Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 8.817
Filtrar
1.
Nat Microbiol ; 7(2): 312-326, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35102304

RESUMO

Host cell chromatin changes are thought to play an important role in the pathogenesis of infectious diseases. Here we describe a histone acetylome-wide association study (HAWAS) of an infectious disease, on the basis of genome-wide H3K27 acetylation profiling of peripheral blood granulocytes and monocytes from persons with active Mycobacterium tuberculosis (Mtb) infection and healthy controls. We detected >2,000 differentially acetylated loci in either cell type in a Singapore Chinese discovery cohort (n = 46), which were validated in a subsequent multi-ethnic Singapore cohort (n = 29), as well as a longitudinal cohort from South Africa (n = 26), thus demonstrating that HAWAS can be independently corroborated. Acetylation changes were correlated with differential gene expression. Differential acetylation was enriched near potassium channel genes, including KCNJ15, which modulates apoptosis and promotes Mtb clearance in vitro. We performed histone acetylation quantitative trait locus (haQTL) analysis on the dataset and identified 69 candidate causal variants for immune phenotypes among granulocyte haQTLs and 83 among monocyte haQTLs. Our study provides proof-of-principle for HAWAS to infer mechanisms of host response to pathogens.


Assuntos
Estudos de Associação Genética , Histonas/genética , Mycobacterium tuberculosis/imunologia , Tuberculose/genética , Tuberculose/imunologia , Acetilação , Adulto , Cromatina , Estudos de Coortes , Feminino , Granulócitos/imunologia , Histonas/imunologia , Humanos , Estudos Longitudinais , Masculino , Monócitos/imunologia , Monócitos/microbiologia , Estudo de Prova de Conceito , Locos de Características Quantitativas , Singapura , África do Sul , Células THP-1 , Tuberculose/microbiologia , Adulto Jovem
2.
Nat Commun ; 13(1): 884, 2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-35173157

RESUMO

Mechanisms underlying variability in transmission of Mycobacterium tuberculosis strains remain undefined. By characterizing high and low transmission strains of M.tuberculosis in mice, we show here that high transmission M.tuberculosis strain induce rapid IL-1R-dependent alveolar macrophage migration from the alveolar space into the interstitium and that this action is key to subsequent temporal events of early dissemination of bacteria to the lymph nodes, Th1 priming, granulomatous response and bacterial control. In contrast, IL-1R-dependent alveolar macrophage migration and early dissemination of bacteria to lymph nodes is significantly impeded in infection with low transmission M.tuberculosis strain; these events promote the development of Th17 immunity, fostering neutrophilic inflammation and increased bacterial replication. Our results suggest that by inducing granulomas with the potential to develop into cavitary lesions that aids bacterial escape into the airways, high transmission M.tuberculosis strain is poised for greater transmissibility. These findings implicate bacterial heterogeneity as an important modifier of TB disease manifestations and transmission.


Assuntos
Macrófagos Alveolares/imunologia , Mycobacterium tuberculosis/imunologia , Receptores Tipo I de Interleucina-1/metabolismo , Células Th17/imunologia , Tuberculose Pulmonar/transmissão , Animais , Movimento Celular/imunologia , Células Dendríticas/imunologia , Feminino , Linfonodos/imunologia , Linfonodos/microbiologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C3H , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/imunologia , Alvéolos Pulmonares/microbiologia , Transdução de Sinais/imunologia , Células Th1/imunologia , Tuberculose Pulmonar/imunologia
3.
Front Immunol ; 13: 750068, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35154093

RESUMO

The role of B cells migrating to the lung and forming follicles during tuberculosis (TB) inflammation is still the subject of debate. In addition to their antibody production and antigen-presenting functions, B cells secrete different cytokines and chemokines, thus participating in complex networks of innate and adaptive immunity. Importantly, lung B-cells produce high amounts of the pleiotropic gp130 cytokine IL-6. Its role during TB infection remains controversial, partly due to the fact that IL-6 is produced by different cell types. To investigate the impact of IL-6 produced by B cells on TB susceptibility and immune responses, we established a mouse strain with specific IL-6 deficiency in B cells (CD19cre-IL-6fl/fl, B-IL-6KO) on the B6 genetic background. Selective abrogation of IL-6 in B cells resulted in shortening the lifespan of TB-infected B-IL-6KO mice compare to the wild-type controls. We provide evidence that at the initial TB stages B cells serve as a critical source of IL-6. In the lung, the effect of IL-6 deficiency in B cells is associated rather with B and T cell functioning, than with macrophage polarization. TB-infected B-IL-6KO mice displayed diminished sizes of B cells themselves, CD4+IFN-γ+, Th17+, and CD4+CXCR5+ follicular T cell populations. The pleiotropic effect of B-cell-derived IL-6 on T-cells demonstrated in our study bridges two major lymphocyte populations and sheds some light on B- and T-cells interactions during the stage of anti-TB response when the host switches on a plethora of acquired immune reactions.


Assuntos
Imunidade Adaptativa , Linfócitos B/imunologia , Interleucina-6/imunologia , Mycobacterium tuberculosis/imunologia , Técnicas de Ablação , Animais , Feminino , Interleucina-6/análise , Interleucina-6/genética , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/imunologia
4.
Cell Rep ; 38(6): 110359, 2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35139377

RESUMO

The two human pathogens Helicobacter pylori and Mycobacterium tuberculosis (Mtb) co-exist in many geographical areas of the world. Here, using a co-infection model of H. pylori and the Mtb relative M. bovis bacillus Calmette-Guérin (BCG), we show that both bacteria affect the colonization and immune control of the respective other pathogen. Co-occurring M. bovis boosts gastric Th1 responses and H. pylori control and aggravates gastric immunopathology. H. pylori in the stomach compromises immune control of M. bovis in the liver and spleen. Prior antibiotic H. pylori eradication or M. bovis-specific immunization reverses the effects of H. pylori. Mechanistically, the mutual effects can be attributed to the redirection of regulatory T cells (Treg cells) to sites of M. bovis infection. Reversal of Treg cell redirection by CXCR3 blockade restores M. bovis control. In conclusion, the simultaneous presence of both pathogens exacerbates the problems associated with each individual infection alone and should possibly be factored into treatment decisions.


Assuntos
Helicobacter pylori/patogenicidade , Infecções por Mycobacterium/microbiologia , Mycobacterium tuberculosis/patogenicidade , Linfócitos T Reguladores/microbiologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/microbiologia , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/microbiologia , Camundongos Endogâmicos C57BL , Mycobacterium bovis/patogenicidade , Mycobacterium tuberculosis/imunologia
5.
Front Immunol ; 13: 830497, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35173740

RESUMO

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. As a result of the coronavirus disease 2019 (COVID-19) pandemic, the global TB mortality rate in 2020 is rising, making TB prevention and control more challenging. Vaccination has been considered the best approach to reduce the TB burden. Unfortunately, BCG, the only TB vaccine currently approved for use, offers some protection against childhood TB but is less effective in adults. Therefore, it is urgent to develop new TB vaccines that are more effective than BCG. Accumulating data indicated that peptides or epitopes play essential roles in bridging innate and adaptive immunity and triggering adaptive immunity. Furthermore, innovations in bioinformatics, immunoinformatics, synthetic technologies, new materials, and transgenic animal models have put wings on the research of peptide-based vaccines for TB. Hence, this review seeks to give an overview of current tools that can be used to design a peptide-based vaccine, the research status of peptide-based vaccines for TB, protein-based bacterial vaccine delivery systems, and animal models for the peptide-based vaccines. These explorations will provide approaches and strategies for developing safer and more effective peptide-based vaccines and contribute to achieving the WHO's End TB Strategy.


Assuntos
Vacina BCG/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/prevenção & controle , Vacinas de Subunidades/imunologia , Animais , Proteínas de Bactérias/imunologia , Modelos Animais de Doenças , Humanos , Camundongos , Peptídeos/imunologia , Tuberculose/imunologia , Tuberculose/mortalidade , Vacinação
6.
Nat Commun ; 13(1): 602, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35105879

RESUMO

The M72/AS01E tuberculosis vaccine showed 50% (95%CI: 2-74%) efficacy in a phase 2B trial in preventing active pulmonary tuberculosis disease, but potential cost-effectiveness of adolescent immunisation is unknown. We estimated the impact and cost-effectiveness of six scenarios of routine adolescent M72/AS01E-like vaccination in South Africa and India. All scenarios suggested an M72/AS01E-like vaccine would be highly (94-100%) cost-effective in South Africa compared to a cost-effectiveness threshold of $2480/disability-adjusted life-year (DALY) averted. For India, a prevention of disease vaccine, effective irrespective of recipient's M. tuberculosis infection status at time of administration, was also highly likely (92-100%) cost-effective at a threshold of $264/DALY averted; however, a prevention of disease vaccine, effective only if the recipient was already infected, had 0-6% probability of cost-effectiveness. In both settings, vaccinating 50% of 18 year-olds was similarly cost-effective to vaccinating 80% of 15 year-olds, and more cost-effective than vaccinating 80% of 10 year-olds. Vaccine trials should include adolescents to ensure vaccines can be delivered to this efficient-to-target population.


Assuntos
Análise Custo-Benefício , Vacinas contra a Tuberculose/imunologia , Vacinação/economia , Adolescente , Custos e Análise de Custo , Humanos , Índia , Mycobacterium tuberculosis/imunologia , África do Sul , Tuberculose/epidemiologia , Tuberculose/prevenção & controle
7.
PLoS One ; 17(2): e0263172, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35113917

RESUMO

BACKGROUND: Ethiopia is one of the high burden countries for extrapulmonary tuberculosis (EPTB); however, the prompt diagnosis of EPTB remains challenging. This study is aimed to evaluate the diagnostic performance of Xpert MTB/RIF and DetermineTM TB-LAM Ag (TB-LAM) for the prompt diagnosis of EPTB in Ethiopia. METHODS: A total of 147 presumptive EPTB patients, including 23 HIV- positive participants were enrolled. Extra-pulmonary samples were collected from all presumptive EPTB cases and tested for Mycobacterium tuberculosis complex (MTBC) using fluorescent microscopy, Xpert MTB/RIF, and culture. Additionally, urine samples were also collected from 126 participants and were tested by DetermineTM TB-LAM Ag (Alere Inc, Waltham, USA). The Sensitivity and specificity of Xpert and TB- LAM tests were calculated by comparing with a composite reference standard (CRS), which comprises smear microscopy, culture and response to empirical anti-TB treatment. RESULTS: Of 147 patients, 23 (15.6%) were confirmed EPTB cases (culture-positive), 14 (9.5%) were probable EPTB (clinically, radiologically or cytologically positive and received anti-TB treatment with good response), and 110 (74.8%) were classified as "non- TB" cases. Compared to the composite reference standard (CRS), the overall sensitivity and specificity of Xpert MTB/RIF were 43.2% and 100%, respectively with the highest sensitivity for Lymph node aspirate (85.7%) and lower sensitivity for pleural fluid (14.3%) and 100% specificity for all specimen types. The sensitivity and specificity of TB-LAM were 33.3% and 94.4% respectively with the highest sensitivity for HIV co-infected participants (83.3%). The sensitivity of the combination of Xpert MTB/RIF and TB-LAM tests regardless of HIV status was 61.1% whereas the sensitivity was improved to 83.3% for HIV-positive cases. CONCLUSION: TB-LAM alone has low sensitivity for EPTB diagnosis; however, the combination of TB-LAM and Xpert MTB/RIF improves the diagnosis of EPTB particularly for countries with high EPTB and HIV cases.


Assuntos
Coinfecção/diagnóstico , Infecções por HIV/complicações , Lipopolissacarídeos/imunologia , Mycobacterium tuberculosis/isolamento & purificação , Reação em Cadeia da Polimerase/métodos , Tuberculose Pulmonar/diagnóstico , Urinálise/métodos , Adulto , Coinfecção/epidemiologia , Coinfecção/etiologia , Feminino , HIV/isolamento & purificação , Infecções por HIV/virologia , Humanos , Lipopolissacarídeos/urina , Masculino , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/imunologia , Análise de Sequência de DNA , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/etiologia , Adulto Jovem
8.
J Immunol ; 208(5): 1042-1056, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35149530

RESUMO

Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that recognize microbial vitamin B metabolites and have emerging roles in infectious disease, autoimmunity, and cancer. Although MAIT cells are identified by a semi-invariant TCR, their phenotypic and functional heterogeneity is not well understood. Here we present an integrated single cell transcriptomic analysis of over 76,000 human MAIT cells during early and prolonged Ag-specific activation with the MR1 ligand 5-OP-RU and nonspecific TCR stimulation. We show that MAIT cells span a broad range of homeostatic, effector, helper, tissue-infiltrating, regulatory, and exhausted phenotypes, with distinct gene expression programs associated with CD4+ or CD8+ coexpression. During early activation, MAIT cells rapidly adopt a cytotoxic phenotype characterized by high expression of GZMB, IFNG and TNF In contrast, prolonged stimulation induces heterogeneous states defined by proliferation, cytotoxicity, immune modulation, and exhaustion. We further demonstrate a FOXP3 expressing MAIT cell subset that phenotypically resembles conventional regulatory T cells. Moreover, scRNAseq-defined MAIT cell subpopulations were also detected in individuals recently exposed to Mycobacterium tuberculosis, confirming their presence during human infection. To our knowledge, our study provides the first comprehensive atlas of human MAIT cells in activation conditions and defines substantial functional heterogeneity, suggesting complex roles in health and disease.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Mycobacterium tuberculosis/imunologia , Proliferação de Células , Células Cultivadas , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Granzimas/metabolismo , Homeostase/imunologia , Humanos , Interferon gama/metabolismo , Células T Invariantes Associadas à Mucosa/citologia , Receptores de Antígenos de Linfócitos T/imunologia , Ribitol/análogos & derivados , Ribitol/imunologia , Análise de Célula Única , Transcriptoma/genética , Fator de Necrose Tumoral alfa/metabolismo , Uracila/análogos & derivados , Uracila/imunologia
9.
PLoS One ; 17(1): e0262454, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35025927

RESUMO

BACKGROUND: People living with HIV (PLHIV) co-infected with tuberculosis (TB) have a distinct clinical presentation and poorer treatment outcomes compared to HIV-seronegative TB patients. Excluding low CD4 count, innate immune factors associated with TB are not fully elucidated. We, therefore, characterised and compared the expression of IL-6, TNF-α, IFN-γ, and IL-10 in whole blood of treatment naïve TB patients stimulated with heat-killed Mycobacterium tuberculosis stratified by HIV status and the level of CD4 count. RESULTS: We recruited 39 HIV seropositive and 31 HIV seronegative TB patients. Median (IQR) age was 35(28-42) years and 31(25-36) years respectively, and a majority had pulmonary tuberculosis i.e. 38(95%) and 30(97%), respectively. The two groups were significantly different in the distribution of CD4 count, 563 [465-702.5 cells/mm3] vs 345 [157-483 cell/mm3] in HIV negative vs HIV positive respectively p = <0.001. Post stimulation, the expression of IL-6 in HIV negative TB patients was significantly higher than in the HIV positive 16,757366 [8,827-23,686 pg/ml] vs. 9,508 [5,514-15,008 pg/ml], respectively; p = 0.0360. TNF-α and IFN-γ were highly expressed in HIV negative TB patients compared to the HIV positive though not statistically significant. We only observed higher expression of IL-6 in HIV negative patients in comparison to the HIV positive when stratified by level of CD4 counts as < 500 and ≥ 500 cell/mm3 for both cohorts. 21,953 [8,990-24,206 pg/ml] vs 9,505 [5,400-15,313 pg/ml], p value = 0.0585 in patients with CD4 count < 500 cell/mm3 and 13,168 [7,087-22,584 pg/ml] vs 10,413 [7,397-14,806 pg/ml], p value = 0.3744 for patients with CD4 count of ≥ 500 cell/mm3 respectively. We found a positive pairwise correlation between TNF-α -alpha and IL-6 in both HIV positive and HIV negative patients, r = 0.61 (95% CI 0.36-0.72; p < 0.0001) and r = 0.48 (95% CI 0.15-0.68; p = 0.005) respectively. The IFNγ/IL-10 ratio was higher in HIV negative when compared to HIV positive individuals, 0.052 [0.0-0.28] vs 0.007 [0-0.32] respectively; p = 0.05759. IL-6 independently reduced the probability of TB/HIV, Adjusted odds ratio 0.99, p value 0.007. CONCLUSIONS: This study suggests that HIV seronegative TB patients have a higher pro-inflammatory response to MTB than HIV seropositive TB patients. Further, it also shows that the level of CD4 influences immunomodulation. The findings suggest that the difference in cytokine expression may be responsible for the distinct patterns of TB presentation between HIV positive and HIV negative patient.


Assuntos
Infecções por HIV/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Adulto , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/metabolismo , Coinfecção/complicações , Estudos Transversais , Feminino , Infecções por HIV/complicações , HIV-1/imunologia , HIV-1/patogenicidade , Humanos , Interferon gama/sangue , Interferon gama/metabolismo , Interleucina-10/sangue , Interleucina-10/metabolismo , Interleucina-6/sangue , Interleucina-6/metabolismo , Masculino , Mycobacterium tuberculosis/patogenicidade , Tuberculose/complicações , Tuberculose Pulmonar/complicações , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo , Zâmbia/epidemiologia
10.
JCI Insight ; 7(3)2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-34990408

RESUMO

BackgroundAdenovirus-vectored (Ad-vectored) vaccines are typically administered via i.m. injection to humans and are incapable of inducing respiratory mucosal immunity. However, aerosol delivery of Ad-vectored vaccines remains poorly characterized, and its ability to induce mucosal immunity in humans is unknown. This phase Ib trial evaluated the safety and immunogenicity of human serotype-5 Ad-vectored tuberculosis (TB) vaccine (AdHu5Ag85A) delivered to humans via inhaled aerosol or i.m. injection.MethodsThirty-one healthy, previously BCG-vaccinated adults were enrolled. AdHu5Ag85A was administered by single-dose aerosol using Aeroneb Solo Nebulizer or by i.m. injection. The study consisted of the low-dose (LD) aerosol, high-dose (HD) aerosol, and i.m. groups. The adverse events were assessed at various times after vaccination. Immunogenicity data were collected from the peripheral blood and bronchoalveolar lavage samples at baseline, as well as at select time points after vaccination.ResultsThe nebulized aerosol droplets were < 5.39 µm in size. Both LD and HD of AdHu5Ag85A administered by aerosol inhalation and i.m. injection were safe and well tolerated. Both aerosol doses, particularly LD, but not i.m., vaccination markedly induced airway tissue-resident memory CD4+ and CD8+ T cells of polyfunctionality. While as expected, i.m. vaccination induced Ag85A-specific T cell responses in the blood, the LD aerosol vaccination also elicited such T cells in the blood. Furthermore, the LD aerosol vaccination induced persisting transcriptional changes in alveolar macrophages.ConclusionInhaled aerosol delivery of Ad-vectored vaccine is a safe and superior way to elicit respiratory mucosal immunity. This study warrants further development of aerosol vaccine strategies against respiratory pathogens, including TB and COVID-19.Trial registrationClinicalTrial.gov, NCT02337270.FundingThe Canadian Institutes for Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada funded this work.


Assuntos
Aerossóis/farmacologia , COVID-19/prevenção & controle , SARS-CoV-2/efeitos dos fármacos , Vacinas contra a Tuberculose/imunologia , Tuberculose/prevenção & controle , Administração por Inalação , Adolescente , Adulto , Aerossóis/administração & dosagem , Anticorpos Neutralizantes/sangue , Vacina BCG/imunologia , COVID-19/imunologia , Feminino , Humanos , Imunidade nas Mucosas/efeitos dos fármacos , Imunidade nas Mucosas/imunologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Tuberculose/imunologia , Vacinação/métodos , Adulto Jovem
11.
J Med Microbiol ; 71(1)2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35037613

RESUMO

Background. Host genetic factors influence both susceptibility to Mycobacterium tuberculosis infection and immune responses generated by vaccination. Genetically susceptible mice help to study mechanisms of immune protection which may differ from those operating in more resistant models.Methods. In this work, we compared the efficacy of protection conferred by subcutaneous vaccination of hypersusceptible I/St mice with BCG and the first-generation, hygromycin resistant version of the vaccine candidate BCGΔBCG1419c, against tuberculosis (TB), measured as survival, weight loss and replication in lungs. We further characterized the relative presence of immune cells in lungs.Results. We found that in I/St mice, vaccination with BCG or BCGΔBCG1419c provided similar level of protection against TB-driven weight loss and M. tuberculosis replication in lungs, while prolonging median survival time compared with unvaccinated controls. Despite affording similar protection to parental BCG, BCGΔBCG1419c led to a reduced presence of macrophages in lungs during early TB and to an increased neutrophil recruitment to the lungs during chronic TB.Conclusions. BCGΔBCG1419c protects I/St mice in a different manner than wild-type BCG against pulmonary TB by promoting different influx of macrophages and neutrophils at distinct times post-infection. These findings prompt us to suggest that preclinical evaluation of novel TB vaccine candidates should include evaluation of efficacy not only in commonly used resistant inbred mice, but also in susceptible hosts, to further determine their potential application to populations varying in their genetic. This would likely impact their intended use depending on host resistance or susceptibility to TB.


Assuntos
Vacina BCG , Macrófagos/imunologia , Neutrófilos/imunologia , Tuberculose Pulmonar , Animais , Vacina BCG/uso terapêutico , Camundongos , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/prevenção & controle , Perda de Peso
12.
Int J Mol Sci ; 23(1)2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-35008950

RESUMO

Mycobacterium tuberculosis (M.tb) is a successful pathogen that can reside within the alveolar macrophages of the host and can survive in a latent stage. The pathogen has evolved and developed multiple strategies to resist the host immune responses. M.tb escapes from host macrophage through evasion or subversion of immune effector functions. M.tb genome codes for PE/PPE/PE_PGRS proteins, which are intrinsically disordered, redundant and antigenic in nature. These proteins perform multiple functions that intensify the virulence competence of M.tb majorly by modulating immune responses, thereby affecting immune mediated clearance of the pathogen. The highly repetitive, redundant and antigenic nature of PE/PPE/PE_PGRS proteins provide a critical edge over other M.tb proteins in terms of imparting a higher level of virulence and also as a decoy molecule that masks the effect of effector molecules, thereby modulating immuno-surveillance. An understanding of how these proteins subvert the host immunological machinery may add to the current knowledge about M.tb virulence and pathogenesis. This can help in redirecting our strategies for tackling M.tb infections.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Interações Hospedeiro-Patógeno/imunologia , Proteínas de Membrana/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Tuberculose/microbiologia , Antígenos de Bactérias/química , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Suscetibilidade a Doenças/imunologia , Glicina/metabolismo , Humanos , Evasão da Resposta Imune , Imunomodulação , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Mycobacterium tuberculosis/metabolismo , Virulência
13.
PLoS Negl Trop Dis ; 16(1): e0010120, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35007304

RESUMO

BACKGROUND: Intestinal parasites and Tuberculosis (TB) co-infection is a major public health problem. The parasitic infection suppresses the cell mediated immunity that protects tuberculosis. Helminthes-induced immune modulation promotes progression to active tuberculosis. However, there is paucity of evidences on the intestinal parasites-tuberculosis co-infection in Ethiopia. This study explores the magnitude and associated factors of intestinal parasitic infection and TB among suspected pulmonary Tuberculosis (PTB) patients. METHODOLOGY: A cross-sectional study design was conducted in Kuyu General Hospital from December 2019-March 2020. The socio-demographic data and associated factors were collected by structured questionnaire and then spot-spot sputum and fresh stool samples were collected following standard guidelines and were processed. Descriptive analysis was conducted and reported in frequency and percentage. Bivariate analysis was computed and a multivariable analysis was conducted to provide an adjusted odds ratio (AOR). P-value <0.05 at 95% confidence interval was considered as statistically significant. RESULTS: The burden of intestinal parasites was 20.2% (49/ 242) and 6.1% (20/ 242) of them were helminths infections and 14.1% (29/ 242) were protozoa infections. Of 242 patients, 14.9% (36/242) were sputum smear-positive for acid fast-bacilli. Of 36 smear positive patients, 9(25%) had TB-intestinal parasites co-infection. Dwelling in rural areas and having untrimmed fingernails were statistically significantly associated with intestinal parasites. Having a contact history of Tb patients was significantly associated with pulmonary tuberculosis. CONCLUSIONS: The magnitude of intestinal parasites and TB among PTB suspected patients were high. Hookworm infection was the predominant helmenthic infection. It is important to consider screening TB patients for intestinal parasites and treat co-infection properly.


Assuntos
Coinfecção/epidemiologia , Enteropatias Parasitárias/epidemiologia , Tuberculose Pulmonar/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ancylostomatoidea/isolamento & purificação , Animais , Criança , Pré-Escolar , Coinfecção/microbiologia , Coinfecção/parasitologia , Estudos Transversais , Etiópia/epidemiologia , Fezes/parasitologia , Feminino , Infecções por Uncinaria/epidemiologia , Infecções por Uncinaria/patologia , Humanos , Lactente , Enteropatias Parasitárias/imunologia , Enteropatias Parasitárias/patologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/isolamento & purificação , Carga Parasitária , Escarro/microbiologia , Inquéritos e Questionários , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia , Adulto Jovem
14.
J Exp Med ; 219(3)2022 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-35061012

RESUMO

Orchestration of an effective T lymphocyte response at infection sites is critical for protection against Mycobacterium tuberculosis (Mtb) infection. However, the local T cell immunity landscape in human tuberculosis is poorly defined. Tuberculous pleural effusion (TPE), caused by Mtb, is characterized by an influx of leukocytes to the pleural space, providing a platform suitable for delineating complex tissue responses to Mtb infection. Using single-cell transcriptomics and T cell receptor sequencing, we analyzed mononuclear cell populations in paired pleural fluid and peripheral blood of TPE patients. While all major cell clusters were present in both tissues, their relative proportions varied significantly by anatomic location. Lineage tracking analysis revealed subsets of CD8 and CD4 T cell populations with distinct effector functions specifically expanded at pleural sites. Granzyme K-expressing CD8 T cells were preferentially enriched and clonally expanded in pleural fluid from TPE, suggesting that they are involved in the pathogenesis of the disease. The findings collectively reveal the landscape of local T cell immunity in tuberculosis.


Assuntos
Mycobacterium tuberculosis/imunologia , Derrame Pleural/etiologia , Derrame Pleural/metabolismo , Derrame Pleural/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Tuberculose/complicações , Tuberculose/imunologia , Biomarcadores , Diferenciação Celular , Suscetibilidade a Doenças , Perfilação da Expressão Gênica/métodos , Interações Hospedeiro-Patógeno , Humanos , Imunofenotipagem , Ativação Linfocitária , Contagem de Linfócitos , Receptores de Antígenos de Linfócitos T/metabolismo , Análise de Célula Única/métodos , Tuberculose/microbiologia , Tuberculose/patologia
15.
J Nanobiotechnology ; 20(1): 36, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35033108

RESUMO

Tuberculosis (TB), induced by Mycobacterium tuberculosis (Mtb) infection, remains a top killer among infectious diseases. While Bacillus Calmette-Guerin (BCG) is the sole TB vaccine, the clumped-clustered features of BCG in intradermal immunization appear to limit both the BCG protection efficacy and the BCG vaccination safety. We hypothesize that engineering of clumped-clustered BCG into nanoscale particles would improve safety and also facilitate the antigen-presenting-cell (APC)'s uptake and the following processing/presentation for better anti-TB protective immunity. Here, we engineered BCG protoplasts into nanoscale membraned BCG particles, termed as "BCG-Nanocage" to enhance the anti-TB vaccination efficiency and safety. BCG-Nanocage could readily be ingested/taken by APC macrophages selectively; BCG-Nanocage-ingested macrophages exhibited better viability and developed similar antimicrobial responses with BCG-infected macrophages. BCG-Nanocage, like live BCG bacilli, exhibited the robust capability to activate and expand innate-like T effector cell populations of Vγ2+ T, CD4+ T and CD8+ T cells of rhesus macaques in the ex vivo PBMC culture. BCG-Nanocage immunization of rhesus macaques elicited similar or stronger memory-like immune responses of Vγ2Vδ2 T cells, as well as Vγ2Vδ2 T and CD4+/CD8+ T effectors compared to live BCG vaccination. BCG-Nanocage- immunized macaques developed rapidly-sustained pulmonary responses of Vγ2Vδ2 T cells upon Mtb challenge. Furthermore, BCG- and BCG-Nanocage- immunized macaques, but not saline controls, exhibited undetectable Mtb infection loads or TB lesions in the Mtb-challenged lung lobe and hilar lymph node at endpoint after challenge. Thus, the current study well justifies a large pre-clinical investigation to assess BCG-Nanocage for safe and efficacious anti-TB vaccination, which is expected to further develop novel vaccines or adjuvants.


Assuntos
Vacina BCG , Linfócitos T CD8-Positivos/imunologia , Mycobacterium tuberculosis/imunologia , Nanoestruturas/química , Tuberculose/imunologia , Animais , Vacina BCG/química , Vacina BCG/imunologia , Células Cultivadas , Feminino , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Macaca mulatta , Masculino
16.
Nat Commun ; 13(1): 78, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013257

RESUMO

T cells recognize mycobacterial glycolipid (mycolipid) antigens presented by CD1b molecules, but the role of CD4 and CD8 co-receptors in mycolipid recognition is unknown. Here we show CD1b-mycolipid tetramers reveal a hierarchy in which circulating T cells expressing CD4 or CD8 co-receptor stain with a higher tetramer mean fluorescence intensity than CD4-CD8- T cells. CD4+ primary T cells transduced with mycolipid-specific T cell receptors bind CD1b-mycolipid tetramer with a higher fluorescence intensity than CD8+ primary T cells. The presence of either CD4 or CD8 also decreases the threshold for interferon-γ secretion. Co-receptor expression increases surface expression of CD3ε, suggesting a mechanism for increased tetramer binding and activation. Targeted transcriptional profiling of mycolipid-specific T cells from individuals with active tuberculosis reveals canonical markers associated with cytotoxicity among CD8+ compared to CD4+ T cells. Thus, expression of co-receptors modulates T cell receptor avidity for mycobacterial lipids, leading to in vivo functional diversity during tuberculosis disease.


Assuntos
Antígenos CD1/imunologia , Glicolipídeos/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Antígenos CD1/genética , Complexo CD3/genética , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/microbiologia , Citotoxicidade Imunológica , Expressão Gênica , Glicolipídeos/metabolismo , Humanos , Interferon gama/genética , Interferon gama/imunologia , Ativação Linfocitária , Mycobacterium tuberculosis/crescimento & desenvolvimento , Cultura Primária de Células , Ligação Proteica , Multimerização Proteica , Transdução Genética , Tuberculose/genética , Tuberculose/microbiologia
17.
Nat Immunol ; 23(2): 318-329, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35058616

RESUMO

Tuberculosis (TB) in humans is characterized by formation of immune-rich granulomas in infected tissues, the architecture and composition of which are thought to affect disease outcome. However, our understanding of the spatial relationships that control human granulomas is limited. Here, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) to image 37 proteins in tissues from patients with active TB. We constructed a comprehensive atlas that maps 19 cell subsets across 8 spatial microenvironments. This atlas shows an IFN-γ-depleted microenvironment enriched for TGF-ß, regulatory T cells and IDO1+ PD-L1+ myeloid cells. In a further transcriptomic meta-analysis of peripheral blood from patients with TB, immunoregulatory trends mirror those identified by granuloma imaging. Notably, PD-L1 expression is associated with progression to active TB and treatment response. These data indicate that in TB granulomas, there are local spatially coordinated immunoregulatory programs with systemic manifestations that define active TB.


Assuntos
Granuloma/imunologia , Tuberculose/imunologia , Antígeno B7-H1/imunologia , Células Cultivadas , Citocinas/imunologia , Perfilação da Expressão Gênica/métodos , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Pulmão/imunologia , Mycobacterium tuberculosis/imunologia , Células Mieloides/imunologia
18.
Immunology ; 165(2): 219-233, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34775598

RESUMO

Tuberculosis (TB) and malaria remain serious threats to global health. Bacillus Calmette-Guerin (BCG), the only licensed vaccine against TB protects against severe disseminated forms of TB in infants but shows poor efficacy against pulmonary TB in adults. Co-infections have been reported as one of the factors implicated in vaccine inefficacy. Given the geographical overlap of malaria and TB in areas where BCG vaccination is routinely administered, we hypothesized that virulence-dependent co-infection with Plasmodium species could alter the BCG-specific immune responses thus resulting in failure to protect against Mycobacterium tuberculosis. We compared virulent Plasmodium berghei and non-virulent Plasmodium chabaudi, their effects on B cells, effector and memory T cells, and the outcome on BCG-induced efficacy against M. tuberculosis infection. We demonstrate that malaria co-infection modulates both B- and T-cell immune responses but does not significantly alter the ability of the BCG vaccine to inhibit the growth of M. tuberculosis irrespective of parasite virulence. This malaria-driven immune regulation may have serious consequences in the early clinical trials of novel vaccines, which rely on vaccine-specific T-cell responses to screen novel vaccines for progression to the more costly vaccine efficacy trials.


Assuntos
Vacina BCG/imunologia , Interações Hospedeiro-Parasita/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunogenicidade da Vacina , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/prevenção & controle , Tuberculose/prevenção & controle , Animais , Apoptose , Contagem de Linfócito CD4 , Modelos Animais de Doenças , Feminino , Humanos , Malária/imunologia , Malária/parasitologia , /metabolismo , Camundongos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Vacinas contra a Tuberculose/imunologia , Vacinação
19.
Appl Biochem Biotechnol ; 194(1): 187-214, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34817805

RESUMO

Mycobacterium tuberculosis (Mtb) is a respiratory pathogen that causes tuberculosis (TB). There are a large number of proteins that are involved in the pathogenesis of TB. Stimulating the immune response against TB is very important to clear the pathogens from host. In the present study, an immunoinformatics conduit is used for designing an epitope based chimeric vaccine against TB. Enhanced intracellular survival (EIS) protein from Mtb is used for designing the chimeric vaccine. One B cell epitope, 8 cytotoxic T lymphocyte (CTL), and 6 helper T lymphocyte (HTL) epitopes were predicted based on the MHC allele binding, immunogenicity, antigenicity, allergenicity, toxicity and IFN epitopes. The selected epitopes were used for chimeric vaccine designing. Furthermore, 3D structure elucidation, structural refinement and validation of the designed chimeric vaccine were carried out. The 3D structure was used for protein-protein docking studies with Toll-like receptor 4 (TLR-4), followed by molecular dynamic simulation (MDS) and the interaction between the chimeric vaccine and TLR-4 complex was verified.


Assuntos
Epitopos de Linfócito B , Epitopos de Linfócito T , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mycobacterium tuberculosis , Vacinas contra a Tuberculose , Epitopos de Linfócito B/genética , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Humanos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/genética , Vacinas contra a Tuberculose/imunologia , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia
20.
Methods Mol Biol ; 2412: 449-455, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34918261

RESUMO

A hypothetical protein (HP) is one that is known to exist only on the basis of a corresponding gene but without any function assigned to it. Many HPs have emerged as attractive vaccine candidates against prokaryotic and eukaryotic pathogens as well as against cancers. Mycobacterium bovis is a serious veterinary pathogen of tremendous zoonotic importance. This protocol describes a computational workflow for the identification of the HPs of M. bovis with vaccine potential and their subsequent structural and functional characterization.


Assuntos
Mycobacterium bovis , Vacinas , Anticorpos Antibacterianos , Proteínas de Bactérias/genética , Vacinas Bacterianas , Mycobacterium bovis/genética , Mycobacterium tuberculosis/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...