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1.
Front Immunol ; 15: 1321657, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38975346

RESUMO

Tuberculosis (TB) remains a significant global health challenge, with approximately 1.5 million deaths per year. The Bacillus Calmette-Guérin (BCG) vaccine against TB is used in infants but shows variable protection. Here, we introduce a novel approach using a double gene knockout mutant (DKO) from wild-type Mycobacterium tuberculosis (Mtb) targeting fbpA and sapM genes. DKO exhibited enhanced anti-TB gene expression in mouse antigen-presenting cells, activating autophagy and inflammasomes. This heightened immune response improved ex vivo antigen presentation to T cells. Subcutaneous vaccination with DKO led to increased protection against TB in wild-type C57Bl/6 mice, surpassing the protection observed in caspase 1/11-deficient C57Bl/6 mice and highlighting the critical role of inflammasomes in TB protection. The DKO vaccine also generated stronger and longer-lasting protection than the BCG vaccine in C57Bl/6 mice, expanding both CD62L-CCR7-CD44+/-CD127+ effector T cells and CD62L+CCR7+/-CD44+CD127+ central memory T cells. These immune responses correlated with a substantial ≥ 1.7-log10 reduction in Mtb lung burden. The DKO vaccine represents a promising new approach for TB immunization that mediates protection through autophagy and inflammasome pathways.


Assuntos
Macrófagos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis , Vacinas contra a Tuberculose , Tuberculose , Animais , Mycobacterium tuberculosis/imunologia , Camundongos , Macrófagos/imunologia , Tuberculose/imunologia , Tuberculose/prevenção & controle , Vacinas contra a Tuberculose/imunologia , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/genética , Inflamassomos/imunologia , Feminino , Vacina BCG/imunologia , Autofagia/imunologia , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/genética , Modelos Animais de Doenças
2.
Front Immunol ; 15: 1423435, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38994354

RESUMO

Introduction: Latent tuberculosis infection (LTBI) is a common coinfection in people living with HIV (PWH). How LTBI and HIV exposure in utero influence the development of infant humoral immunity is not well characterized. To address this question, we assessed the relationship between maternal humoral responses in pregnant women with HIV or with HIV/LTBI on humoral responses in infants to BCG vaccination and TB acquisition. Methods: Plasma samples were obtained from mother infant pairs during pregnancy (14-34 wks gestation) and in infants at 12 and 44 wks of age from the IMPAACT P1078 clinical trial. LTBI was established by Interferon gamma release assay (IGRA). Progression to active TB (ATB) disease was observed in 5 women at various times after giving birth. All infants were BCG vaccinated at birth and tested for IGRA at 44 weeks. Mtb (PPD, ESAT6/CFP10, Ag85A, LAM), HIV (GP120), and Influenza (HA) specific IgG, IgM, and IgA were measured in plasma samples using a bead based Luminex assay with Flexmap 3D. Results: In maternal plasma there were no differences in Mtb-specific antibodies or viral antibodies in relation to maternal IGRA status. ATB progressors showed increases in Mtb-specific antibodies at diagnosis compared to study entry. However, when compared to the non-progressors at entry, progressors had higher levels of Ag85A IgG and reduced ESAT6/CFP10 IgG and LAM IgG, IgM, and IgA1. All infants showed a decrease in IgG to viral antigens (HIV GP120 and HA) from 12 to 44 weeks attributed to waning of maternally transferred antibody titers. However, Mtb-specific (PPD, ESAT6/CFP10, Ag85A, and LAM) IgG and IgM increased from 12 to 44 weeks. HIV and HA IgG levels in maternal and 12-week infant plasma were highly correlated, and ESAT6/CFP10 IgG and LAM IgG showed a relationship between maternal and infant Abs. Finally, in the subset of infants that tested IGRA positive at 44 weeks, we observed a trend for lower LAM IgM compared to IGRA- infants at 44 weeks. Discussion: The results from our study raise the possibility that antibodies to LAM are associated with protection from progression to ATB and support further research into the development of humoral immunity against TB through infection or vaccination.


Assuntos
Anticorpos Antibacterianos , Infecções por HIV , Imunidade Humoral , Tuberculose Latente , Humanos , Feminino , Tuberculose Latente/imunologia , Infecções por HIV/imunologia , Gravidez , Lactente , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Adulto , Mycobacterium tuberculosis/imunologia , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/sangue , Vacina BCG/imunologia , Recém-Nascido , Coinfecção/imunologia , Masculino , Efeitos Tardios da Exposição Pré-Natal/imunologia
3.
Front Cell Infect Microbiol ; 14: 1410015, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38957797

RESUMO

Background: Tuberculosis (TB) persists as a global health challenge, with its treatment hampered by the side effects of long-term combination drug therapies and the growing issue of drug resistance. Therefore, the development of novel therapeutic strategies is critical. This study focuses on the role of immune checkpoint molecules (ICs) and functions of CD8+ T cells in the search for new potential targets against TB. Methods: We conducted differential expression genes analysis and CD8+ T cell functional gene analysis on 92 TB samples and 61 healthy individual (HI) samples from TB database GSE83456, which contains data on 34,603 genes. The GSE54992 dataset was used to validated the findings. Additionally, a cluster analysis on single-cell data from primates infected with mycobacterium tuberculosis and those vaccinated with BCG was performed. Results: The overexpression of LAG-3 gene was found as a potentially important characteristic of both pulmonary TB (PTB) and extrapulmonary TB (EPTB). Further correlation analysis showed that LAG-3 gene was correlated with GZMB, perforin, IL-2 and IL-12. A significant temporal and spatial variation in LAG-3 expression was observed in T cells and macrophages during TB infection and after BCG vaccination. Conclusion: LAG-3 was overexpressed in TB samples. Targeting LAG-3 may represent a potential therapeutic target for tuberculosis.


Assuntos
Antígenos CD , Linfócitos T CD8-Positivos , Proteína do Gene 3 de Ativação de Linfócitos , Mycobacterium tuberculosis , Tuberculose , Humanos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/genética , Linfócitos T CD8-Positivos/imunologia , Tuberculose/imunologia , Tuberculose/microbiologia , Animais , Antígenos CD/genética , Vacina BCG/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Interleucina-2/metabolismo , Interleucina-2/genética , Perfilação da Expressão Gênica , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Interleucina-12/genética , Interleucina-12/metabolismo , Perforina/genética , Perforina/metabolismo , Masculino
4.
BMC Public Health ; 24(1): 1795, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38970039

RESUMO

BACKGROUND: The COVID-19 pandemic had a profound impact on healthcare systems and services, including routine immunization (RI). To date, there is limited information on the effects of the COVID-19 pandemic on RI in West African countries such as Sierra Leone, which had already experienced public health emergencies that disrupted its healthcare system. Here, we describe the impact of the COVID-19 pandemic on the RI of key antigens in Sierra Leone. METHODS: We used vaccination data from the District Health Information System for BCG, measles-rubella 1 and 2, and pentavalent 1 and 3 antigens. We compared 2019, 2020, 2021, and 2022 annual coverage rates for the selected antigens at the national and district levels. We used the Pearson chi-square test to assess the difference between annual coverage rates between 2019 and 2020, 2020-2021, and 2021-2022. RESULTS: National coverage rates for all antigens declined in 2019-2020, notably measles-rubella 1 and pentavalent 3 (-5.4% and - 4.9%). Between 2020 and 2021, there was an overall increase in coverage (+ 0.2% to + 2.5%), except for measles-rubella 2 (-1.8%). Measles-rubella antigens rebounded in 2021-2022, while others decreased between - 0.5 and - 1.9% in coverage. Overall, all district-level coverage rates in 2022 were lower than those in 2019. Most districts decreased between 2019 and 2022, though a few had a continuous increase; some had an increase/recovery between 2020 and 2021; some districts had recovered 2019 levels by 2022. CONCLUSION: The COVID-19 pandemic impacted Sierra Leone's national BCG, measles-rubella, and pentavalent antigen immunization, which were not fully restored in 2022. Most districts experienced notable coverage declines during the pandemic, though a few reached or surpassed 2019 rates in 2022. Examining pandemic impact can benefit from a focus beyond the national level to identify vulnerable regions. Sierra Leone's post-pandemic RI reestablishment needs targeted strategies and continual investments for equitable access and coverage, as well as to prevent vaccine-preventable diseases.


Assuntos
COVID-19 , Cobertura Vacinal , Serra Leoa/epidemiologia , Humanos , COVID-19/prevenção & controle , COVID-19/epidemiologia , Cobertura Vacinal/estatística & dados numéricos , Programas de Imunização/estatística & dados numéricos , Vacina BCG/administração & dosagem , Vacina BCG/uso terapêutico
5.
Nat Commun ; 15(1): 5191, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890283

RESUMO

A recent clinical trial demonstrated that Bacille Calmette-Guérin (BCG) revaccination of adolescents reduced the risk of sustained infection with Mycobacterium tuberculosis (M.tb). In a companion phase 1b trial, HVTN 602/Aeras A-042, we characterize in-depth the cellular responses to BCG revaccination or to a H4:IC31 vaccine boost to identify T cell subsets that could be responsible for the protection observed. High-dimensional clustering analysis of cells profiled using a 26-color flow cytometric panel show marked increases in five effector memory CD4+ T cell subpopulations (TEM) after BCG revaccination, two of which are highly polyfunctional. CITE-Seq single-cell analysis shows that the activated subsets include an abundant cluster of Th1 cells with migratory potential. Additionally, a small cluster of Th17 TEM cells induced by BCG revaccination expresses high levels of CD103; these may represent recirculating tissue-resident memory cells that could provide pulmonary immune protection. Together, these results identify unique populations of CD4+ T cells with potential to be immune correlates of protection conferred by BCG revaccination.


Assuntos
Vacina BCG , Linfócitos T CD4-Positivos , Mycobacterium tuberculosis , Mycobacterium tuberculosis/imunologia , Humanos , Adolescente , Linfócitos T CD4-Positivos/imunologia , Vacina BCG/imunologia , Imunização Secundária , Tuberculose/imunologia , Tuberculose/prevenção & controle , Tuberculose/microbiologia , Feminino , Masculino , Fenótipo , Análise de Célula Única , Células Th1/imunologia , Memória Imunológica/imunologia
7.
Sci Rep ; 14(1): 13133, 2024 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849432

RESUMO

The short-lived nature and heterogeneity of Natural Killer (NK) cells limit the development of NK cell-based therapies, despite their proven safety and efficacy against cancer. Here, we describe the biological basis, detailed phenotype and function of long-lived anti-tumour human NK cells (CD56highCD16+), obtained without cell sorting or feeder cells, after priming of peripheral blood cells with Bacillus Calmette-Guérin (BCG). Further, we demonstrate that survival doses of a cytokine combination, excluding IL18, administered just weekly to BCG-primed NK cells avoids innate lymphocyte exhaustion and leads to specific long-term proliferation of innate cells that exert potent cytotoxic function against a broad range of solid tumours, mainly through NKG2D. Strikingly, a NKG2C+CD57-FcεRIγ+ NK cell population expands after BCG and cytokine stimulation, independently of HCMV serology. This strategy was exploited to rescue anti-tumour NK cells even from the suppressor environment of cancer patients' bone marrow, demonstrating that BCG confers durable anti-tumour features to NK cells.


Assuntos
Proliferação de Células , Células Matadoras Naturais , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Humanos , Proliferação de Células/efeitos dos fármacos , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Vacina BCG/imunologia , Vacina BCG/administração & dosagem , Mycobacterium bovis/imunologia , Ativação Linfocitária/efeitos dos fármacos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Interleucinas/metabolismo , Antígeno CD56/metabolismo , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo
8.
Int J Mycobacteriol ; 13(2): 213-217, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38916394

RESUMO

Bacille Calmette-Guérin (BCG) is a live-attenuated vaccine routinely administered to newborns to prevent severe forms of tuberculosis (TB) in TB-endemic countries. Disseminated BCG vaccine disease is a classic feature of children with human immunodeficiency virus (HIV) or primary immunodeficiency disorders (PIDs) and is associated with high mortality. We report a case of a 6-month-old infant with disseminated BCG disease and hemophagocytic lymphohistiocytosis mimicking juvenile myelomonocytic leukemia with no demonstrable features of HIV or PID even after extensive laboratory work-up and succumbed to progressive disease. Disseminated BCG disease is a rare and potentially fatal complication of BCG vaccine, and prompt immunological evaluation complemented by initiation of 4-drug antitubercular therapy and definitive treatment with antiretroviral therapy or hematopoietic stem cell transplant is warranted.


Assuntos
Vacina BCG , Leucemia Mielomonocítica Juvenil , Linfo-Histiocitose Hemofagocítica , Tuberculose , Humanos , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/complicações , Lactente , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Vacina BCG/efeitos adversos , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Tuberculose/complicações , Diagnóstico Diferencial , Evolução Fatal , Masculino , Mycobacterium bovis , Antituberculosos/uso terapêutico
10.
Eur J Pharmacol ; 977: 176707, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38830456

RESUMO

The 5-HT3 receptor and indoleamine 2,3-dioxygenase 1 (IDO1) enzyme play a crucial role in the pathogenesis of depression as their activation reduces serotonin contents in the brain. Since molecular docking analysis revealed lycopene as a potent 5-HT3 receptor antagonist and IDO1 inhibitor, we hypothesized that lycopene might disrupt the interplay between the 5-HT3 receptor and IDO1 to mitigate depression. In mice, the depression-like phenotypes were induced by inoculating Bacillus Calmette-Guerin (BCG). Lycopene (intraperitoneal; i.p.) was administered alone or in combination with 5-HT3 receptor antagonist ondansetron (i.p.) or IDO1 inhibitor minocycline (i.p.), and the behavioral screening was performed by the sucrose preference test, open field test, tail suspension test, and splash test which are based on the different principles. Further, the brains were subjected to the biochemical analysis of serotonin and its precursor tryptophan by the HPLC. The results showed depression-like behavior in BCG-inoculated mice, which was reversed by lycopene administration. Moreover, prior treatment with ondansetron or minocycline potentiated the antidepressant action of lycopene. Minocycline pretreatment also enhanced the antidepressant effect of ondansetron indicating the regulation of IDO1 activity by 5-HT3 receptor-triggered signaling. Biochemical analysis of brain samples revealed a drastic reduction in the levels of tryptophan and serotonin in depressed animals, which were restored following treatment with lycopene and its combination with ondansetron or minocycline. Taken together, the data from molecular docking, behavioral experiments, and biochemical estimation suggest that lycopene might block the 5-HT3 receptor and consequently inhibit the activity of IDO1 to ameliorate BCG-induced depression in mice.


Assuntos
Encéfalo , Depressão , Indolamina-Pirrol 2,3,-Dioxigenase , Licopeno , Receptores 5-HT3 de Serotonina , Animais , Licopeno/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Camundongos , Depressão/tratamento farmacológico , Depressão/metabolismo , Masculino , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Fenótipo , Simulação de Acoplamento Molecular , Serotonina/metabolismo , Vacina BCG/farmacologia , Ondansetron/farmacologia , Comportamento Animal/efeitos dos fármacos , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Antidepressivos/farmacologia , Minociclina/farmacologia
11.
Front Immunol ; 15: 1380069, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38835781

RESUMO

Bacillus Calmette-Guérin (BCG) is the first line treatment for bladder cancer and it is also proposed for melanoma immunotherapy. BCG modulates the tumor microenvironment (TME) inducing an antitumor effective response, but the immune mechanisms involved still poorly understood. The immune profile of B16-F10 murine melanoma cells was assessed by infecting these cells with BCG or stimulating them with agonists for different innate immune pathways such as TLRs, inflammasome, cGAS-STING and type I IFN. B16-F10 did not respond to any of those stimuli, except for type I IFN agonists, contrasting with bone marrow-derived macrophages (BMDMs) that showed high production of proinflammatory cytokines. Additionally, we confirmed that BCG is able to infect B16-F10, which in turn can activate macrophages and spleen cells from mice in co-culture experiments. Furthermore, we established a subcutaneous B16-F10 melanoma model for intratumoral BCG treatment and compared wild type mice to TLR2-/-, TLR3-/-, TLR4-/-, TLR7-/-, TLR3/7/9-/-, caspase 1-/-, caspase 11-/-, IL-1R-/-, cGAS-/-, STING-/-, IFNAR-/-, MyD88-/-deficient animals. These results in vivo demonstrate that MyD88 signaling is important for BCG immunotherapy to control melanoma in mice. Also, BCG fails to induce cytokine production in the co-culture experiments using B16-F10 and BMDMs or spleen cells derived from MyD88-/- compared to wild-type (WT) animals. Immunotherapy with BCG was not able to induce the recruitment of inflammatory cells in the TME from MyD88-/- mice, impairing tumor control and IFN-γ production by T cells. In conclusion, MyD88 impacts on both innate and adaptive responses to BCG leading to an efficient antitumor response against melanoma.


Assuntos
Vacina BCG , Imunoterapia , Melanoma Experimental , Fator 88 de Diferenciação Mieloide , Transdução de Sinais , Animais , Camundongos , Vacina BCG/imunologia , Vacina BCG/uso terapêutico , Linhagem Celular Tumoral , Citocinas/metabolismo , Imunoterapia/métodos , Macrófagos/imunologia , Macrófagos/metabolismo , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium bovis/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Microambiente Tumoral/imunologia
12.
Medicina (Kaunas) ; 60(6)2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38929483

RESUMO

Background and Objectives: Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccine administration has been suggested to prevent glucose metabolism abnormalities and fatty liver in genetically obese ob/ob mice; however, it is not clear whether the beneficial effects of BCG are also observed in the progression of glucose intolerance induced by a high-fat diet (HFD). Therefore, the effects of BCG vaccination on changes in glucose tolerance and insulin response were investigated in HFD-fed C57BL/6 mice. Materials and Methods: We used the BCG Tokyo 172 strain to determine effects on abnormalities in glucose metabolism. For vaccination, five-week-old male mice were injected intraperitoneally with BCG and maintained on a HFD for three weeks. The mice were regularly subjected to intraperitoneal glucose tolerance and insulin tolerance tests (IGTTs and ITTs). These tests were also performed in mice transplanted with bone marrow cells from BCG-vaccinated donor mice. Results: Significant effects of BCG vaccination on blood glucose levels in the IGTTs and ITTs were observed from week 12 of the experiment. BCG vaccination significantly improved changes in fasting glucose and insulin levels, insulin resistance indexes, and glucagon-to-insulin ratios in conjunction with the HFD at the end of the experiment. Significant inhibitory effects in the IGTTs and ITTs on glucose intolerance were also observed with transplantation with bone marrow cells derived from BCG-vaccinated donor mice. Conclusions: BCG vaccination significantly delayed glucose intolerance progression, suggesting a beneficial effect of BCG on the pathogenesis of type 2 diabetes. It has also been suggested that the effects of BCG vaccination may be at least partially due to an immune memory (trained immunity) for hematopoietic stem and progenitor cells of the bone marrow.


Assuntos
Vacina BCG , Dieta Hiperlipídica , Intolerância à Glucose , Camundongos Endogâmicos C57BL , Animais , Dieta Hiperlipídica/efeitos adversos , Vacina BCG/administração & dosagem , Camundongos , Masculino , Glicemia/análise , Resistência à Insulina , Progressão da Doença , Teste de Tolerância a Glucose , Insulina/sangue , Modelos Animais de Doenças , Vacinação/métodos
13.
Expert Opin Biol Ther ; 24(6): 415-423, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38861054

RESUMO

INTRODUCTION: BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) represent a significant therapeutic challenge in the treatment of bladder cancer. Nadofaragene firadenovec, represents a breakthrough in this area, offering a novel approach for the treatment of BCG-unresponsive NMIBC. AREAS COVERED: This overview explores the historical development of nadofaragene firadenovec, assessing its efficacy and safety, and discusses future NMIBC therapy directions. EXPERT OPINION: Patients with high grade NMIBC who are BCG unresponsive will have a growing number of treatment alternatives to bladder removal. Nadofaragene firadenovec offers good short-term efficacy but lacks significant durability for most patients. Its strengths include ease of administration and low risk of adverse events. This will need to balance with risk of progression and cost. Furthermore, the likely approval of other agents will require consideration of which therapy to use and for which patient. The need for biomarkers to tailor treatment choices to individual patient needs is becoming more critical. The treatment field is rapidly advancing, with several Phase 3 single-arm trials underway, indicating a potential broader range of treatment options for NMIBC. Further research will be necessary to determine the optimal choice for patients.


Assuntos
Vacina BCG , Neoplasias da Bexiga Urinária , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Humanos , Vacina BCG/uso terapêutico , Invasividade Neoplásica , Vacinas Anticâncer/uso terapêutico , Neoplasias não Músculo Invasivas da Bexiga
14.
Vet Res ; 55(1): 71, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38822398

RESUMO

In the wake of the COVID-19 pandemic caused by SARS-CoV-2, questions emerged about the potential effects of Bacillus Calmette-Guérin (BCG) vaccine on the immune response to SARS-CoV-2 infection, including the neurodegenerative diseases it may contribute to. To explore this, an experimental study was carried out in BCG-stimulated and non-stimulated k18-hACE2 mice challenged with SARS-CoV-2. Viral loads in tissues determined by RT-qPCR, histopathology in brain and lungs, immunohistochemical study in brain (IHC) as well as mortality rates, clinical signs and plasma inflammatory and coagulation biomarkers were assessed. Our results showed BCG-SARS-CoV-2 challenged mice presented higher viral loads in the brain and an increased frequency of neuroinvasion, with the greatest differences observed between groups at 3-4 days post-infection (dpi). Histopathological examination showed a higher severity of brain lesions in BCG-SARS-CoV-2 challenged mice, mainly consisting of neuroinflammation, increased glial cell population and neuronal degeneration, from 5 dpi onwards. This group also presented higher interstitial pneumonia and vascular thrombosis in lungs (3-4 dpi), BCG-SARS-CoV-2 mice showed higher values for TNF-α and D-dimer values, while iNOS values were higher in SARS-CoV-2 mice at 3-4 dpi. Results presented in this study indicate that BCG stimulation could have intensified the inflammatory and neurodegenerative lesions promoting virus neuroinvasion and dissemination in this experimental model. Although k18-hACE2 mice show higher hACE2 expression and neurodissemination, this study suggests that, although the benefits of BCG on enhancing heterologous protection against pathogens and tumour cells have been broadly demonstrated, potential adverse outcomes due to the non-specific effects of BCG should be considered.


Assuntos
Vacina BCG , Encéfalo , COVID-19 , SARS-CoV-2 , Animais , Camundongos , Vacina BCG/administração & dosagem , COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2/fisiologia , Encéfalo/patologia , Encéfalo/virologia , Carga Viral , Pulmão/patologia , Pulmão/virologia , Pulmão/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Camundongos Transgênicos , Feminino
15.
Int J Tuberc Lung Dis ; 28(6): 273-277, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38822485

RESUMO

BACKGROUNDTB remains an important cause of childhood morbidity and mortality. Underdiagnosis, underreporting and limited data on the outcomes of childhood TB have led to an underestimation of its impact.METHODSThis was a systematic review to characterise childhood TB outcomes. Studies reporting relevant epidemiological data on children between 0 and 14 years of age, with a particular focus on treatment outcomes, from countries with universal bacilli Calmette-Guérin (BCG) vaccination and conducted between 2000 and 2020 were selected. Random effects meta-analysis was performed in R software.RESULTSWe identified 1,806 references and included 35 articles. Among children with TB, the overall proportion of unfavourable outcomes was 19.5% (95% CI 14.4-25.8) and pooled case-fatality ratio was 6.1% (95% CI 4.3-8.4). The proportion of deaths observed among children between 0 and 4 years old was 6.6% (95% CI 4.9-8.7) and 4.6% (95% CI 3.1-6.9) in older children. TB and HIV co-infected children presented a case-fatality ratio of 15.1% (95% CI 7.9-27.0).CONCLUSIONSDespite the efforts made in the last decades, treatment outcomes in childhood TB are still worrisome. Efforts to fill existing gaps and design health policies targeting vulnerable populations, such as children, should be intensified to tackle the global TB burden..


Assuntos
Vacina BCG , Tuberculose , Humanos , Vacina BCG/administração & dosagem , Lactente , Criança , Pré-Escolar , Tuberculose/epidemiologia , Tuberculose/prevenção & controle , Adolescente , Recém-Nascido , Vacinação/estatística & dados numéricos , Política de Saúde
16.
Euro Surveill ; 29(24)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38873798

RESUMO

BackgroundDenmark possesses an exceptional historical data collection on tuberculosis (TB) from 1876 to the present, providing a unique opportunity to assess TB epidemiology over 147 years in Denmark.AimOur aim was to describe the TB disease burden in Denmark in relation to historical events, living conditions and health interventions during the past 147 years.MethodsWe performed a nationwide register-based ecological study including all persons with TB in Denmark from 1876 through 2022, correlating the TB incidence to social, economic and health indicators.ResultsIn Denmark, the overall TB incidence and mortality declined markedly over the past 147 years, only marginally influenced by specific TB interventions such as sanatoria, Bacillus Calmette-Guèrin (BCG) vaccination, mass screenings and antibiotics. Parallel to this decline, the country experienced improved living conditions, as illustrated by decreased infant mortality and increased life expectancy and wealth. In 1978, Denmark became a low-incidence country for TB with risk groups predominantly affected, and with a continuous change in demographics towards fewer Danish-born cases and relatively more migrant cases.ConclusionsThe decline over time in TB incidence and mortality in Denmark preceded specific TB interventions and can, first of all, be attributed to improved living conditions. TB has now become a rare disease in Denmark, predominantly occurring in particular risk groups. Future elimination of TB will require a combination of specific health interventions in these risk groups combined with a continued focus on improving socioeconomic status and living conditions.


Assuntos
Sistema de Registros , Tuberculose , Humanos , Dinamarca/epidemiologia , Incidência , Tuberculose/epidemiologia , Tuberculose/prevenção & controle , Feminino , Masculino , História do Século XX , História do Século XIX , História do Século XXI , Adulto , Pessoa de Meia-Idade , Lactente , Fatores Socioeconômicos , Programas de Rastreamento , Idoso , Expectativa de Vida , Adolescente , Vacina BCG/administração & dosagem , Fatores de Risco , Pré-Escolar , Adulto Jovem , Criança , Vigilância da População
17.
PLoS One ; 19(5): e0302722, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38722827

RESUMO

BACKGROUND: Pakistan is endemic to a diverse set of parasitic, mycobacterial and viral diseases. The recognition of BCG Trained Immunity (TI) led us to postulate that the continued presence of BCG-TI may play a protective role, previously reported for both infectious and noninfectious conditions. Most of the previous studies have addressed the issue of BCG-TI in the paediatric populations. This study addressed the key issue of maintenance of BCG-TI in a wider age range (adolescent and adults) to identify the strength and quality of the immune responses. OBJECTIVE: To assess the BCG-induced recall responses in healthy individuals by cytokines secreted from the TI network and its potential role in providing cross-protection against COVID-19 and other viral infections. STUDY DESIGN: In this cross-sectional study, healthy young adults and adolescents (n = 20) were recruited from 16-40 years of age, with no prior history of TB treatment, autoimmune, or chronic inflammatory condition. METHODS: BCG-induced cytokine responses were assessed using prototypic markers for cells of the TI network [macrophages [M1 (TNFα, IFNγ), M2 (IL10)], NK (IL2), Gamma delta (γδ) T (IL17, IL4)] and SARS CoV2 IgG antibodies against RBD using short-term (12 hrs.) cultures assay. RESULTS: Significant differences were observed in the magnitude of recall responses to BCG with macrophage cytokines showing the highest mean levels of TNFα (9148 pg/ml) followed by IL10 (488 pg/ml) and IFNγ (355 pg/ml). The ratio of unstimulated vs.BCG-stimulated cytokines was 132 fold higher for TNFα, 40 fold fo r IL10, and 27 fold for IFNγ. Furthermore, SARS-CoV-2 antibodies were also detected in unstimulated plasma which showed cross reactivity with BCG. CONCLUSION: The presence of cross reactive antibodies to SARS-CoV-2 and the relative ratio of pro- and anti-inflammatory cytokines secreted by activated TI cellular network may play a pivotal role in protection in the early stages of infection as observed during the COVID-19 pandemic in the younger age groups resulting in lower morbidity and mortality.


Assuntos
Anticorpos Antivirais , Vacina BCG , COVID-19 , Citocinas , SARS-CoV-2 , Humanos , Vacina BCG/imunologia , Adulto , COVID-19/imunologia , COVID-19/prevenção & controle , Adolescente , Estudos Transversais , Masculino , Feminino , SARS-CoV-2/imunologia , Citocinas/imunologia , Adulto Jovem , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Reações Cruzadas/imunologia , Vacinação , Paquistão/epidemiologia , Imunidade Treinada
18.
PLoS One ; 19(5): e0300731, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38722971

RESUMO

BACKGROUND: The risk factors for tuberculosis (TB) disease development in children remained understudied, particularly in low-income countries like Ethiopia. The objective of this study was to identify determinants of TB disease development in general and in relation to BCG vaccination in children in central Ethiopia. METHODS: We employed a 1:1 age-matched case-control design to compare the characteristics of children who developed TB (cases) with those who did not (controls). Data were collected in healthcare facilities in Addis Ababa city, Adama, and Bishoftu towns between September 25, 2021, and June 24, 2022. Two hundred and fifty-six cases were drawn at random from a list of childhood TB patients entered into SPSS software, and 256 controls were selected sequentially at triage from the same healthcare facilities where the cases were treated. A bivariate conditional logistic regression analysis was performed first to select candidate variables with p-values less than or equal to 0.20 for the multivariable model. Finally, variables with a p-value less than 0.05 for a matched adjusted odds ratio (mORadj) were reported as independent determinants of TB disease development. RESULTS: The mean age of the cases was nine years, while that of the controls was 10 years. Males comprised 126 cases (49.2%) and 119 controls (46.5%), with the remainder being females. Ninety-nine (38.7%) of the cases were not BCG-vaccinated, compared to 58 (22.7%) of the controls. Household TB contact was experienced by 43 (16.8%) of the cases and 10 (3.9%) of the controls. Twenty-two (8.6%) of the cases and six (2.3%) of the controls were exposed to a cigarette smoker in their household. Twenty-two (8.6%) of the cases and three (1.2%) of the controls were positive for HIV. Children who were not vaccinated with BCG at birth or within two weeks of birth had more than twice the odds (mORadj = 2.11, 95% CI = 1.28-3.48) of developing TB compared to those who were. Children who ever lived with a TB-sick family member (mORadj = 4.28, 95% CI = 1.95-9.39), smoking family members (mORadj = 3.15, 95% CI = 1.07-9.27), and HIV-infected children (mORadj = 8.71, 95% CI = 1.96-38.66) also had higher odds of developing TB disease than their counterparts. CONCLUSIONS: Being BCG-unvaccinated, having household TB contact, having a smoker in the household, and being HIV-infected were found to be independent determinants of TB disease development among children.


Assuntos
Vacina BCG , Tuberculose , Humanos , Etiópia/epidemiologia , Masculino , Feminino , Estudos de Casos e Controles , Criança , Fatores de Risco , Tuberculose/epidemiologia , Pré-Escolar , Lactente , Adolescente , Vacinação
19.
Urol Oncol ; 42(9): 289.e7-289.e12, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38802293

RESUMO

PURPOSE: To evaluate the efficacy of intravesical (IVe) Bacillus Calmette-Guerin (BCG) to treat non-muscle invasive bladder cancer (NMIBC) recurrences in patients who have previously undergone nephroureterectomy for upper tract urothelial carcinoma (UTUC). METHODS: We performed a single institution retrospective review of patients who underwent nephroureterectomy for UTUC from 2009 to 2021. Patients who subsequently developed NMIBC treated with transurethral resection followed by IVe BCG were included in the study group. A control cohort was formed by retrospective review of patents with primary NMIBC treated with BCG during the same period. Patients in the control cohort were matched by stage of bladder cancer at a 2:1 ratio of control to study subjects. Demographic data, pathology of bladder tumors prior to and following BCG, use of maintenance BCG (mBCG), time to recurrence, time to progression, progression to cystectomy, and progression to metastatic disease were collected on all patients. Descriptive statistics were utilized to compare the 2 groups. The primary outcome was progression to muscle invasive disease. Secondary outcomes included intravesical recurrence free survival, disease free survival, and progression to metastatic disease. Univariable and multivariable logistic regression analysis was performed to elucidate independent variables associated with bladder tumor recurrence. Multivariable Cox regression analysis was used to assess the impact of prior UTUC on time to bladder tumor recurrence. RESULTS: One-hundred and ninety-one patients underwent nephroureterectomy at our institution from 2009 to 2021 for UTUC. Twenty-five patients were identified to have subsequently developed NMIBC recurrences treated with inductions BCG. The control group was comprised of 50 patients with primary NMIBC matched by stage of bladder cancer for which BCG was indicated in the study group. Median (interquartile range [IQR]) follow-up was significantly longer in the control group relative to the study group (64.8 [50.1-85.6] vs 25 months [17-35]; P = 0.001). There were no significant differences in demographics between the study and control groups. The rate of progression to muscle invasive disease was 17% vs 0% in the study group and control group respectively (P = 0.0521). History of UTUC was associated with increased risk of intravesical bladder tumor recurrence post BCG on multivariable analysis (HR 2.5; P = 0.017) and Kaplan Meier survival analysis (P = 0.039). The mean time to bladder tumor recurrence after treatment with BCG was significantly worse in the study group at (7.9 vs. 23.9 months; P = 0.0322). Similarly, the rate of progression to metastatic disease was worse in the study group (24% vs 2%; P = 0.0047). Overall disease-free survival was also noted to be significantly worse on Kaplan Meier survival analysis in the study group (P = 0.0074). No statistically significant differences in the stage grade of bladder tumor recurrence, grade of bladder tumor recurrence, or rate of progression to cystectomy were identified. CONCLUSIONS: Our study suggests reduced efficacy of BCG for NMIBC in patients with a history of UTUC. Patients in this population should be counseled accordingly. Research into alternative treatments for bladder tumor recurrence and more aggressive prophylactic regimens after nephroureterectomy for prevention of bladder tumor recurrence in this population is encouraged.


Assuntos
Vacina BCG , Carcinoma de Células de Transição , Invasividade Neoplásica , Nefroureterectomia , Neoplasias Ureterais , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Vacina BCG/uso terapêutico , Masculino , Feminino , Estudos Retrospectivos , Idoso , Nefroureterectomia/métodos , Carcinoma de Células de Transição/cirurgia , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Ureterais/cirurgia , Neoplasias Ureterais/patologia , Neoplasias Ureterais/tratamento farmacológico , Adjuvantes Imunológicos/uso terapêutico , Pessoa de Meia-Idade , Resultado do Tratamento , Administração Intravesical , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Neoplasias Renais/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias não Músculo Invasivas da Bexiga
20.
PLoS One ; 19(5): e0303050, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38722990

RESUMO

BACKGROUND: Neonates are at risk of nosocomial tuberculosis (TB) infection from health care workers (HCWs) in neonatal care facilities, which can progress to severe TB diseases. Tuberculin skin test (TST) is commonly used for TB diagnosis, but its accuracy in neonates is influenced by various factors, including bacilli Calmette-Guérin (BCG) vaccination. This study aimed to identify predictors of positive TSTs in neonates exposed to HCWs with pulmonary TB. METHODS: A retrospective observational study was conducted to compare the frequency of predictors between TST-positive and TST-negative neonates. Demographic, epidemiological, and clinical data of neonates exposed to TB, along with that of HCW and household contacts, were collected retrospectively through contact investigations with the Korean National TB Surveillance System (KNTSS) database. TSTs using 2 tuberculin units of purified protein derivative RT23 were performed on exposed neonates at the end of preventive TB treatment. Firth logistic regression was performed to identify predictors of TST positivity. RESULTS: Contact investigations revealed that 152 neonates and 54 HCWs were exposed to infectious TB index cases in 3 neonatal care facilities. Of 152 exposed neonates, 8 (5.3%) had positive TST results. Age of 6 days or more at the initial exposure is a statistically significant predictor of positive TST (Firth coefficient 2.1, 95% confidence interval 0.3-3.9, P = 0.024); BCG vaccination showed no statistical significance in both univariable and multivariable analysis. Sex, prematurity, exposure duration, duration from initial exposure to contact investigation, and isoniazid preventive treatment duration were not significant predictors. CONCLUSION: Age at the initial exposure is a significant predictor of positive TST in neonates exposed to active pulmonary TB. Given the complexities of TST interpretation, including false positives due to BCG vaccination, careful risk assessment is necessary for appropriate decision-making and resource allocation in the management of neonatal TB exposure.


Assuntos
Teste Tuberculínico , Tuberculose Pulmonar , Humanos , Recém-Nascido , Feminino , Masculino , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/imunologia , Estudos Retrospectivos , Vacina BCG/imunologia , Infecção Hospitalar/diagnóstico , Pessoal de Saúde
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