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1.
Front Immunol ; 12: 656419, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34745081

RESUMO

Tuberculosis (TB) is the global health problem with the second highest number of deaths from a communicable disease after COVID-19. Although TB is curable, poor health infrastructure, long and grueling TB treatments have led to the spread of TB pandemic with alarmingly increasing multidrug-resistant (MDR)-TB prevalence. Alternative host modulating therapies can be employed to improve TB drug efficacies or dampen the exaggerated inflammatory responses to improve lung function. Here, we investigated the adjunct therapy of natural immune-modulatory compound berberine in C57BL/6 mouse model of pulmonary TB. Berberine treatment did not affect Mtb growth in axenic cultures; however, it showed increased bacterial killing in primary murine bone marrow-derived macrophages and human monocyte-derived macrophages. Ad libitum berberine administration was beneficial to the host in combination with rifampicin and isoniazid. Berberine adjunctive treatment resulted in decreased lung pathology with no additive or synergistic effects on bacterial burdens in mice. Lung immune cell flow cytometry analysis showed that adjunctive berberine treatment decreased neutrophil, CD11b+ dendritic cell and recruited interstitial macrophage numbers. Late onset of adjunctive berberine treatment resulted in a similar phenotype with consistently reduced numbers of neutrophils both in lungs and the spleen. Together, our results suggest that berberine can be supplemented as an immunomodulatory agent depending on the disease stage and inflammatory status of the host.


Assuntos
Antituberculosos/uso terapêutico , Berberina/uso terapêutico , Fatores Imunológicos/uso terapêutico , Isoniazida/uso terapêutico , Rifampina/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Animais , Antituberculosos/farmacologia , Berberina/farmacologia , Citocinas/imunologia , Células Dendríticas/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Humanos , Fatores Imunológicos/farmacologia , Isoniazida/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Rifampina/farmacologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/microbiologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
2.
Comput Math Methods Med ; 2021: 9463577, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630630

RESUMO

Objective: To investigate the effects of health education combined with dietary guidance on nutritional indicators, immune level, and quality of life of patients with pulmonary tuberculosis. Method: A total of 123 patients with pulmonary tuberculosis who were hospitalized to our hospital between October 2019 and October 2020 were chosen for the study and were separated into 60 control cases and 63 observation cases based on the ward they were assigned to. Patients in the two groups were compared in terms of nutritional risk, nutritional indicator levels in serum, immunological function, treatment compliance, sputum culture conversion rate, and quality of life. Result: With the prolongation of patients' illness, the total NRS 2002 score gradually increased in both groups and the total NRS 2002 score of patients in the control group was higher than that of patients in the observation group at the same time point after discharge. The difference between the total NRS 2002 score of patients in both groups was significant at 3 and 6 months after discharge. After the intervention, the Hb, ALB, CD4+, and CD4+/CD8+ levels of patients in both groups were higher than those at the time of admission, and the CD8+ levels were lower than those at the time of admission. At 6 months after discharge, the Hb, ALB, CD4+, and CD4+/CD8+ levels of patients in the observation group were significantly higher than those in the control group, and the CD8+ levels were significantly lower than those in the control group. The treatment compliance rate of patients in the observation group (96.83%) was significantly higher than that of the control group (75%), and the negative sputum culture transfer rate (85.71%) was significantly higher than that in the control group (60%). The overall quality of life scores of patients in the observation group was significantly higher than that in the control group. Conclusion: Health education combined with dietary guidance for patients with pulmonary tuberculosis can deepen patients' understanding of disease and nutritional knowledge, improve treatment compliance, improve their nutritional status, enhance their immune function, accelerate sputum bacterial conversion, enhance treatment effect, and improve their quality of life.


Assuntos
Educação em Saúde , Tuberculose Pulmonar/terapia , Adulto , Estudos de Casos e Controles , China , Biologia Computacional , Dieta , Feminino , Hemoglobinas/metabolismo , Humanos , Imunidade Celular , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Cooperação do Paciente , Qualidade de Vida , Albumina Sérica/metabolismo , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/imunologia
3.
J Immunol ; 207(7): 1857-1870, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34479945

RESUMO

The lungs harbor multiple resident microbial communities, otherwise known as the microbiota. There is an emerging interest in deciphering whether the pulmonary microbiota modulate local immunity, and whether this knowledge could shed light on mechanisms operating in the response to respiratory pathogens. In this study, we investigate the capacity of a pulmonary Lactobacillus strain to modulate the lung T cell compartment and assess its prophylactic potential upon infection with Mycobacterium tuberculosis, the etiological agent of tuberculosis. In naive mice, we report that a Lactobacillus murinus (Lagilactobacillus murinus) strain (CNCM I-5314) increases the presence of lung Th17 cells and of a regulatory T cell (Treg) subset known as RORγt+ Tregs. In particular, intranasal but not intragastric administration of CNCM I-5314 increases the expansion of these lung leukocytes, suggesting a local rather than systemic effect. Resident Th17 and RORγt+ Tregs display an immunosuppressive phenotype that is accentuated by CNCM I-5314. Despite the well-known ability of M. tuberculosis to modulate lung immunity, the immunomodulatory effect by CNCM I-5314 is dominant, as Th17 and RORγt+ Tregs are still highly increased in the lung at 42-d postinfection. Importantly, CNCM I-5314 administration in M. tuberculosis-infected mice results in reduction of pulmonary inflammation, without increasing M. tuberculosis burden. Collectively, our findings provide evidence for an immunomodulatory capacity of CNCM I-5314 at steady state and in a model of chronic inflammation in which it can display a protective role, suggesting that L. murinus strains found in the lung may shape local T cells in mice and, perhaps, in humans.


Assuntos
Lactobacillus/fisiologia , Pulmão/imunologia , Mycobacterium tuberculosis/fisiologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Tuberculose Pulmonar/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Pulmão/microbiologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia
4.
PLoS One ; 16(8): e0247745, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34460817

RESUMO

BACKGROUND: The monocyte-to-lymphocyte ratio (MLR) has been advocated as a biomarker in tuberculosis. Our objective was to evaluate its clinical value and associations. METHODS: Blood counts, inflammatory markers and clinical parameters were measured in patients with and those screened for tuberculosis. Complete blood counts (CBCs) from a multi-ethnic population aged 16 to 65 years were evaluated; a sub-group with normal hematological indices was used to define the range of MLRs. RESULTS: Multivariate analysis in proven tuberculosis (n = 264) indicated MLR associated with low serum albumin, high white cell counts and a positive culture; values were higher in sputum smear-positive pulmonary tuberculosis (S+PTB). Analysis in S+PTB (n = 296) showed higher MLRs in males and those with high neutrophil counts, low serum albumin and high C-reactive protein. The diagnostic value of MLRs was assessed by comparing notified patients with TB (n = 264) with denotified cases (n = 50), active case-finding in non-contacts (TB n = 111 and LTBI n = 373) and contacts of S+PTB (n = 149) with S+PTB found at screening (n = 75). Sensitivities and specificities ranged from 58.0-62.5% and 50.0-70.0% respectively for optimal cut-off values, defined by ROC curves. In CBCs obtained over one month, ratios correlated with neutrophil counts (ρ = 0.48, P<0.00001, n = 14,573; MLR = 0.45 at 8-8.9 x 109/L) and were higher in males than females (P<0.0001). The MLR range (mean ± 2SD) in those with normal hematological indices (n = 3921: females 0.122-0.474; males 0.136-0.505) paralleled LTBI MLRs. Ratios did not predict death (n = 29) nor response to treatment (n = 178 S+PTB with follow-up CBCs). Ratios were higher in males than female in the 16-45 years age group, where immune differences due to sex hormones are likely greatest. CONCLUSIONS: Severe tuberculosis and male sex associated with high MLRs; the same variables likely affect the performance of other biomarkers. The ratio performed poorly as a clinical aid.


Assuntos
Contagem de Leucócitos , Contagem de Linfócitos , Monócitos/patologia , Tuberculose Pulmonar/diagnóstico , Adolescente , Adulto , Idoso , Proteína C-Reativa/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Curva ROC , Valores de Referência , Sensibilidade e Especificidade , Albumina Sérica/análise , Índice de Gravidade de Doença , Fatores Sexuais , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia , Adulto Jovem
5.
Comput Math Methods Med ; 2021: 5593864, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367319

RESUMO

A deterministic model was formulated and employed in the analysis of the dynamics of tuberculosis with a keen emphasis on vaccination and drug resistance as the first line of treatment. It was assumed that some of the susceptible population were vaccinated but with temporal immunity. This is due to the fact that vaccines do not confer permanent immunity. Moreover, part of the infected individual after treatment grows resistance to the drug. Infective immigrants were also considered to be part of the population. The basic reproductive number for the model is estimated using the next-generation matrix method. The equilibrium points of the TB model and their local and global stability were determined. It was established that if the basic reproductive number was less than unity (R 0 < 1), then the disease free equilibrium is stable and unstable if R 0 > 1. Furthermore, we investigated the optimal prevention, treatment, and vaccination as control measures for the disease. As the objective functional was optimised, there have been a significant reduction in the number of infections and an increase in the number of recovery. The best control measure in combating tuberculosis infections is prevention and vaccination of the susceptible population.


Assuntos
Modelos Biológicos , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/prevenção & controle , Número Básico de Reprodução/estatística & dados numéricos , Biologia Computacional , Simulação por Computador , Suscetibilidade a Doenças , Farmacorresistência Bacteriana/imunologia , Humanos , Conceitos Matemáticos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/farmacologia , Tuberculose Pulmonar/imunologia , Vacinação/estatística & dados numéricos
6.
PLoS Negl Trop Dis ; 15(7): e0009605, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34324509

RESUMO

BACKGROUND: Regulatory T cells (Tregs) play a critical role during Mycobacterium tuberculosis (Mtb) infection, modulating host responses while neutralizing excessive inflammation. However, their impact on regulating host protective immunity is not completely understood. Here, we demonstrate that Treg cells abrogate the in vitro microbicidal activity against Mtb. METHODS: We evaluated the in vitro microbicidal activity of peripheral blood mononuclear cells (PBMCs) from patients with active tuberculosis (TB), individuals with latent tuberculosis infection (LTBI, TST+/IGRA+) and healthy control (HC, TST-/IGRA-) volunteers. PBMCs, depleted or not of CD4+CD25+ T-cells, were analyzed to determine frequency and influence on microbicidal activity during in vitro Mtb infection with four clinical isolates (S1, S5, R3, and R6) and one reference strain (H37Rv). RESULTS: The frequency of CD4+CD25highFoxP3+ cells were significantly higher in Mtb infected whole blood cultures from both TB patients and LTBI individuals when compared to HC. Data from CD4+CD25+ T-cells depletion demonstrate that increase of CD4+CD25highFoxP3+ is associated with an impairment of Th-1 responses and a diminished in vitro microbicidal activity of LTBI and TB groups. CONCLUSIONS: Tregs restrict host anti-mycobacterial immunity during active disease and latent infection and thereby may contribute to both disease progression and pathogen persistence.


Assuntos
Atividade Bactericida do Sangue , Antígenos CD4/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Antígenos CD4/genética , Estudos de Casos e Controles , Fatores de Transcrição Forkhead/genética , Humanos , Subunidade alfa de Receptor de Interleucina-2/genética , Linfócitos T Reguladores
7.
Immunity ; 54(8): 1758-1771.e7, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34256013

RESUMO

Apoptosis can potently defend against intracellular pathogens by directly killing microbes and eliminating their replicative niche. However, the reported ability of Mycobacterium tuberculosis to restrict apoptotic pathways in macrophages in vitro has led to apoptosis being dismissed as a host-protective process in tuberculosis despite a lack of in vivo evidence. Here we define crucial in vivo functions of the death receptor-mediated and BCL-2-regulated apoptosis pathways in mediating protection against tuberculosis by eliminating distinct populations of infected macrophages and neutrophils and priming T cell responses. We further show that apoptotic pathways can be targeted therapeutically with clinical-stage compounds that antagonize inhibitor of apoptosis (IAP) proteins to promote clearance of M. tuberculosis in mice. These findings reveal that any inhibition of apoptosis by M. tuberculosis is incomplete in vivo, advancing our understanding of host-protective responses to tuberculosis (TB) and revealing host pathways that may be targetable for treatment of disease.


Assuntos
Apoptose/imunologia , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Neutrófilos/imunologia , Tuberculose Pulmonar/imunologia , Animais , Caspase 8/genética , Caspase 8/metabolismo , Linhagem Celular , Dipeptídeos/uso terapêutico , Humanos , Indóis/uso terapêutico , Ativação Linfocitária/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/microbiologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Linfócitos T/imunologia , Tiazóis/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico
8.
Front Immunol ; 12: 676679, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149712

RESUMO

Introduction: Protective host responses in those exposed to or infected with tuberculosis (TB) is thought to require a delicate balance between pro-inflammatory and regulatory immune responses. Myeloid-derived suppressor cells (MDSCs), regulatory cells that dampen T-cell function, have been described in cancer and other infectious diseases but there are limited data on their role in TB. Methods: Peripheral blood was obtained from patients with active pulmonary TB and participants with presumed latent TB infection (LTBI) from Cape Town, South Africa. MDSC frequency was ascertained by flow cytometry. Purified MDSCs were used to assess (i) their suppressive effect on T-cell proliferation using a Ki67 flow cytometric assay and (ii) their effect on mycobacterial containment by co-culturing with H37Rv-infected monocyte-derived macrophages and autologous pre-primed effector T-cells with or without MDSCs. Mycobacterial containment was measured by plating colony forming units (CFU). Results: MDSCs (CD15+HLA-DR-CD33+) had significantly higher median frequencies (IQR) in patients with active TB (n=10) versus LTBI (n= 10) [8.2% (6.8-10.7) versus 42.2% (27-56) respectively; p=0.001]. Compared to MDSC-depleted peripheral blood mononuclear and effector T cell populations, dilutions of purified MDSCs isolated from active TB patients suppressed T-cell proliferation by up to 72% (n=6; p=0.03) and significantly subverted effector T-cell-mediated containment of H37Rv in monocyte-derived macrophages (n=7; 0.6% versus 8.5%; p=0.02). Conclusion: Collectively, these data suggest that circulating MDSCs are induced during active TB disease and can functionally suppress T-cell proliferation and subvert mycobacterial containment. These data may inform the design of vaccines and immunotherapeutic interventions against TB but further studies are required to understand the mechanisms underpinning the effects of MDSCs.


Assuntos
Granulócitos/imunologia , Tuberculose Latente/imunologia , Viabilidade Microbiana/imunologia , Mycobacterium tuberculosis/genética , Células Supressoras Mieloides/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Proliferação de Células , Técnicas de Cocultura , Feminino , Antígenos HLA-DR/metabolismo , Humanos , Hidrolases/imunologia , Tuberculose Latente/sangue , Tuberculose Latente/epidemiologia , Tuberculose Latente/microbiologia , Antígenos CD15/metabolismo , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Dados Preliminares , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , África do Sul/epidemiologia , Linfócitos T/imunologia , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/microbiologia
9.
Front Immunol ; 12: 627638, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936040

RESUMO

Background: Tuberculosis (TB) is still a major challenge for humankind. Because regions with the highest incidence also have a high prevalence of helminthiasis and nutritional scarcity, we wanted to understand the impact of these on TB progression. Methods: We have developed an experimental murine model for active TB in C3HeB/FeJ, coinfected with Trichuris muris and Heligmosomoides polygyrus nematodes, and exposed to an environmental mycobacterium (M. manresensis) and intermittent fasting. Cause-effect relationships among these factors were explored with Partial Least Squares Path modelling (PLSPM). Results: Previous parasitization had a major anti-inflammatory effect and reduced systemic levels of ADA, haptoglobin, local pulmonary levels of IL-1ß, IL-6, TNF-α, CXCL-1, CXCL-5 and IL-10. Oral administration of heat-killed M. manresensis resulted in a similar outcome. Both interventions diminished pulmonary pathology and bacillary load, but intermittent food deprivation reduced this protective effect increasing stress and inflammation. The PLSPM revealed nematodes might have protective effects against TB progression. Conclusions: Significantly higher cortisol levels in food-deprivation groups showed it is a stressful condition, which might explain its deleterious effect. This highlights the impact of food security on TB eradication policies and the need to prioritize food supply over deworming activities.


Assuntos
Coinfecção , Privação de Alimentos , Helmintíase/parasitologia , Enteropatias Parasitárias/parasitologia , Pulmão/microbiologia , Mycobacterium tuberculosis/patogenicidade , Nematospiroides dubius/patogenicidade , Infecções por Strongylida/parasitologia , Tricuríase/parasitologia , Trichuris/patogenicidade , Tuberculose Pulmonar/microbiologia , Fenômenos Fisiológicos da Nutrição Animal , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Helmintíase/imunologia , Helmintíase/metabolismo , Interações Hospedeiro-Parasita , Mediadores da Inflamação/metabolismo , Enteropatias Parasitárias/imunologia , Enteropatias Parasitárias/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos C3H , Mycobacterium tuberculosis/imunologia , Nematospiroides dubius/imunologia , Estado Nutricional , Infecções por Strongylida/imunologia , Infecções por Strongylida/metabolismo , Tricuríase/imunologia , Tricuríase/metabolismo , Trichuris/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/metabolismo
10.
Front Immunol ; 12: 660916, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33953722

RESUMO

Following infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), most human hosts are able to contain the infection and avoid progression to active TB disease through expression of a balanced, homeostatic immune response. Proinflammatory mechanisms aiming to kill, slow and sequester the pathogen are key to a successful host response. However, an excessive or inappropriate pro-inflammatory response may lead to granuloma enlargement and tissue damage, which may prolong the TB treatment duration and permanently diminish the lung function of TB survivors. The host also expresses certain anti-inflammatory mediators which may play either beneficial or detrimental roles depending on the timing of their deployment. The balance between the timing and expression levels of pro- and anti-inflammatory responses plays an important role in the fate of infection. Interestingly, M. tuberculosis appears to manipulate both sides of the human immune response to remodel the host environment for its own benefit. Consequently, therapies which modulate either end of this spectrum of immune responses at the appropriate time may have the potential to improve the treatment of TB or to reduce the formation of permanent lung damage after microbiological cure. Here, we highlight host-directed TB therapies targeting pro- or anti-inflammatory processes that have been evaluated in pre-clinical models. The repurposing of already available drugs known to modulate these responses may improve the future of TB therapy.


Assuntos
Anti-Inflamatórios/uso terapêutico , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Inflamação/tratamento farmacológico , Tuberculose/tratamento farmacológico , Tuberculose/imunologia , Antituberculosos/uso terapêutico , Ensaios Clínicos como Assunto , Reposicionamento de Medicamentos , Humanos , Mycobacterium tuberculosis/imunologia , Transdução de Sinais , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/imunologia
11.
Mol Immunol ; 135: 285-293, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33957478

RESUMO

Despite its critical roles in immune responses against tuberculosis infection and immune pathology, the molecular details of interleukin (IL)-1ß production in tuberculosis infection remain elusive. To explore IL-1ß production in tuberculosis infection, we infected mouse bone marrow-derived macrophages (BMDM) with Mycobacterium tuberculosis (Mtb) H37Rv, its early secreted antigenic target protein of 6 kDa (ESAT-6) gene deletion (H37Rv:Δ3875) or complemented strain (H37Rv:Δ3875C) and evaluated IL-1ß production. H37Rv induced significantly increased IL-1ß production by BMDMs compared to non-infected BMDMs. In contrast, H37Rv:Δ3875 induced significantly less mature IL-1ß production despite eliciting comparable levels of pro-IL-1ß and IL-8 from BMDMs compared to H37Rv and H37Rv:Δ3875C. Blocking either NLRP3 or K+ efflux diminished H37Rv-induced IL-1ß production by BMDMs. Infection of mice intranasally with H37Rv:Δ3875 induced less IL-1ß production in the lungs compared with H37Rv. Intranasal delivery of ESAT-6 but not CFP10 induced production of IL-1ß in mouse lungs and RNA-Seq analysis identified serum amyloid A (SAA) 3 as one of the highly expressed genes in mouse lungs. Infection of mice with H37Rv but not H37Rv:Δ3875 induced expression of lung SAA3 mRNA and protein, consistent with the effect of intranasal delivery of ESAT-6. Silencing SAA3 reduced Mtb-induced IL-1ß production by BMDMs. We conclude that SAA3 plays critical role in ESAT-6 dependent IL-1ß production by macrophages in tuberculosis infection.


Assuntos
Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Interleucina-1beta/biossíntese , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Proteína Amiloide A Sérica/imunologia , Animais , Feminino , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína Amiloide A Sérica/genética , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
12.
J Immunol Res ; 2021: 6643808, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33977110

RESUMO

Tissue-resident memory T (TRM) cells are well known to play critical roles in peripheral tissues during virus infection and tumor immunology. Our previous studies indicated that CD69+CD4+ and CD69+CD8+ T cells in tuberculous pleural effusion (TPE) were antigen-specific memory T cells. However, the phenotypical and functional characteristics of CD8+ TRM cells in tuberculosis remain unknown. We found that CD103+CD8+ T cells were the predominant subset of CD103+ lymphocytes in TPE; both CD103 and CD69 expressed on memory CD8+ T cells from TPE were significantly increased compared with those from paired peripheral blood. Phenotypically, CD103+CD69+ and CD103+CD69-CD8+ T cells expressed higher levels of CD45RO than CD103-CD69+CD8+ T cells did; CD103+CD69-CD8+ T cells highly expressed CD27, CD127, and CD62L and some chemokine receptors. We further compared the functional differences among the four distinct CD45RO+CD8+ T subsets identified by CD103 and CD69 expression. In consist with our published results, CD69+CD8+ T cells, but not CD103+CD8+, produced high levels of IFN-γ after treatment with BCG in the presence of BFA. Nevertheless, CD103-CD69+ and CD103+CD69+ memory CD8+ T cells expressed higher levels of Granzyme B, while CD103+CD69- memory CD8+ T cells were characterized as a possibly immunosuppressive subset by highly expressing CTLA-4, CD25, and FoxP3. Furthermore, TGF-ß extremely increased CD103 expression but not CD69 in vitro. Together, CD103+CD8+ T cells form the predominant subset of CD103+ lymphocytes in TPE; CD103 and CD69 expression defines distinct CD8+ TRM-like subsets exhibiting phenotypical and functional heterogeneity. Our findings provide an important theoretical basis to optimize and evaluate new tuberculosis vaccines.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Derrame Pleural/imunologia , Subpopulações de Linfócitos T/imunologia , Tuberculose Pleural/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Idoso , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Feminino , Voluntários Saudáveis , Humanos , Memória Imunológica , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/imunologia , Cavidade Pleural/citologia , Cavidade Pleural/imunologia , Cavidade Pleural/microbiologia , Derrame Pleural/sangue , Derrame Pleural/microbiologia , Derrame Pleural/patologia , Subpopulações de Linfócitos T/metabolismo , Tuberculose Pleural/sangue , Tuberculose Pleural/complicações , Tuberculose Pleural/microbiologia , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/microbiologia , Adulto Jovem
13.
J Immunol Res ; 2021: 6654220, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33977111

RESUMO

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains as a leading infectious cause of death worldwide. The increasing number of multidrug-resistant TB (MDR-TB) cases contributes to the poor control of the TB epidemic. Currently, little is known about the immunological requirements of protective responses against MDR-TB. This is of major relevance to identify immune markers for treatment monitoring and targets for adjuvant immunotherapies. Here, we hypothesized that MDR-TB patients display unique immunophenotypical features and immune cell migration dynamics compared to drug-sensitive TB (DS-TB). Hence, we prospectively conducted an extensive characterization of the immune profile of MDR-TB patients at different time points before and after pharmacological therapy. For this purpose, we focused on the leukocyte expression of chemokine receptors, distribution of different monocyte and lymphocyte subsets, plasma levels of chemotactic factors, and in vitro migration capacity of immune cells. Our comparative cohort consisted of DS-TB patients and healthy volunteer donors (HD). Our results demonstrate some unique features of leukocyte migration dynamics during MDR-TB. These include increased and prolonged circulation of CD3+ monocytes, CCR4+ monocytes, EM CD4+ T cells, EM/CM CD8+ T cells, and CXCR1+CXCR3+ T cells that is sustained even after the administration of anti-TB drugs. We also observed shared characteristics of both MDR-TB and DS-TB that include CCR2+ monocyte depletion in the blood; high plasma levels of MPC-1, CCL-7, and IP-10; and increased responsiveness of leukocytes to chemotactic signals in vitro. Our study contributes to a better understanding of the MDR-TB pathobiology and uncovers immunological readouts of treatment efficacy.


Assuntos
Antituberculosos/farmacologia , Leucócitos Mononucleares/imunologia , Receptores de Quimiocinas/metabolismo , Tuberculose Resistente a Múltiplos Medicamentos/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Antituberculosos/uso terapêutico , Biomarcadores/análise , Biomarcadores/metabolismo , Estudos de Casos e Controles , Movimento Celular/imunologia , Monitoramento de Medicamentos/métodos , Seguimentos , Voluntários Saudáveis , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/isolamento & purificação , Estudos Prospectivos , Receptores de Quimiocinas/análise , Tuberculose Resistente a Múltiplos Medicamentos/sangue , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia
15.
J Immunol Res ; 2021: 5517856, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34007850

RESUMO

The mechanisms underlying the immunopathology of tuberculous meningitis (TBM), the most severe clinical form of extrapulmonary tuberculosis (TB), are not understood. It is currently believed that the spread of Mycobacterium tuberculosis (Mtb) from the lung is an early event that occurs before the establishment of adaptive immunity. Hence, several innate immune mechanisms may participate in the containment of Mtb infection and prevent extrapulmonary disease manifestations. Natural killer (NK) cells participate in defensive processes that distinguish latent TB infection (LTBI) from active pulmonary TB (PTB). However, their role in TBM is unknown. Here, we performed a cross-sectional analysis of circulating NK cellCID="C008" value="s" phenotype in a prospective cohort of TBM patients (n = 10) using flow cytometry. Also, we addressed the responses of memory-like NK cell subpopulations to the contact with Mtb antigens in vitro. Finally, we determined plasma levels of soluble NKG2D receptor ligands in our cohort of TBM patients by enzyme-linked immunosorbent assay (ELISA). Our comparative groups consisted of individuals with LTBI (n = 11) and PTB (n = 27) patients. We found that NK cells from TBM patients showed lower absolute frequencies, higher CD69 expression, and poor expansion of the CD45RO+ memory-like subpopulation upon Mtb exposure in vitro compared to LTBI individuals. In addition, a reduction in the frequency of CD56brightCD16- NK cells characterized TBM patients but not LTBI or PTB subjects. Our study expands on earlier reports about the role of NK cells in TBM showing a reduced frequency of cytokine-producing cells compared to LTBI and PTB.


Assuntos
Células Matadoras Naturais/imunologia , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Meníngea/imunologia , Tuberculose Pulmonar/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Citocinas/metabolismo , Feminino , Humanos , Imunidade Inata , Imunofenotipagem , Células Matadoras Naturais/metabolismo , Tuberculose Latente/sangue , Tuberculose Latente/microbiologia , Masculino , México , Pessoa de Meia-Idade , Estudos Prospectivos , Tuberculose Meníngea/sangue , Tuberculose Meníngea/microbiologia , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/microbiologia , Adulto Jovem
16.
Sci Rep ; 11(1): 10687, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34021178

RESUMO

Tuberculosis (TB) is still a major worldwide health threat and primarily a lung disease. The innate immune response against Mycobacterium tuberculosis (Mtb) is orchestrated by dendritic cells, macrophages, neutrophils, natural killer cells and apparently mast cells (MCs). MCs are located at mucosal sites including the lungs and contribute in host-defence against pathogens, but little is known about their role during Mtb infection. This study investigates the location and characteristics of MCs in TB lesions to assess their contribution to TB pathology. To this purpose, number, location and phenotype of MCs was studied in 11 necropsies of pulmonary TB and 3 necropsies of non-TB infected lungs that were used as controls. MCs were localised at pneumonic areas, in the granuloma periphery and particularly abundant in fibrotic tissue. Furthermore, MCs displayed intracellular Mtb and IL-17A and TGF-ß immunostaining. These findings were validated by analysing, post-mortem lung tissue microarrays from 44 individuals with pulmonary TB and 25 control subjects. In affected lungs, increased numbers of MCs expressing intracellularly both tryptase and chymase were found at fibrotic sites. Altogether, our data suggest that MCs are recruited at the inflammatory site and that actively produce immune mediators such as proteases and TGF-ß that may be contributing to late fibrosis in TB lesions.


Assuntos
Contagem de Leucócitos , Mastócitos/imunologia , Mastócitos/metabolismo , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Antígenos de Bactérias/imunologia , Fibrose , Granuloma do Sistema Respiratório/patologia , Humanos , Imuno-Histoquímica , Triptases/metabolismo
17.
Nat Immunol ; 22(6): 781-793, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34031617

RESUMO

Multimodal T cell profiling can enable more precise characterization of elusive cell states underlying disease. Here, we integrated single-cell RNA and surface protein data from 500,089 memory T cells to define 31 cell states from 259 individuals in a Peruvian tuberculosis (TB) progression cohort. At immune steady state >4 years after infection and disease resolution, we found that, after accounting for significant effects of age, sex, season and genetic ancestry on T cell composition, a polyfunctional type 17 helper T (TH17) cell-like effector state was reduced in abundance and function in individuals who previously progressed from Mycobacterium tuberculosis (M.tb) infection to active TB disease. These cells are capable of responding to M.tb peptides. Deconvoluting this state-uniquely identifiable with multimodal analysis-from public data demonstrated that its depletion may precede and persist beyond active disease. Our study demonstrates the power of integrative multimodal single-cell profiling to define cell states relevant to disease and other traits.


Assuntos
Memória Imunológica , Mycobacterium tuberculosis/imunologia , Células Th17/imunologia , Tuberculose Pulmonar/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Progressão da Doença , Feminino , Seguimentos , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Peru , RNA-Seq , Fatores Sexuais , Análise de Célula Única , Fatores Socioeconômicos , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/microbiologia , Adulto Jovem
18.
Cell Immunol ; 365: 104381, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34049011

RESUMO

MAIT cells are unconventional innate-like T lymphocytes contributing to host immune protection against Mycobacteria tuberculosis (Mtb) infection. CD4- MAIT cells play a major role in immune protection against tuberculosis (TB), however, the role of CD4+ MAIT cells was elusive due to their low abundance. We firstly investigated the frequency and functions of CD4+ MAIT cells in pulmonary tuberculosis (PTB) patients before and after anti-TB treatment. We found that the frequency of Mtb-reactive CD4+ MAIT cells and IFN-γ, granzyme B (GrzB), CD69 expression on them were increased while LAG-3+ cells of them were decreased in PTB patients. After the treatment, the frequency of Mtb-reactive CD4+ MAIT cells and CD69, IFN-γ, GrzB expression on them were decreased while LAG-3 increased. The results indicated the expression profile is distinct between CD4+ MAIT cells and CD4- MAIT cells in PTB patients, the increased IFN-γ and GrzB expression of CD4+ MAIT cells play a role in anti-TB immunity.


Assuntos
Pulmão/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Adolescente , Adulto , Antígenos CD4/metabolismo , Feminino , Granzimas/metabolismo , Humanos , Interferon gama/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Cell Immunol ; 364: 104359, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33865151

RESUMO

Conventional anti-tuberculosis (TB) therapies comprise lengthy antibiotic treatment regimens, exacerbated by multi-drug resistant and extensively drug resistant mycobacterial strains. We assessed the ability of all-trans retinoic acid (ATRA), as repurposed compound serving as host-directed therapy (HDT), to counteract the suppressive effects of myeloid-derived suppressor cells (MDSCs) obtained from active TB cases (untreated or during week one of treatment) on T-cell responsiveness. We show for the first time that MDSCs suppress non-specific T-cell activation and production of interleukin (IL)-2, IL-4, IL-13 and GM-CSF via contact-dependent mechanisms. ATRA treatment decreases MDSC frequency, but fails to mature MDSCs to non-suppressive, terminally differentiated myeloid cells and does not restore T-cell function or cytokine production in the presence of MDSCs. The impact of ATRA treatment on improved immunity, using the concentration tested here, is likely to be minimal, but further identification and development of MDSC-targeting TB host-directed therapies are warranted.


Assuntos
Imunossupressores/farmacologia , Mycobacterium tuberculosis/fisiologia , Células Supressoras Mieloides/imunologia , Linfócitos T/imunologia , Tretinoína/farmacologia , Tuberculose Pulmonar/imunologia , Adulto , Células Cultivadas , Citocinas/metabolismo , Reposicionamento de Medicamentos , Feminino , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Linfócitos T/efeitos dos fármacos , Tuberculose Pulmonar/terapia
20.
Clin Immunol ; 227: 108724, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33845192

RESUMO

Sarcoidosis and tuberculosis have many clinical and laboratory similarities, which allowed researchers to assume the presence of common pathogenetic mechanisms in the development of both diseases. Recently, much attention has been paid to investigate the autoimmune origins in these pathologies. The aim of this study is to find out the characteristics of the autoinflammatory immune response in sarcoidosis and tuberculosis. In patients with sarcoidosis (n = 93), tuberculosis (n = 28), and in healthy donors (n = 40), the serum anti-MCV concentration was measured by ELISA, and B cell subpopulations were analyzed by flow cytometry. Based on the results obtained, the formula ([B-naïve%]\[B-memory%]) * ([B-CD38%] + [B-CD5%]) / [anti-MCV] was described. The increase in the calculated index by more than 5 units with a sensitivity of 80.00% and a specificity of 93.10% (AUC = 0.926) suggest the presence of the autoimmune component, which is more typical for sarcoidosis, rather than tuberculosis patients and may serve as a diagnostic criterion.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Autoimunidade/imunologia , Linfócitos B/imunologia , Inflamação/imunologia , Sarcoidose Pulmonar/imunologia , Tuberculose Pulmonar/imunologia , Vimentina/imunologia , Estudos de Casos e Controles , Citrulinação , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Memória Imunológica , Imunofenotipagem , Masculino , Estudos Prospectivos
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