HIV-infected individuals with pleural TB as the second most common location. Even though mycobacteria are cleared, mycobacterial antigens may persist in infected tissues, causing sustained inflammation and chronicity of the disease. The aim of this study was to explore various mycobacterial antigens in pleural effusions, the impact of HIV infection and CD4+ T-cell depletion on the presence of antigens, and the diagnostic potential of antigens for improved and rapid diagnosis of pleural TB. METHODS: Pleural fluid specimens were collected from patients presenting with clinically suspected pleural TB, and processed routinely for culture, cytology, and adenosine deaminase activity analysis. HIV status and CD4+ T-cell counts were recorded. Pleural fluid mononuclear cells (PFMC) were isolated, and cell smears were stained with acid-fast staining and immunocytochemistry for various mycobacterial antigens. Real-time and nested-PCR were performed. Patients were categorized as pleural TB or non-TB cases using a composite reference standard. Performance of the mycobacterial antigens as diagnostic test was assessed. RESULTS: A total of 41 patients were enrolled, of which 32 were classified as pleural TB and 9 as non-TB. Thirteen patients had culture confirmed pleural TB, 26 (81%) were HIV-TB co-infected, and 64% had < 100 CD4+ T-cells/microL. Both secreted and cell-wall mycobacterial antigens were detected in PFMC. Lipoarabinomannan (LAM) was the most frequently detected antigen. There was no direct correlation between positive culture and antigens. Cases with low CD4+ T-cell counts had higher bacterial and antigen burden. By combining detection of secreted antigen or LAM, the sensitivity and specificity to diagnose pleural TB was 56 and 78%, respectively, as compared to 41 and 100% for culture, 53 and 89% for nested PCR, and 6 and 100% for real-time PCR. CONCLUSION: Mycobacterial antigens were detectable in PFMC from tuberculous pleural effusions, even in cases where viable mycobacteria or bacterial DNA were not always detected. Thus, a combination of secreted antigen and LAM detection by immunocytochemistry may be a complement to acid-fast staining and contribute to rapid and accurate diagnosis of pleural TB.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Linfócitos T CD4-Positivos/imunologia , Coinfecção/diagnóstico , Testes Diagnósticos de Rotina/métodos , Lipopolissacarídeos/genética , Lipopolissacarídeos/imunologia , Mycobacterium tuberculosis/imunologia , Derrame Pleural/microbiologia , Tuberculose Pleural/diagnóstico , Adulto , Idoso , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Contagem de Linfócito CD4 , Coinfecção/microbiologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Derrame Pleural/patologia , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e Especificidade , Adulto Jovem
18.
Ig Sanita Pubbl ; 76(1): 59-66, 2020.
Artigo em Italiano | MEDLINE | ID: mdl-32668448

RESUMO

Tuberculosis (TB) is an infectious and contagious disease caused by Mycobacterium tuberculosis, commonly called Koch's bacillus. TB is spread by air and is present all over the world. Not everyone who become infected develop the disease; the immune system can cope with the infection and the bacterium can remain dormant for years. Despite advances in therapy and prevention, TB remains one of the top 10 causes of death worldwide. Over 9 million new cases and over 1 million deaths occur each year. Since 1921 BCG has been the only authorized vaccine. More than ten experimental vaccines are currently in different stages of development. Depending on the type, they are divided into vaccines consisting of: live attenuated, inactivated mycobacteria and subunits. According to their purpose they can be divided in: vaccines aimed at preventing infection, vaccines aimed at preventing disease, vaccines aimed at preventing recurrence and therapeutic vaccines. Hopefully, these numerous attempts to develop new vaccination approaches will lead to obtain products with greater immunogenicity and efficacy.


Assuntos
Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/prevenção & controle , Humanos , Tuberculose/diagnóstico , Vacinação
19.
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
20.
PLoS Pathog ; 16(7): e1008655, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32673357

RESUMO

Progress in tuberculosis vaccine development is hampered by an incomplete understanding of the immune mechanisms that protect against infection with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. Although the M72/ASOE1 trial yielded encouraging results (54% efficacy in subjects with prior exposure to Mtb), a highly effective vaccine against adult tuberculosis remains elusive. We show that in a mouse model, establishment of a contained and persistent yet non-pathogenic infection with Mtb ("contained Mtb infection", CMTB) rapidly and durably reduces tuberculosis disease burden after re-exposure through aerosol challenge. Protection is associated with elevated activation of alveolar macrophages, the first cells that respond to inhaled Mtb, and accelerated recruitment of Mtb-specific T cells to the lung parenchyma. Systems approaches, as well as ex vivo functional assays and in vivo infection experiments, demonstrate that CMTB reconfigures tissue resident alveolar macrophages via low grade interferon-γ exposure. These studies demonstrate that under certain circumstances, the continuous interaction of the immune system with Mtb is beneficial to the host by maintaining elevated innate immune responses.


Assuntos
Modelos Animais de Doenças , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Tuberculose/virologia , Animais , Macrófagos Alveolares/imunologia , Camundongos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA