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1.
Immunology ; 159(1): 121-129, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31606895

RESUMO

The transcription factor hypoxia-inducible factor-1 alpha (HIF-1α) is a key regulator of the response and function of myeloid cells in hypoxic and inflammatory microenvironments. To define the role of HIF-1α in tuberculosis, the progression of aerosol Mycobacterium tuberculosis infection was analysed in mice deficient in HIF-1α in the myeloid lineage (mHIF-1α-/- ). We show that myeloid HIF-1α is not required for the containment of the infection, as both wild-type (WT) and mHIF-1α-/- mice mounted normal Th1 responses and maintained control of bacterial growth throughout infection. However, during chronic infection mHIF-1α-/- mice developed extensive lymphocytic inflammatory involvement of the interstitial lung tissue and died earlier than WT mice. These data support the hypothesis that HIF-1α activity coordinates the response of myeloid cells during M. tuberculosis infection to prevent excessive leucocyte recruitment and immunopathological consequences to the host.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pulmão/metabolismo , Mycobacterium tuberculosis/crescimento & desenvolvimento , Células Mieloides/metabolismo , Pneumonia/metabolismo , Tuberculose Pulmonar/metabolismo , Animais , Carga Bacteriana , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Interações Hospedeiro-Patógeno , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Pulmão/imunologia , Pulmão/microbiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/imunologia , Células Mieloides/imunologia , Células Mieloides/microbiologia , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/microbiologia , Transdução de Sinais , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia
2.
Rev Soc Bras Med Trop ; 52: e20190315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800922

RESUMO

INTRODUCTION: Immunological control of Mycobacterium tuberculosis infection is dependent on the cellular immune response, mediated predominantly by Th1 type CD4+ T cells. Polarization of the immune response to Th2 can inhibit the host immune protection against pathogens. Patients with tuberculosis coinfected with helminths demonstrate more severe pulmonary symptoms, a deficiency in the immune response against tuberculosis, and an impaired response to anti-tuberculosis therapy. METHODS: We evaluated the cellular immune response and the impact of the presence of Ascaris lumbricoides on the immune and clinical response in pulmonary tuberculosis patients. Ninety-one individuals were included in the study: 38 tuberculosis patients, 11 tuberculosis patients coinfected with Ascaris lumbricoides and other helminths, 10 Ascaris lumbricoides patients, and 34 non-infected control individuals. Clinical evolution of pulmonary tuberculosis was studied on 0, 30, 60, and 90 days post-diagnosis of Mycobacterium tuberculosis and Ascaris lumbricoides. Furthermore, immune cells and plasma cytokine profiles were examined in mono/coinfection by Mycobacterium tuberculosis and Ascaris lumbricoides using flow cytometry. RESULTS: There were no statistical differences in any of the evaluated parameters and the results indicated that Ascaris lumbricoides infection does not lead to significant clinical repercussions in the presentation and evolution of pulmonary tuberculosis. CONCLUSIONS: The association with Ascaris lumbricoides did not influence the Th1, Th2, and Th17 type responses, or the proportions of T lymphocyte subpopulations. However, higher serum levels of IL-6 in tuberculosis patients may explain the pulmonary parenchymal damage.


Assuntos
Ascaríase/imunologia , Ascaris lumbricoides , Interleucina-6/sangue , Tuberculose Pulmonar/imunologia , Adulto , Animais , Anticorpos Anti-Helmínticos/sangue , Ascaríase/complicações , Estudos de Casos e Controles , Coinfecção , Citocinas/sangue , Citocinas/imunologia , Progressão da Doença , Feminino , Citometria de Fluxo , Humanos , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Tuberculose Pulmonar/complicações , Adulto Jovem
3.
BMC Infect Dis ; 19(1): 1006, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779590

RESUMO

BACKGROUND: Monocytes are the predominant innate immune cells at the early stage of Mycobacterium tuberculosis (M. tb) infection as the host defense against intracellular pathogens. Understanding the profile of different monocyte subpopulations and the dynamics of monocyte-related biomarkers may be useful for the diagnosis and prognosis of tuberculosis. METHODS: We enrolled 129 individuals comprising patients with pulmonary tuberculosis (PTB) (n = 39), tuberculous pleurisy (TBP) (n = 28), malignant pleural effusion (MPE) (n = 21), latent tuberculosis infection (LTBI) (n = 20), and healthy controls (HC) (n = 21). Surface expression of CD14, CD16, and CD163 on monocytes was detected using flow cytometry. In addition, soluble CD163 (sCD163) was determined by enzyme linked immunosorbent assay. RESULTS: Higher frequency of CD14+CD16+ (15.7% vs 7.8%, P < 0.0001) and CD14-CD16+ (5.3% vs 2.5%, P = 0.0011) monocytes and a decreased percentage of CD14+CD16- (51.0% vs 70.4%, P = 0.0110) cells was observed in PTB patients than in HCs. Moreover, PTB patients displayed a higher frequency of CD163+ cells in CD16+ monocytes than those in the HC group (40.4% vs 11.3%, P < 0.0001). The level of sCD163 was elevated in TBP patients and was higher in pleural effusion than in plasma (2116.0 ng/ml vs 1236.0 ng/ml, P < 0.0001). sCD163 levels in pleural effusion and plasma could be used to distinguish TBP from MPE patients (cut-off values: 1950.0 and 934.7 ng/ml, respectively; AUCs: 0.8418 and 0.8136, respectively). Importantly, plasma sCD163 levels in TBP patients decreased significantly after anti-TB treatment. CONCLUSIONS: Higher expression of membrane and soluble CD163 in active tuberculosis patients might provide insights regarding the pathogenesis of tuberculosis, and sCD163 may be a novel biomarker to distinguish TBP from MPE and to predict disease severity.


Assuntos
Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Monócitos/metabolismo , Receptores de Superfície Celular/análise , Tuberculose/diagnóstico , Adulto , Idoso , Antígenos CD/sangue , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/sangue , Antígenos de Diferenciação Mielomonocítica/metabolismo , Área Sob a Curva , Estudos de Casos e Controles , Feminino , Humanos , Imunidade Inata , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Monócitos/imunologia , Prognóstico , Curva ROC , Receptores de Superfície Celular/sangue , Receptores de Superfície Celular/metabolismo , Receptores de IgG/metabolismo , Índice de Gravidade de Doença , Tuberculose/imunologia , Tuberculose/patologia , Tuberculose Pleural/imunologia , Tuberculose Pleural/patologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia
4.
Rev Port Cir Cardiotorac Vasc ; 26(2): 151-153, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31476818

RESUMO

Mucormycosis is a life-threatening fungal infection that occurs mainly in immunocompromised patients. Its occurrence isolated in the lung rare and carries a high mortality risk if untreated. We report the case of a 76-year old male immunocompetent patient, under treatment for pulmonary tuberculosis, admitted to the emergency department with hemoptysis. Bronchoscopy was performed and active bleeding from the middle lobe bronchus was found. Chest CT scan identified a solitary cavitary lesion in the middle lobe. The patient was proposed for urgent open middle lobectomy. Postoperative period was uneventful. Pulmonary mucormycosis was confirmed and adjuvant therapy with Amphotericin B was performed for 30 days. Despite its rarity, mucormycosis prevalence is expected to raise together with increasing number of immunocompromised patients. A high level of suspicion is recommended as early diagnosis can be determinant.


Assuntos
Pneumopatias Fúngicas/terapia , Mucormicose/terapia , Tuberculose Pulmonar/terapia , Idoso , Anti-Infecciosos/uso terapêutico , Humanos , Imunocompetência , Pneumopatias Fúngicas/complicações , Pneumopatias Fúngicas/diagnóstico , Pneumopatias Fúngicas/imunologia , Masculino , Mucormicose/complicações , Mucormicose/diagnóstico , Mucormicose/imunologia , Pneumonectomia , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/imunologia
5.
Vet Immunol Immunopathol ; 215: 109884, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31420066

RESUMO

Many vaccines against childhood diseases are administered early after birth, but vaccine development studies frequently test efficacy in adult rather than in neonatal animal models. In countries with endemic tuberculosis (TB), Bacillus Calmette-Guerin (BCG) is administered as part of the neonatal vaccine regimen because it prevents against the disseminated form of TB in children, although it has variable efficacy against pulmonary TB. Several promising new vaccines against TB are currently being tested in adult animal models. Here we evaluated neonatal piglets as an animal model to test vaccine efficacy. For this purpose, minipigs were vaccinated or not with BCG 48 h after birth and their immune response followed longitudinally until adolescence. We characterized the memory and activation phenotype of T cells, cytokine profile, and monocyte activation in response to BCG stimulation from 4 weeks of age into adolescence- age of 24 weeks. Immunological responses in vaccinated and non-vaccinated animals were further monitored upon infection with a low dose exposure to Mycobacterium tuberculosis strain HN878 via the aerosol route. Comparing the immunological response elicited by BCG vaccination in minipigs vs similar studies in infants, suggest that minipigs have the potential to serve as an effective neonatal animal model for vaccine development.


Assuntos
Vacina BCG/imunologia , Modelos Animais de Doenças , Mycobacterium tuberculosis/imunologia , Porco Miniatura/imunologia , Tuberculose Pulmonar/imunologia , Animais , Animais Recém-Nascidos , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Imunogenicidade da Vacina , Memória Imunológica , Imunofenotipagem , Estudos Longitudinais , Ativação Linfocitária , Masculino , Monócitos/imunologia , Suínos , Tuberculose/imunologia , Tuberculose Pulmonar/prevenção & controle
6.
Medicine (Baltimore) ; 98(23): e15977, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31169732

RESUMO

BACKGROUND: Tuberculosis (TB) is a highly contagious and chronic disease. The microbiological examination to confirm children TB disease are limited due to paucibacillary Mycobacterium, specimens and detecting facilities. Considering these limitations in diagnosing children TB, new and reliable methods that detect children TB should be developed. Recently, Interferon gamma-induced protein 10 (IP-10) has been identified as a sensitive parameter in detecting children TB. The present study aims to synthesis and analysis the diagnostic value of IP-10 for children TB. METHODS: We will search PubMed, Embase, the Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure, and Chinese Biological Medical Databases. We will search relevant citations up to May 2019. The quality of individual study will be assessed using the Quality Assessment of Diagnostic Accuracy Studies tool-2 (QUADAS-2). Stata 14.0 software will be used to calculate the pooled sensitivity, pooled specificity, pooled positive likelihood ratio (PLR), pooled negative likelihood ratio (NLR), pooled diagnostic odds ratio (DOR), pre-test probability, post-test probability and the hierarchical summary receiver operating characteristic (HSROC) curve. RESULTS: The results of this study will be published in a peer-reviewed journal. DISCUSSION: The evidence will indicate that IP-10 test is an alternative immunological test in detecting children TB. This is a protocol of systematic review and meta-analysis, so the ethical approval and patient consent are not required. PROTOCOL REGISTRATION NUMBER: CRD42019129743.


Assuntos
Quimiocina CXCL10/análise , Testes Imunológicos/estatística & dados numéricos , Mycobacterium/imunologia , Tuberculose Pulmonar/diagnóstico , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Testes Imunológicos/métodos , Lactente , Funções Verossimilhança , Masculino , Metanálise como Assunto , Projetos de Pesquisa , Sensibilidade e Especificidade , Revisão Sistemática como Assunto , Tuberculose Pulmonar/imunologia
7.
Mol Immunol ; 112: 175-181, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31170628

RESUMO

Regulatory B cells (Bregs) have critical roles as a negative regulator of immunity, mainly due to the fact that it secrets high a level of interleukin 10 (IL-10). Recently, a new subset of Bregs was identified as a key source of IL-35, which is an immunosuppressive cytokine and conventionally thought to be secreted by regulatory T cells (Tregs). Our previous study showed that the level of IL-35 in serum was elevated in the patients with active tuberculosis (ATB). However, none of the studies reported that IL-35 is secreted by B cells in ATB patients. In the current study, we found that the mRNA expressions of the both subunits (p35 and Ebi3) of IL-35 by circulating B cells were increased in ATB patients. By using immunohistochemistry and immunofluorescence staining, we found a subset of B cells infiltrated into the tuberculous granuloma of ATB patients also expressed IL-35. Moreover, Mycobacterium tuberculosis (MTB) lysate stimulation assay also demonstrated higher levels of IL-35 were exerted by MTB lysate within purified B cells from healthy control group (HC). Flow cytometry analysis further showed that the IL-35-producing B cells from ATB patients produced a higher level of IL-10. Taken together, IL-35-producing B cells may play a regulatory role during MTB infection by producing IL-10.


Assuntos
Linfócitos B Reguladores/imunologia , Interleucina-10/imunologia , Interleucinas/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Interferon gama/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/microbiologia , Tuberculose Pulmonar/microbiologia , Adulto Jovem
8.
Int J Mycobacteriol ; 8(2): 190-195, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31210165

RESUMO

Background: Tuberculosis (TB) control is challenging due to failure of drug compliance and resistance. Mycobacterial antigen-induced cytokine secretions are helpful in detecting Mycobacterium tuberculosis infection and to determine prediction for the fate of TB infection and its cure. Considering immunological response to be a crucial factor in pathogenesis and cure of TB, it can be explored to determine clinical prospects in different categorical tubercular infections. This study was designed to compare serum levels of inflammatory (tumor necrosis factor [TNF]-alpha and interferon [IFN]-gamma) and anti-inflammatory cytokines/chemokines (interleukin [IL]-10 and IL-8) among different TB groups (freshly diagnosed, relapse, cases on antitubercular treatment [ATT], and healthy controls). Methods: This cross-sectional study included total 100 subjects. The study subjects were further divided into four study groups with 25 cases in each of freshly diagnosed TB, TB relapse cases, cases on ATT, and 25 healthy controls. Levels of serum cytokines/chemokines (TNF-alpha, IFN-gamma, IL-10, and IL-8) were measured by flow cytometry. Results: Data analysis observed statistically significant differences in serum levels of TNF-alpha and IFN-gamma among the studied groups with significantly low levels in subjects on ATT and markedly high levels in TB relapse subjects. No statistically significant difference was observed in IL-10 and IL-8 levels. However, subjects with relapse revealed low IL-8 and high IL-10 levels. Conclusion: TNF-alpha and IFN-gamma have important roles in immune response and might be considered as indicators for response to ATT. However, high levels of IL-10 with low IL-8 appear to be associated with poor outcome and possibility of relapse.


Assuntos
Quimiocinas/sangue , Citocinas/sangue , Tuberculose/diagnóstico , Tuberculose/imunologia , Antituberculosos/uso terapêutico , Biomarcadores/sangue , Estudos de Casos e Controles , Quimiocinas/imunologia , Citocinas/imunologia , Monitoramento Epidemiológico , Humanos , Interferon gama/sangue , Interferon gama/imunologia , Mycobacterium tuberculosis , Prognóstico , Tuberculose/tratamento farmacológico , Tuberculose Pulmonar/imunologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
9.
Scand J Immunol ; 90(4): e12772, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31055842

RESUMO

Bacillus Calmette-Guérin (BCG) remains the only licensed vaccine against human tuberculosis (TB). BCG is a live-attenuated strain of Mycobacterium bovis, with limitations in efficacy against respiratory TB, the most common form of the disease responsible for transmission. However, continues to be used in the immunization programmes of different countries in the absence of another alternative. In order to improve BCG efficacy against pulmonary TB, in the current clinical TB vaccine pipeline, there are live-attenuated TB vaccines to replace BCG. This review discusses the current status of the development of live vaccine candidates designed to replace BCG from the rational strategies and immunological challenges to its clinical trial and identify key areas in the next years considered essential to confer improved safety and efficacy over BCG.


Assuntos
Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/fisiologia , Vacinas contra a Tuberculose/imunologia , Tuberculose Pulmonar/imunologia , Vacinas Atenuadas/imunologia , Animais , Humanos , Vacinação
10.
Immunopharmacol Immunotoxicol ; 41(2): 292-298, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31046503

RESUMO

Objective: The current therapeutic regimens for tuberculosis (TB) are complex and involve the prolonged use of multiple antibiotics with diverse side effects that lead to therapeutic failure and bacterial resistance. The standard appliance of immunotherapy may aid as a powerful tool to combat the ensuing threat of TB. We have earlier reported the immunotherapeutic potential of N-formylated peptides of two secretory proteins of Mycobacterium tuberculosis H37Rv. Here, we investigated the immunotherapeutic effect of an N-formylated peptide from Listeria monocytogenes in experimental TB. Methods: The N-terminally formylated listerial peptide with amino acid sequence 'f-MIGWII' was tested for its adjunctive therapeutic efficacy in combination with anti-tuberculosis drugs (ATDs) in the mouse model of TB. In addition, its potential to generate reactive oxygen species (ROS) in murine neutrophils was also evaluated. Results: The LemA peptide (f-MIGWII) induced a significant increase in the intracellular ROS levels of mouse neutrophils (p ≤ .05). The ATD treatment reduced the colony forming units (CFU) in lungs and spleen of infected mice by 2.39 and 1.67 log10 units, respectively (p < .001). Treatment of the infected mice with combination of ATDs and LemA peptide elicited higher therapeutic efficacy over ATDs alone. The histopathological changes in the lungs of infected mice also correlated well with the CFU data. Conclusions: Our results clearly indicate that LemA peptide conferred an additional therapeutic effect when given in combination with the ATDss (p < .01) and hence can be used as adjunct to the conventional chemotherapy against TB.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/farmacologia , Listeria monocytogenes/classificação , Oligopeptídeos/farmacologia , Tuberculose Pulmonar/tratamento farmacológico , Animais , Proteínas de Bactérias/química , Quimioterapia Combinada , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/imunologia , Neutrófilos/patologia , Oligopeptídeos/química , Espécies Reativas de Oxigênio/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia
11.
Scand J Immunol ; 90(2): e12774, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31054193

RESUMO

Tuberculosis (TB) remains one of a major health problem worldwide. Tuberculosis vaccine research has made an extraordinary progress over the past few years. However, there is still no replacement for the Bacillus Calmette-Guérin vaccine, the only TB vaccine licensed for human use. Therefore, the discovery and development of new TB vaccines remains a priority. This article discusses current strategies used to diversify TB vaccines and includes discussion of the status of efforts to improve protection against Mycobacterium tuberculosis (M tb) infection or TB disease by developing new and safe TB vaccines. This article also highlights the current research efforts in immune-enhancing approaches to improve vaccination efficacy. The development of more effective TB vaccines might have significant impact on global TB control.


Assuntos
Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose Pulmonar/prevenção & controle , Humanos , Tuberculose Pulmonar/imunologia , Vacinação , Vacinas Atenuadas/imunologia
12.
Mol Immunol ; 111: 145-151, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31054408

RESUMO

Tuberculosis (TB) is a global epidemic with devastating consequences. Emerging evidence suggests that B-cells have the ability to modulate the immune response and understanding these roles during Mycobacterium tuberculosis (M.tb) infection can help to find new strategies to treat TB. The immune system of individuals with pulmonary TB form granulomas in the lung which controls the infection by inhibiting the M.tb growth and acts as a physical barrier. Thereafter, surviving M.tb become dormant and in most cases the host's immunity prevents TB reactivation. B-cells execute several immunological functions and are regarded as protective regulators of immune responses by antibody and cytokine production, as well as presenting antigen. Some of these B-cells, or regulatory B-cells, have been shown to express death-inducing ligands, such as Fas ligand (FasL). This expression and binding to the Fas receptor leads to apoptosis, a major immune regulation mechanism, in addition to the ability to induce T-cell tolerance. Here, I discuss the relevance of B-cells, in particular their non-humoral functions by addressing their regulatory properties during M.tb infection.


Assuntos
Linfócitos B/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Latência Viral/imunologia , Apoptose/imunologia , Proteína Ligante Fas/imunologia , Ativação Linfocitária/imunologia , Receptor fas/imunologia
13.
Tuberculosis (Edinb) ; 116S: S11-S18, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31072689

RESUMO

TB is a catastrophic infectious disease, affecting roughly one third of the world's population. Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize vitamin B metabolites produced by bacteria, possess effector memory phenotype, and express tissue-homing markers driving migration to sites of infection. Previous research in both Mtb and HIV infections has shown that MAIT cells are depleted in the human periphery, possibly migrating to the tissue sites of infection. We investigated this hypothesis using rhesus macaques (RMs) with active TB, latent TB (LTBI), and SIV-coinfection to explore the effects of different disease states on the MAIT cell populations in vivo. Early in infection, we observed that MAIT cells increased in the blood and bronchoalveolar lavage fluid (BAL) of all infected RMs, irrespective of clinical outcome. However, the frequency of MAIT cells rapidly normalized such that they had returned to baseline levels prior to endpoint. Furthermore, following infection, the chemokines expressed on MAIT cells reflected a strong shift towards a Th1 phenotype from a shared Th1/Th17 phenotype. In conclusion, MAIT cells with enhanced Th1 functions migrating to the site of Mtb-infection. The anti-mycobacterial effector functions of MAIT cells, particularly during the early stages of Mtb infection, had been of interest in promoting protective long-term TB immunity. Our research shows, however, that they have relatively short-acting responses in the host.


Assuntos
Movimento Celular , Proliferação de Células , Imunidade nas Mucosas , Tuberculose Latente/microbiologia , Pulmão/microbiologia , Ativação Linfocitária , Células T Invariáveis Associadas à Mucosa/microbiologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/microbiologia , Animais , Coinfecção , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Tuberculose Latente/imunologia , Pulmão/imunologia , Macaca mulatta , Células T Invariáveis Associadas à Mucosa/imunologia , Células T Invariáveis Associadas à Mucosa/virologia , Mycobacterium tuberculosis/imunologia , Fenótipo , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus 40 dos Símios/imunologia , Vírus 40 dos Símios/patogenicidade , Células Th1/imunologia , Células Th1/microbiologia , Células Th2/imunologia , Células Th2/microbiologia , Fatores de Tempo , Tuberculose Pulmonar/imunologia
14.
Arch Med Res ; 50(1): 19-20, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-31101238

RESUMO

There are severa influencing factors that affect the burden of tuberculosis (TB), including host immune responses and migration. For example, co-infection of parasitic infections with TB suppresses protective immune response against TB. As such, migration is one of the important influencing factors that affect the TB burden, especially in multidrug-resistant (MDR-TB). In this article, these important and neglected factors are discussed.


Assuntos
Antituberculosos/uso terapêutico , Helmintíase/imunologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/imunologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/imunologia , África ao Sul do Saara , Animais , Europa Oriental , Helmintos/imunologia , Humanos , Tuberculose Resistente a Múltiplos Medicamentos/patologia , Tuberculose Pulmonar/patologia
15.
Pak J Pharm Sci ; 32(2 (Supplementary)): 779-784, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31103972

RESUMO

Prevalence of pulmonary tuberculosis (TB) in Pakistan is due to poor living conditions, malnutrition and low immunity. The present project was conducted to show the role of selenium complement to enhance the immune status against TB. Total of 80 human TB patients were divided into treatment (selenium and anti-tuberculosis drug) and control groups (anti-tuberculosis drug). Levels of selenium, immunoglobulin and leukocyte count were determined before and after treatment. Selenium showed significant increase in levels of immunoglobulin and leukocyte count in patients as compared to control group. The level of SOD, catalase, glutathione and total antioxidants were remarkably lowered among control type group as compared to treatment type group (P<0.01). However, the values of lipid peroxidation products malondialdehyde (MDA) were notably higher in control group than treatment group.


Assuntos
Antioxidantes/uso terapêutico , Antituberculosos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Selênio/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Antioxidantes/metabolismo , Catalase/sangue , Suplementos Nutricionais , Feminino , Glutationa/sangue , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Contagem de Leucócitos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Selênio/sangue , Superóxido Dismutase/sangue , Resultado do Tratamento , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia
16.
Tuberculosis (Edinb) ; 116S: S114-S117, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31076321

RESUMO

A vaccine that prevents transmission of infection is urgently needed in the fight against tuberculosis (TB). Results of clinical trials have been disappointing. Major problems include lack of biomarkers and understanding of the mechanisms of disease and protection. A more fundamental problem is that the scientific community seldom recognizes that primary and post-primary TB are distinct disease entities. Nearly all vaccine candidates have been designed and tested in models of primary TB, while transmission of infection is mediated by post-primary TB. Post-primary TB is seldom studied because no animal develop complete symptoms of the disease as it exists in humans. Nevertheless, mice, guinea pigs and rabbits all develop infections that at certain points appear to be models of human post-primary TB. Slowly progressive pulmonary TB in immunocompetent mice is an example. It is characterized by an alveolitis with infected foamy macrophages that have multiple characteristics of the human disease. We demonstrated that inclusion of an immune modulating agent, lactoferrin, with a BCG vaccine in this model induced a sustained reduction in lung pathology, but not numbers of organisms in tissue. Since the animals die of expanding pathology, this demonstrates the feasibility of using selected animal models for studies of vaccines against post-primary TB.


Assuntos
Adjuvantes Imunológicos/farmacologia , Vacina BCG/farmacologia , Lactoferrina/farmacologia , Pulmão/microbiologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/prevenção & controle , Animais , Vacina BCG/imunologia , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Humanos , Lactoferrina/imunologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/microbiologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/transmissão
17.
Indian J Pathol Microbiol ; 62(2): 232-238, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30971546

RESUMO

Background: As an immune checkpoint, upregulation of B and T lymphocyte attenuator (BTLA) contributes to T-cell exhaustion in chronic infection. However, the characteristics of BTLA on T cells of patients with pulmonary tuberculosis (PTB) are still uncovered. Aims: The aim of the study was to elucidate the dynamics and clinical significance of BTLA expression on circulating CD4+ and CD8+ T cells of PTB patients. Materials and Methods: BTLA expression on T cells from PTB patients with smear positivity (n = 86) and healthy controls (HCs) (n = 40) were determined using flow cytometry. Results: The levels of BTLA expression on circulating CD4+ and CD8+ T cells of PTB patients with smear positivity were both upregulated, compared with HC. At the same time, the levels of BTLA expression on CD4+ and CD8+ T cells of patients with retreatment were both higher than that of those with initial treatment and gradually upregulated along with the increase of the bacillary load in sputum. In addition, the patients with lung cavity were discovered to present higher levels of BTLA expression on CD4+ and CD8+ T cells than those without lung cavity. Whereas we noted that there was no correlation between the levels of BTLA expression and the positivity or negativity of anti-Mycobacterium tuberculosis antibody. Conclusions: The levels of BTLA expression were upregulated on CD4+ and CD8+ T cells of PTB patients and associated with disease progression. Thereby, BTLA expression on T cells may be considered as a potential clinical indicator and utilized as a therapeutic target for PTB.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Receptores Imunológicos/genética , Tuberculose Pulmonar/imunologia , Adulto , Antituberculosos/uso terapêutico , Estudos de Casos e Controles , Progressão da Doença , Feminino , Citometria de Fluxo , Humanos , Pulmão/imunologia , Pulmão/microbiologia , Masculino , Pessoa de Meia-Idade , Receptores Imunológicos/imunologia , Tuberculose Pulmonar/tratamento farmacológico , Regulação para Cima
18.
Nat Commun ; 10(1): 1823, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015452

RESUMO

Granulomas are the pathological hallmark of tuberculosis (TB) and the niche where bacilli can grow and disseminate or the immunological microenvironment in which host cells interact to prevent bacterial dissemination. Here we show 34 immune transcripts align to the morphology of lung sections from Mycobacterium tuberculosis-infected mice at cellular resolution. Colocalizing transcript networks at <10 µm in C57BL/6 mouse granulomas increase complexity with time after infection. B-cell clusters develop late after infection. Transcripts from activated macrophages are enriched at subcellular distances from M. tuberculosis. Encapsulated C3HeB/FeJ granulomas show necrotic centers with transcripts associated with immunosuppression (Foxp3, Il10), whereas those in the granuloma rims associate with activated T cells and macrophages. We see highly diverse networks with common interactors in similar lesions. Different immune landscapes of M. tuberculosis granulomas depending on the time after infection, the histopathological features of the lesion, and the proximity to bacteria are here defined.


Assuntos
Linfócitos B/imunologia , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculoma/imunologia , Tuberculose Pulmonar/imunologia , Animais , Linfócitos B/metabolismo , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-10/metabolismo , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/metabolismo , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/isolamento & purificação , RNA Mensageiro/isolamento & purificação , Fatores de Tempo , Tuberculoma/microbiologia , Tuberculoma/patologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
19.
J Biol Chem ; 294(19): 7615-7631, 2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-30894414

RESUMO

Mycobacteriophages express various peptides/proteins to infect Mycobacterium tuberculosis (M. tb). Particular attention has been paid to mycobacteriophage-derived endolysin proteins. We herein characterized a small mycobacteriophage-derived peptide designated AK15 with potent anti-M. tb activity. AK15 adopted cationic amphiphilic α-helical structure, and on the basis of this structure, we designed six isomers with increased hydrophobic moment by rearranging amino acid residues of the helix. We found that one of these isomers, AK15-6, exhibits enhanced anti-mycobacterial efficiency. Both AK15 and AK15-6 directly inhibited M. tb by trehalose 6,6'-dimycolate (TDM) binding and membrane disruption. They both exhibited bactericidal activity, cell selectivity, and synergistic effects with rifampicin, and neither induced drug resistance to M. tb They efficiently attenuated mycobacterial load in the lungs of M. tb-infected mice. We observed that lysine, arginine, tryptophan, and an α-helix are key structural requirements for their direct anti-mycobacterial action. Of note, they also exhibited immunomodulatory effects, including inhibition of proinflammatory response in TDM-stimulated or M. tb-infected murine bone marrow-derived macrophages (BMDMs) and M.tb-infected mice and induction of only a modest level of cytokine (tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6)) production in murine BMDMs and a T-cell cytokine (interferin-γ (IFN-γ) and TNF-α) response in murine lung and spleen. In summary, characterization of a small mycobacteriophage-derived peptide and its improved isomer revealed that both efficiently restrain M. tb infection via dual mycobactericidal-immunoregulatory activities. Our work provides clues for identifying small mycobacteriophage-derived anti-mycobacterial peptides and improving those that have cationic amphiphilic α-helices.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Micobacteriófagos/química , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/tratamento farmacológico , Proteínas Virais/farmacologia , Animais , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/agonistas , Peptídeos Catiônicos Antimicrobianos/química , Sinergismo Farmacológico , Humanos , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/virologia , Rifampina/agonistas , Rifampina/farmacologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia , Proteínas Virais/química
20.
Mucosal Immunol ; 12(3): 795-804, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30846830

RESUMO

Mycobacterium tuberculosis (M.tb) is deposited into the alveolus where it first encounters the alveolar lining fluid (ALF) prior contacts host cells. We demonstrated that M.tb-exposure to human ALF alters its cell surface, driving better M.tb infection control by professional phagocytes. Contrary to these findings, our results with non-professional phagocytes alveolar epithelial cells (ATs) define two distinct subsets of human ALFs; where M.tb exposure to Low (L)-ALF or High(H)-ALF results in low or high intracellular bacterial growth rates in ATs, respectively. H-ALF exposed-M.tb growth within ATs was independent of M.tb-uptake, M.tb-trafficking, and M.tb-infection induced cytotoxicity; however, it was associated with enhanced bacterial replication within LAMP-1+/ABCA1+ compartments. H-ALF exposed-M.tb infection of ATs decreased AT immune mediator production, decreased AT surface adhesion expression, and downregulated macrophage inflammatory responses. Composition analysis of H-ALF vs. L-ALF showed H-ALF with higher protein tyrosine nitration and less functional ALF-innate proteins important in M.tb pathogenesis. Replenishment of H-ALF with functional ALF-innate proteins reversed the H-ALF-M.tb growth rate to the levels observed for L-ALF-M.tb. These results indicate that dysfunctionality of innate proteins in the H-ALF phenotype promotes M.tb replication within ATs, while limiting inflammation and phagocyte activation, thus potentiating ATs as a reservoir for M.tb replication and survival.


Assuntos
DNA Bacteriano/genética , Células Epiteliais/fisiologia , Pulmão/patologia , Mycobacterium tuberculosis/fisiologia , Alvéolos Pulmonares/patologia , Mucosa Respiratória/imunologia , Tuberculose Pulmonar/imunologia , Células A549 , Apoptose , Adesão Celular , Citotoxicidade Imunológica , Replicação do DNA , Células Epiteliais/imunologia , Humanos , Imunidade Inata , Pulmão/microbiologia , Fagocitose , Alvéolos Pulmonares/imunologia
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