Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.106
Filtrar
1.
F1000Res ; 82019.
Artigo em Inglês | MEDLINE | ID: mdl-31602294

RESUMO

"Infection resisters" are broadly defined as individuals who despite significant exposure to Mycobacterium tuberculosis remain persistently unreactive to conventional detection assays, suggesting that they remain uninfected or rapidly clear their infection early on following exposure. In this review, we highlight recent studies that point to underlying host immune mechanisms that could mediate this natural resistance. We also illustrate some additional avenues that are likely to be differently modulated in resisters and possess the potential to be targeted, ranging from early mycobacterial sensing leading up to subsequent killing. Emerging research in this area can be harnessed to provide valuable insights into the development of novel therapeutic and vaccine strategies against M. tuberculosis.


Assuntos
Imunidade Inata , Mycobacterium tuberculosis , Tuberculose/imunologia , Humanos
2.
J Microbiol Biotechnol ; 29(10): 1506-1521, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31581380

RESUMO

Tuberculosis, which is caused by Mycobacterium tuberculosis (Mtb), is among the most pressing worldwide problems. Mtb uniquely interacts with innate immune cells through various pattern recognition receptors. These interactions initiate several inflammatory pathways that play essential roles in controlling Mtb pathogenesis. Although the TLR signaling pathways have essential roles in numerous host's immune defense responses, the role of TLR signaling in the response to Mtb infection is still unclear. This review presents discussions on host-Mtb interactions in terms of Mtb-mediated TLR signaling. In addition, we highlight recent discoveries pertaining to these pathways that may help in new immunotherapeutic opportunities.


Assuntos
Mycobacterium tuberculosis/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , Transdução de Sinais , Receptores Toll-Like/metabolismo , Tuberculose/imunologia , Animais , Citocinas/metabolismo , Humanos , Imunidade Inata , Imunoterapia , Mycobacterium tuberculosis/patogenicidade , Tuberculose/metabolismo , Tuberculose/terapia
4.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(7): 577-582, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31537240

RESUMO

Objective To investigate the roles of Th1 cytokines tumor necrosis factor α (TNF-α), interferon gamma (IFN-γ) and multifunctional T cells in nucleotides binding oligomer domain 2 knockout (NOD2-/-) mice infected with Mycobacterium tuberculosis (MTB) H37Ra. Methods Mouse models of pulmonary infection were established by tracheal instillation of MTB strain H37Ra into NOD2-/- mice and C57BL/6 mice (n=10 each group). Lung tissues were removed and stained by HE staining and pathological scores were evaluated 4 weeks after infection. The levels of TNF-α and IFN-γ in the lung homogenates were detected by ELISA, and the ratio of multifunctional CD4+ T and CD8+ T cells in the spleen were examined by flow cytometry. Results MTB infection promoted lung inflammation of NOD2-/- mice. The levels of TNF-α and IFN-γ in the lung tissues of NOD2-/- mice increased. Compared with normal saline group, TNF-α+, IFN-γ+ cells and TNF-α+IFN-γ+ cells in CD4+/CD8+T cells significantly increased in NOD2-/- mice and C57BL/6 mice after the infection. TNF-α+CD4+T cells, IFN-γ+CD4+T cells and IFN-γ+CD8+T cells in MTB-infected NOD2-/- mice were significantly higher than those in MTB-infected C57BL/6 mice. Conclusion H37Ra can induce Th1 immune response in NOD2-/- mice.


Assuntos
Mycobacterium tuberculosis , Células Th1/imunologia , Tuberculose/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Interferon gama/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Adaptadora de Sinalização NOD2/genética , Baço/citologia , Baço/imunologia , Fator de Necrose Tumoral alfa/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.
Braz J Infect Dis ; 23(3): 151-159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31271732

RESUMO

BACKGROUND: HIV infection harms adaptive cellular immunity mechanisms. Long-term virological control by combined antiretroviral therapy (cART) reduces the risk of mycobacterial infections. Thus, we aimed to study cellular responses to mycobacterial antigens in 20 HIV-infected adolescents with at least one year of virological control (HIV-RNA <40 copies/mL) and 20 healthy adolescents. METHODS: We evaluated CD8 and γδ T-cell degranulation by measurement of CD107a membrane expression after stimulation with lysates from BCG (10 µg/mL) and H37RA Mycobacterium tuberculosis (Mtb, 10 µg/mL). Immune activation and antigen-presenting ability were also assessed by determination of HLA-DR, CD80, and CD86 markers. RESULTS: TCR γδ T-cell CD107a expression was similar between groups in response to mycobacterial antigens, and lower in the HIV-infected group in response to mitogen. Higher baseline HLA-DR expression and lower mycobacterial-stimulated expression was found within the HIV-infected group. CONCLUSIONS: Similar degranulation in stimulated CD8+ and TCR γδ T-cells from HIV-infected adolescents, when compared to healthy controls suggests long-term immunological preservation with immune reconstitution under successful cART. However, differences in HLA-DR expression may represent ongoing inflammation and lower specific responses in HIV-infected youth. These features may be relevant in the context of the precocity and severity of vertically acquired HIV infection.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/imunologia , Fármacos Anti-HIV/uso terapêutico , Antígenos de Bactérias/imunologia , Linfócitos T CD8-Positivos/imunologia , Mycobacterium tuberculosis/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Tuberculose/imunologia , Apresentação do Antígeno/imunologia , Antígenos de Bactérias/efeitos dos fármacos , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Imunofenotipagem , Transmissão Vertical de Doença Infecciosa , Masculino , Estudos Prospectivos , Adulto Jovem
7.
BMC Infect Dis ; 19(1): 568, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262260

RESUMO

BACKGROUND: With the aim of preparing a more effective, safe and economical vaccine for tuberculosis, inhalable live mycobacterium formulations were evaluated. METHODS: Alginate particles in the size range of 2-4 µm were prepared by encapsulating live Bacille Calmette-Guérin (BCG) and "Mycobacterium indicus pranii" (MIP). These particles were characterized for their size, stability and release profile. Mice were immunized with liquid aerosol or dry powder aerosol (DPA) alginate encapsulated mycobacterium particles and their in-vitro recall response and infection with mycobacterium H37Rv were investigated. RESULTS: It was found that the DPA of alginate encapsulated mycobacterium particles invoked superior immune response and provided higher protection in mice than the liquid aerosol. The BCG encapsulated in alginate particles (BEAP) and MIP encapsulated in alginate particles (MEAP) were engulfed by bone marrow dendritic cells (BMDCs) and co-localized with lysosome. The MEAP/BEAP activated BMDCs exhibited higher chemotaxis movement and had enhanced ability of antigen presentation to T cells. The in-vitro recall response of BEAP/MEAP immunized mice when compared in terms of proliferation index and Interferon gamma (IFN-gamma) released by splenocytes and mediastinal lymph node cells was found to be higher than mice immunized by liquid aerosol of BCG/MIP. Finally, different groups of immunized mice were infected with M. tb H37Rv and after 16 weeks the Colony forming units (CFUs) in lung and spleen estimated. The bacilli burden in the BEAP/MEAP immunized mice was significantly less than the respective liquid aerosol immunized mice and the histopathology of BEAP/MEAP immunized mice lungs showed very little damage. CONCLUSIONS: These inhale-able vaccines formulation of alginate coated live mycobacterium are more immunogenic as compared to the aerosol of bacilli and they provide better protection in mice when infected with H37Rv.


Assuntos
Aerossóis/administração & dosagem , Pulmão/imunologia , Vacinas contra a Tuberculose/farmacologia , Tuberculose/prevenção & controle , Alginatos/química , Animais , Vacina BCG/imunologia , Sistemas de Liberação de Medicamentos/métodos , Interferon gama/imunologia , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Complexo Mycobacterium avium/química , Complexo Mycobacterium avium/imunologia , Mycobacterium bovis/química , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Baço/microbiologia , Linfócitos T/imunologia , Linfócitos T/microbiologia , Tuberculose/imunologia , Vacinas contra a Tuberculose/administração & dosagem , Vacinas contra a Tuberculose/imunologia , Vacinação/métodos
8.
BMC Infect Dis ; 19(1): 673, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31357953

RESUMO

BACKGROUND: Previous qualitative studies suggested that the false negative rate of the T cell spot test for tuberculosis infection (T-SPOT.TB) is associated with many risk factors in tuberculosis patients. However, more precise quantitative studies are lacking. The purpose of this study was to investigate the factors affecting quantified spot-forming cells (SFCs) to early secreted antigenic target 6 kDa (ESAT-6) or culture filtrate protein 10 kDa (CFP-10) in patients with active tuberculosis. METHODS: We retrospectively analyzed the data of 360 patients who met the inclusion criteria. Using the SFCs to ESAT-6 or CFP-10 levels as dependent variables, variables with statistical significance in the univariate analysis were subjected to optimal scaling regression analysis. The combination of ESAT-6 and CFP-10 (i.e., T-SPOT.TB) was analyzed by the exact logistic regression model. RESULTS: The results showed that the SFCs to ESAT-6 regression model had statistical significance (P < 0.001) and that previous treatment and CD4+ and platelet counts were its independent risk factors (all P < 0.05). Their importance levels were 0.095, 0.596 and 0.100, respectively, with a total of 0.791. The SFCs to CFP-10 regression model also had statistical significance (P < 0.001); platelet distribution width and alpha-2 globulin were its independent risk factors (all P < 0.05). Their importance levels were 0.287 and 0.247, respectively, with a total of 0.534. The quantification graph showed that quantified SFCs to ESAT-6 or CFP-10 grading had a linear correlation with risk factors. Albumin-globulin ratio, CD4+ and CD8+ were independent risk factors for false negative T-SPOT.TB (all P < 0.05). CONCLUSIONS: In T-SPOT.TB-assisted diagnosis of patients with active tuberculosis, previous treatment, decreased CD4+ and platelet count might lead to the decreased SFCs to ESAT-6, decreased alpha-2 globulin and high platelet distribution width might lead to the decreased SFCs to CFP-10, decreased albumin-globulin ratio, CD4+ and CD8+ might lead to an increase in the false negative rate of the T-SPOT.TB.


Assuntos
Antígenos de Bactérias/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/diagnóstico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Estudos Retrospectivos , Linfócitos T/imunologia , Tuberculose/imunologia , Tuberculose/microbiologia , Tuberculose/patologia
9.
Biomed Environ Sci ; 32(6): 427-437, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31262388

RESUMO

OBJECTIVE: This study aimed to characterize the diagnostic and vaccine potential of a novel Mycobacterium tuberculosis antigen Rv0674. METHODS: To evaluate the diagnostic potential and antigenicity of Rv0674, IgG was evaluated using ELISA and interferon (IFN)-γ was done by using ELISpot assay among TB patients and healthy donors. For immunogenicity evaluation, BALB/c mice were immunized with Rv0674. Cytokine production was determined by cytokine release assay using an ELISA kit, and the antibodies were tested using ELISA. RESULTS: The results of serum Elisa tests showed that Rv0674 specific immunoglobulin G (IgG) response was higher in TB patients than negative controls. And Rv0674 had good performance in serological test with sensitivity and specificity of 77.1% and 81.1%, respectively. While it shows poor sensitivity and specificity of 26.23% and 79.69% for IFN-γ tests. In BALB/c mice, Rv0674 adjuvant by DDA/Poly I:C could also induce a high level of IFN-γ, interleukin-2 and interleukin-6 as well as a high IgG titer in both high- and low-dose groups indicating that Rv0674 is essential in humoral and cellular immunity. Moreover, the cytokine profile and IgG isotype characterized Rv0674 as a Th1/Th2-mixed-type protective immunity with the predominance of Th1 cytokines. CONCLUSION: Rv0674 may be a good potential candidate for the development of TB serological diagnosis and a new TB vaccine.


Assuntos
Antígenos de Bactérias/imunologia , Tuberculose/imunologia , Adulto , Idoso , Animais , Feminino , Humanos , Imunidade Celular , Imunidade Humoral , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Tuberculose/diagnóstico , Adulto Jovem
10.
Microbiol Immunol ; 63(8): 316-327, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31254409

RESUMO

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) and remains a major cause of morbidity and mortality worldwide. In the host's immune response system, T cells play a critical role in mediating protection against Mtb infection, but the role of CD8+ T cells is still controversial. We evaluated the phenotypical characterization and cytotoxic ability of CD8+ T cells by flow cytometry-based assay. Cytokine levels in serum were measured by multiplex cytokine assay. Our data show that cells from TB patients have an increased percentage of peripheral blood CD8+ αß+ T (p = 0.02) and CD56+ CD8+ T (p = 0.02) and a decreased frequency of NKG2D+ CD8+ T (p = 0.02) compared with healthy donors. Unlike CD8+ T cells from healthy donors, CD8+ T cells from TB patients exhibit greater cytotoxicity, mediated by HLA class I molecules, on autologous monocytes in the presence of mycobacterial antigens (p = 0.005). Finally, TB patients have a proinflammatory profile characterized by serum high level of TNF-α (p = 0.02) and IL-8 (p = 0.0001), but, interestingly, IL-4 (p = 0.002) was also increased compared with healthy donors. Our data show evidence regarding the highly cytotoxic status of CD8+ T cells in Mtb infection. These cytotoxic cells restricted to HLA-A, B, and C could be used to optimize strategies for designing new TB vaccines or for identifying markers of disease progression.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Citotoxinas/toxicidade , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Adolescente , Adulto , Antígenos de Bactérias/imunologia , Citocinas/sangue , Feminino , Citometria de Fluxo , Antígenos HLA-A/imunologia , Antígenos HLA-B/imunologia , Antígenos HLA-C/imunologia , Humanos , Interleucina-4/sangue , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade , Vacinas contra a Tuberculose/imunologia , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
11.
Nat Med ; 25(6): 977-987, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31110348

RESUMO

Exposure to Mycobacterium tuberculosis (Mtb) results in heterogeneous clinical outcomes including primary progressive tuberculosis and latent Mtb infection (LTBI). Mtb infection is identified using the tuberculin skin test and interferon-γ (IFN-γ) release assay IGRA, and a positive result may prompt chemoprophylaxis to prevent progression to tuberculosis. In the present study, we report on a cohort of Ugandan individuals who were household contacts of patients with TB. These individuals were highly exposed to Mtb but tested negative disease by IFN-γ release assay and tuberculin skin test, 'resisting' development of classic LTBI. We show that 'resisters' possess IgM, class-switched IgG antibody responses and non-IFN-γ T cell responses to the Mtb-specific proteins ESAT6 and CFP10, immunologic evidence of exposure to Mtb. Compared to subjects with classic LTBI, 'resisters' display enhanced antibody avidity and distinct Mtb-specific IgG Fc profiles. These data reveal a distinctive adaptive immune profile among Mtb-exposed subjects, supporting an expanded definition of the host response to Mtb exposure, with implications for public health and the design of clinical trials.


Assuntos
Tuberculose Latente/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Adulto , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/imunologia , Criança , Estudos de Coortes , Feminino , Humanos , Interferon gama/imunologia , Testes de Liberação de Interferon-gama , Masculino , Teste Tuberculínico , Uganda , Adulto Jovem
12.
Int J Nanomedicine ; 14: 3129-3143, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118627

RESUMO

Background: Bacillus Calmette-Guérin, the attenuated strain of Mycobacterium bovis, remains the only available vaccine against tuberculosis (TB). However, its ineffectiveness in adults against pulmonary TB and varied protective efficacy (0-80%) speak to an urgent need for the development of an improved and efficient TB vaccine. In this milieu, poly(lactic-co-glycolic acid) (PLGA), is a preferential candidate, due to such properties as biocompatibility, targeted delivery, sustained antigen release, and atoxic by-products. Methods: In this study, we formulated PLGA nanoparticles (NPs) encapsulating the bivalent H1 antigen, a fusion of Mycobacterium tuberculosis (Mtb) Ag85B and ESAT6 proteins, and investigated its role in immunomodulation and protection against Mtb challenge. Using the classical water-oil-water solvent-evaporation method, H1-NPs were prepared, with encapsulation efficiency of 86.1%±3.2%. These spherical NPs were ~244.4±32.6 nm in diameter, with a negatively charged surface (ζ-potential -4±0.6 mV). Results: Under physiological conditions, NPs degraded slowly and the encapsulated H1 antigen was released over a period of weeks. As a proof-of-concept vaccine candidate, H1 NPs were efficiently internalized by the THP-1 human macrophages. Six weeks after a single-dose vaccination, H1 NP-immunized C57BL/6J mice showed significant increase in the production of total serum IgG (P<0.0001) and its isotypes compared to H1 alone, IgG2a being the predominant one, followed by IgG1. Further, the cytokine-release profile of antigen-stimulated splenocyteculture supernatant indicated a strong TH1-biased immunoresponse in H1 NP-vaccinated mice, with ~6.03- and ~2.8-fold increase in IFNγ and TNFα cytokine levels, and ~twofold and 1.6 fold increase in IL4 and IL10 cytokines, respectively, compared to H1 alone-immunized mice. In protection studies, H1 NP-vaccinated mice displayed significant reductions in lung and spleen bacillary load (P<0.05) at 5-week post-Mtb H37Rv challenge and prolonged survival, with a mean survival time of 177 days, compared to H1 alone-vaccinated mice (mean survival time 80 days). Conclusion: Altogether, our findings highlight the significance of the H1-PLGA nanoformulation in terms of providing long-term protection in mice with a single dose.


Assuntos
Imunidade , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Proteínas Recombinantes de Fusão/metabolismo , Tuberculose/imunologia , Tuberculose/prevenção & controle , Animais , Citocinas/metabolismo , Relação Dose-Resposta Imunológica , Liberação Controlada de Fármacos , Endocitose , Epitopos , Feminino , Humanos , Imunidade Humoral , Imunização , Imunoglobulina G/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/imunologia , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Baço/citologia , Baço/imunologia , Análise de Sobrevida , Células THP-1 , Células Th1/imunologia , Vacinas contra a Tuberculose/imunologia , Vacinação
13.
Nat Commun ; 10(1): 2329, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-31133636

RESUMO

Variability in bacterial sterilization is a key feature of Mycobacterium tuberculosis (Mtb) disease. In a population of human macrophages, there are macrophages that restrict Mtb growth and those that do not. However, the sources of heterogeneity in macrophage state during Mtb infection are poorly understood. Here, we perform RNAseq on restrictive and permissive macrophages and reveal that the expression of genes involved in GM-CSF signaling discriminates between the two subpopulations. We demonstrate that blocking GM-CSF makes macrophages more permissive of Mtb growth while addition of GM-CSF increases bacterial control. In parallel, we find that the loss of bacterial control that occurs in HIV-Mtb coinfected macrophages correlates with reduced GM-CSF secretion. Treatment of coinfected cells with GM-CSF restores bacterial control. Thus, we leverage the natural variation in macrophage control of Mtb to identify a critical cytokine response for regulating Mtb survival and identify components of the antimicrobial response induced by GM-CSF.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Transdução de Sinais/imunologia , Tuberculose/imunologia , Buffy Coat/citologia , Células Cultivadas , Perfilação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , HIV/imunologia , HIV/patogenicidade , Infecções por HIV/imunologia , Infecções por HIV/microbiologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Macrófagos/microbiologia , Mycobacterium tuberculosis/patogenicidade , Cultura Primária de Células , Análise de Sequência de RNA , Tuberculose/microbiologia , Vitamina D/imunologia , Vitamina D/metabolismo
14.
BMC Infect Dis ; 19(1): 366, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039752

RESUMO

BACKGROUND: Independent of HIV infection, extrapulmonary TB (EPTB) risk is increased in women, persons of black race or foreign birth, and by genetic variants in vitamin D receptor (VDR), interleukin-1 beta (IL-1ß), and toll-like receptor (TLR)-2; functional correlates are unclear. We evaluated macrophage expression of VDR, TLR2, cathelicidin, and TNF-α, and production of IL-1ß in HIV-seronegative persons with previous EPTB, previous pulmonary TB, latent M. tuberculosis infection, and uninfected TB contacts. Persons with previous pleural TB were excluded due to enhanced immune responses at the site of disease. METHODS: Macrophages were stimulated with TLR-2 agonist M. tuberculosis lipoprotein (LpqH), live and gamma-irradiated M. tuberculosis. RESULTS: M. tuberculosis - infected macrophages from persons with previous EPTB had increased VDR expression (29.17 relative value unit increase in median expression vs. uninfected contacts, after adjusting for foreign-born status; P = 0.02). Macrophages from persons with previous EPTB had a 38.88 µg/mL increase in median IL-1ß production after stimulation with LpqH compared to uninfected contacts (P = 0.01); the effect was similar (44.99 µg/mL) but not statistically significant after controlling for foreign-born status. Median 25-hydroxyvitamin D levels were low but not significantly different between groups. CONCLUSIONS: There was increased macrophage expression of VDR after stimulation with live M. tuberculosis in persons with previous extrapulmonary TB. If post-treatment VDR expression reflects expression prior to disease, it may identify persons at risk for extrapulmonary TB.


Assuntos
Macrófagos/metabolismo , Mycobacterium tuberculosis/fisiologia , Receptores de Calcitriol/metabolismo , Tuberculose/patologia , Adulto , Idoso , Proteínas de Bactérias/imunologia , Estudos de Casos e Controles , DNA Bacteriano/genética , DNA Bacteriano/metabolismo , Feminino , Raios gama , Expressão Gênica , Humanos , Interleucina-1beta/análise , Macrófagos/citologia , Macrófagos/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efeitos da radiação , Receptores de Calcitriol/genética , Receptor 2 Toll-Like/agonistas , Tuberculose/imunologia , Vitamina D/análogos & derivados , Vitamina D/sangue
15.
Infect Immun ; 87(6)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30962399

RESUMO

The specific chemokine receptors utilized by Th1 cells to migrate into the lung during Mycobacterium tuberculosis infection are unknown. We previously showed in mice that CXCR3+ Th1 cells enter the lung parenchyma and suppress M. tuberculosis growth, while CX3CR1+ KLRG1+ Th1 cells accumulate in the lung vasculature and are nonprotective. Here we quantify the contributions of these chemokine receptors to the migration and entry rate of Th1 cells into M. tuberculosis-infected lungs using competitive adoptive transfer migration assays and mathematical modeling. We found that in 8.6 h half of M. tuberculosis-specific CD4 T cells migrate from the blood to the lung parenchyma. CXCR3 deficiency decreases the average rate of Th1 cell entry into the lung parenchyma by half, while CX3CR1 deficiency doubles it. KLRG1 blockade has no effect on Th1 cell lung migration. CCR2, CXCR5, and, to a lesser degree, CCR5 and CXCR6 also promote the entry of Th1 cells into the lungs of infected mice. Moreover, blockade of G-protein-coupled receptors with pertussis toxin treatment prior to transfer only partially inhibits T cell migration into the lungs. Thus, the fraction of Th1 cell input into the lungs during M. tuberculosis infection that is regulated by chemokine receptors likely reflects the cumulative effects of multiple chemokine receptors that mostly promote but that can also inhibit entry into the parenchyma.


Assuntos
Linfócitos T CD4-Positivos/citologia , Pulmão/imunologia , Mycobacterium tuberculosis/fisiologia , Tuberculose/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Movimento Celular , Feminino , Humanos , Pulmão/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/imunologia , Receptores de Quimiocinas , Células Th1/imunologia , Tuberculose/genética , Tuberculose/microbiologia , Tuberculose/fisiopatologia
16.
Microb Pathog ; 131: 158-163, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30953746

RESUMO

Mycobacterium tuberculosis (Mtb) has the extraordinary ability to persist for decades within granulomas in the human host. These histopathological structures involved in both protection and pathogenesis, are subject to various influences from the host systemically and through micro-niche environments. Despite the fact that vitamin D (VD) has a key role in macrophage activation and mycobacterial clearance in the early stages of Mtb infection, the overall role of VD in granuloma maintenance or functionality has been scarcely studied. VD deficiency has long time been known to influence on gut microbiota composition, and recent studies have shown that it can also impact on respiratory microbiome. The human microbiota plays an important role in pathogen colonization resistance, and it has been proposed to play a potential role in TB pathogenesis. In this article, we have reviewed current knowledge on the interaction between VD, the lung microbiome and TB, and propose mechanisms by which the tuberculous granuloma's outcome could be modulated by these two factors. The determinants of the final fate of lung granulomas are still unclear, and deciphering the underlying drivers of Mtb infection outcome within those structures is of critical importance.


Assuntos
Microbioma Gastrointestinal/fisiologia , Granuloma/imunologia , Pulmão/microbiologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose/imunologia , Vitamina D/metabolismo , Disbiose , Microbioma Gastrointestinal/imunologia , Granuloma/patologia , Interações Hospedeiro-Patógeno , Humanos , Pulmão/patologia , Ativação de Macrófagos , Tuberculose/patologia , Vitamina D/imunologia , Deficiência de Vitamina D/complicações
17.
BMC Vet Res ; 15(1): 70, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30823881

RESUMO

BACKGROUND: Serum antibody detection has potential as a complementary diagnostic tool in animal tuberculosis (TB) control, particularly in multi-host systems. The objective of the present study was to assess the specificity (Sp) of an enzyme-linked immunosorbent assay (ELISA) based on the new multiprotein complex P22 for the detection of specific antibodies against the Mycobacterium tuberculosis complex (MTC) in the four most relevant domestic animals acting as MTC hosts: cattle, goat, sheep and pig. We used sera from an officially TB-free (OTF) country, Norway, and from a non-OTF one, Spain. The samples included sera from goats that had been vaccinated against M. avium subsp. paratuberculosis (MAP) and sheep from a herd in which Corynebacterium pseudotuberculosis had been isolated. RESULTS: In cattle, the Sp ranged from 92.5 (IC95% 90.7-94) to 99.4% (IC95% 98.3-99.8) depending on the cut-off used and the origin of the samples (Spain or Norway). Sp in cattle (cut-off point 100) was significantly higher (P < 0.05) for Norwegian samples. By contrast, Sp in goats was consistently low at the 100 cut-off [30.9 (CI95%23.4-39.5)-78% (CI95% 68.9-85)]. A higher cut-off of 150 improved Sp in Norwegian goats [97% (CI95% 91.6-99)], but still yielded a poor Sp of 56.1% (CI95% 47.3-64.6) in Spanish goats. In Norway at the 100 cut-off the Sp was 58.3 (CI95% 42.2-72.9) and 90.6% (CI95% 81-95.6) in MAP vaccinated and non-vaccinated goats, respectively, indicating interference due to MAP vaccination. Sp in sheep was between 94.4 (CI95% 91.7-96.3) and 100% (CI95% 96.3-100) depending on the cut-off and country, and no diagnostic interference due to infection with C. pseudotuberculosis was recorded. Sp in pigs was 100%, regardless the cut-off point applied, and no significant differences were observed between pigs from Norway and from Spain. CONCLUSIONS: Due to its excellent Sp in pigs and acceptable Sp in cattle and sheep, this ELISA may constitute a suitable option for TB screening at herd level, particularly in OTF-countries.


Assuntos
Doenças dos Animais/diagnóstico , Ensaio de Imunoadsorção Enzimática/veterinária , Mycobacterium tuberculosis/imunologia , Tuberculose/veterinária , Doenças dos Animais/epidemiologia , Doenças dos Animais/imunologia , Animais , Bovinos , Corynebacterium pseudotuberculosis/imunologia , Cabras , Mycobacterium avium subsp. paratuberculosis/imunologia , Noruega/epidemiologia , Sensibilidade e Especificidade , Estudos Soroepidemiológicos , Ovinos , Espanha/epidemiologia , Suínos , Tuberculose/diagnóstico , Tuberculose/imunologia
18.
Microbiol Spectr ; 7(2)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30848232

RESUMO

Mycobacterium tuberculosis has evolved to become the single greatest cause of death from an infectious agent. The pathogen spends most of its infection cycle in its human host within a phagocyte. The bacterium has evolved to block the normal maturation and acidification of its phagosome and resides in a vacuole contiguous with the early endosomal network. Cytokine-mediated activation of the host cell can overcome this blockage, and an array of antimicrobial responses can limit its survival. The survival of M. tuberculosis in its host cell is fueled predominantly by fatty acids and cholesterol. The ability of M. tuberculosis to degrade sterols is an unusual metabolic characteristic that was likely retained from a saprophytic ancestor. Recent results with fluorescent M. tuberculosis reporter strains demonstrate that bacterial survival differs with the host macrophage population. Tissue-resident alveolar macrophages, which are biased towards an alternatively activated, M2-like phenotype, are more permissive to bacterial growth than monocyte-derived, inflammatory, M1-like interstitial macrophages. The differential growth of the bacterium in these different phagocyte populations appears to be linked to host cell metabolism.


Assuntos
Macrófagos/microbiologia , Mycobacterium tuberculosis/fisiologia , Tuberculose/microbiologia , Animais , Antibacterianos/farmacologia , Citocinas/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Viabilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/metabolismo , Fagócitos/microbiologia , Fagossomos/microbiologia , Tuberculose/imunologia , Vacúolos/microbiologia
19.
PLoS Pathog ; 15(3): e1007643, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30830940

RESUMO

Eradication of tuberculosis (TB), the world's leading cause of death due to infectious disease, requires a highly efficacious TB vaccine. Many TB vaccine candidates are in pre-clinical and clinical development but only a few can be advanced to large-scale efficacy trials due to limited global resources. We aimed to perform a statistically rigorous comparison of the antigen-specific T cell responses induced by six novel TB vaccine candidates and the only licensed TB vaccine, Bacillus Calmette-Guérin (BCG). We propose that the antigen-specific immune response induced by such vaccines provides an objective, data-driven basis for prioritisation of vaccine candidates for efficacy testing. We analyzed frequencies of antigen-specific CD4 and CD8 T cells expressing IFNγ, IL-2, TNF and/or IL-17 from adolescents or adults, with or without Mycobacterium tuberculosis (M.tb) infection, who received MVA85A, AERAS-402, H1:IC31, H56:IC31, M72/AS01E, ID93+GLA-SE or BCG. Two key response characteristics were analyzed, namely response magnitude and cytokine co-expression profile of the memory T cell response that persisted above the pre-vaccination response to the final study visit in each trial. All vaccines preferentially induced antigen-specific CD4 T cell responses expressing Th1 cytokines; levels of IL-17-expressing cells were low or not detected. In M.tb-uninfected and -infected individuals, M72/AS01E induced higher memory Th1 cytokine-expressing CD4 T cell responses than other novel vaccine candidates. Cytokine co-expression profiles of memory CD4 T cells induced by different novel vaccine candidates were alike. Our study suggests that the T cell response feature which most differentiated between the TB vaccine candidates was response magnitude, whilst functional profiles suggested a lack of response diversity. Since M72/AS01E induced the highest memory CD4 T cell response it demonstrated the best vaccine take. In the absence of immunological correlates of protection, the likelihood of finding a protective vaccine by empirical testing of candidates may be increased by the addition of candidates that induce distinct immune characteristics.


Assuntos
Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/metabolismo , Vacinas contra a Tuberculose/farmacologia , Adjuvantes Imunológicos/farmacologia , Adolescente , Adulto , Antígenos de Bactérias , Vacina BCG , Linfócitos T CD4-Positivos , Citocinas , Combinação de Medicamentos , Feminino , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imunidade Humoral/imunologia , Imunidade Humoral/fisiologia , Interferon gama , Interleucina-17 , Interleucina-2 , Lipídeo A/análogos & derivados , Masculino , Mycobacterium bovis , Mycobacterium tuberculosis/patogenicidade , Saponinas , Células Th1 , Tuberculose/imunologia , Tuberculose/metabolismo , Fator de Necrose Tumoral alfa
20.
Proc Natl Acad Sci U S A ; 116(13): 6371-6378, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30850538

RESUMO

Tuberculosis (TB) remains a leading killer among infectious diseases, and a better TB vaccine is urgently needed. The critical components and mechanisms of vaccine-induced protection against Mycobacterium tuberculosis (Mtb) remain incompletely defined. Our previous studies demonstrate that Vγ2Vδ2 T cells specific for (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) phosphoantigen are unique in primates as multifunctional effectors of immune protection against TB infection. Here, we selectively immunized Vγ2Vδ2 T cells and assessed the effect on infection in a rhesus TB model. A single respiratory vaccination of macaques with an HMBPP-producing attenuated Listeria monocytogenes (Lm ΔactA prfA*) caused prolonged expansion of HMBPP-specific Vγ2Vδ2 T cells in circulating and pulmonary compartments. This did not occur in animals similarly immunized with an Lm ΔgcpE strain, which did not produce HMBPP. Lm ΔactA prfA* vaccination elicited increases in Th1-like Vγ2Vδ2 T cells in the airway, and induced containment of TB infection after pulmonary challenge. The selective immunization of Vγ2Vδ2 T cells reduced lung pathology and mycobacterial dissemination to extrapulmonary organs. Vaccine effects coincided with the fast-acting memory-like response of Th1-like Vγ2Vδ2 T cells and tissue-resident Vγ2Vδ2 effector T cells that produced both IFN-γ and perforin and inhibited intracellular Mtb growth. Furthermore, selective immunization of Vγ2Vδ2 T cells enabled CD4+ and CD8+ T cells to mount earlier pulmonary Th1 responses to TB challenge. Our findings show that selective immunization of Vγ2Vδ2 T cells can elicit fast-acting and durable memory-like responses that amplify responses of other T cell subsets, and provide an approach to creating more effective TB vaccines.


Assuntos
Imunização , Ativação Linfocitária/efeitos dos fármacos , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Tuberculose/prevenção & controle , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Feminino , Memória Imunológica/imunologia , Interferon gama/metabolismo , Listeria monocytogenes/genética , Listeria monocytogenes/imunologia , Pulmão/imunologia , Pulmão/patologia , Macaca mulatta/imunologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Mycobacterium tuberculosis/efeitos dos fármacos , Organofosfatos , Fatores de Terminação de Peptídeos/genética , Fatores de Terminação de Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/imunologia , Tuberculose/patologia , Vacinas contra a Tuberculose/farmacologia , Vacinas Atenuadas/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA