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2.
PLoS One ; 15(9): e0239289, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32936814

RESUMO

Mycobacterium tuberculosis (Mtb) is the causative agent for tuberculosis, the most extended infectious disease around the world. When Mtb enters inside the pulmonary alveolus it is rapidly phagocytosed by the alveolar macrophage. Although this controls the majority of inhaled microorganisms, in this case, Mtb survives inside the macrophage and multiplies. A posterior chemokine and cytokine cascade generated by the irruption of monocytes, neutrophils and posteriorly, by T-cells, does not necessarily stop the growth of the granuloma. Interestingly, the encapsulation process built by fibroblasts is able to surround the lesion and stop its growing. The success of this last process determines if the host enters in an asymptomatic latent state or continues into a life-threatening and infective active tuberculosis disease (TB). Understanding such dichotomic process is challenging, and computational modeling can bring new ideas. Thus, we have modeled the different stages of the infection, first in a single alveolus (a sac with a radius of 0.15 millimeters) and, second, inside a secondary lobule (a compartment of the lungs of around 3 cm3). We have employed stochastic reaction-diffusion equations to model the interactions among the cells and the diffusive transport to neighboring alveolus. The whole set of equations have successfully described the encapsulation process and determine that the size of the lesions depends on its position on the secondary lobule. We conclude that size and shape of the secondary lobule are the relevant variables to control the lesions, and, therefore, to avoid the evolution towards TB development. As lesions appear near to interlobular connective tissue they are easily controlled and their growth is drastically stopped, in this sense secondary lobules with a more flattened shape could control better the lesion.


Assuntos
Simulação por Computador , Granuloma/patologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose/imunologia , Quimiocinas/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Difusão , Granuloma/imunologia , Granuloma/microbiologia , Humanos , Tuberculose Latente/imunologia , Tuberculose Latente/microbiologia , Tuberculose Latente/patologia , Pulmão/imunologia , Pulmão/metabolismo , Macrófagos Alveolares/enzimologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Mycobacterium tuberculosis/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Fagocitose/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Tuberculose/microbiologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
3.
PLoS One ; 15(9): e0239668, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32970762

RESUMO

We developed an approach for substantial attenuation of Mycobacterium tuberculosis by prolonged culturing under gradually acidifying conditions. Bacteria subjected to acidification lost the capacity to form colonies on solid media, but readily resuscitated their growth in the murine host, providing a useful model to study in vivo development of infection mimicking latent and reactivation tuberculosis (TB) in humans. Here we characterize biomarkers of lung pathology and immune responses triggered by such attenuated bacteria in genetically TB-susceptible and resistant mice. In susceptible I/St mice, CFU counts in lungs and spleens were ~1.5-log higher than in resistant B6 mice, accompanied by diffuse pneumonia and excessive lung infiltration with highly activated CD44+CD62L- T-lymphocytes resulting in death between months 7-9 post challenge. B6 mice were characterized by development of local inflammatory foci, higher production of pro-inflammatory IL-6 and IL-11 cytokines and a more balanced T-cell activation in their lungs. CFU counts remained stable in B6 mice during the whole 18-mo observation period, and all mice survived. Thus, we established a mouse model of fatal reactivation TB vs. indefinite mycobacterial possession after identical challenge and characterized the features of immune responses in the lung tissue underlining these polar phenotypes.


Assuntos
Predisposição Genética para Doença , Interleucinas/metabolismo , Pulmão/imunologia , Ativação Linfocitária , Tuberculose Pulmonar/imunologia , Tuberculose Esplênica/imunologia , Animais , Carga Bacteriana , Células Cultivadas , Feminino , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Interleucinas/genética , Selectina L/genética , Selectina L/metabolismo , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/patogenicidade , Baço/imunologia , Baço/microbiologia , Linfócitos T/imunologia , Tuberculose Pulmonar/genética , Tuberculose Esplênica/genética
4.
Vaccine ; 38(45): 7146-7155, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-32943265

RESUMO

BACKGROUND: COVID-19 pandemic has affected routine immunization globally. Impact will likely be higher in low and middle-income countries with limited healthcare resources and fragile health systems. We quantified the impact, spatial heterogeneity, and determinants for childhood immunizations of 48 million population affected in the Sindh province of Pakistan. METHODS: We extracted individual immunization records from real-time provincial Electronic Immunization Registry from September 23, 2019, to July 11, 2020. Comparing baseline (6 months preceding the lockdown) and the COVID-19 lockdown period, we analyzed the impact on daily immunization coverage rate for each antigen by geographical area. We used multivariable logistic regression to explore the predictors associated with immunizations during the lockdown. RESULTS: There was a 52.5% decline in the daily average total number of vaccinations administered during lockdown compared to baseline. The highest decline was seen for Bacille Cal-mette Guérin (BCG) (40.6% (958/2360) immunization at fixed sites. Around 8438 children/day were missing immunization during the lockdown. Enrollments declined furthest in rural districts, urban sub-districts with large slums, and polio-endemic super high-risk sub-districts. Pentavalent-3 (penta-3) immunization rates were higher in infants born in hospitals (RR: 1.09; 95% CI: 1.04-1.15) and those with mothers having higher education (RR: 1.19-1.50; 95% CI: 1.13-1.65). Likelihood of penta-3 immunization was reduced by 5% for each week of delayed enrollment into the immunization program. CONCLUSION: One out of every two children in Sindh province has missed their routine vaccinations during the provincial COVID-19 lockdown. The pool of un-immunized children is expanding during lockdown, leaving them susceptible to vaccine-preventable diseases. There is a need for tailored interventions to promote immunization visits and safe service delivery. Higher maternal education, facility-based births, and early enrollment into the immunization program continue to show a positive association with immunization uptake, even during a challenging lockdown.


Assuntos
Infecções por Coronavirus/psicologia , Sarampo/prevenção & controle , Pandemias , Pneumonia Viral/psicologia , Quarentena , Infecções por Rotavirus/prevenção & controle , Tuberculose Pulmonar/prevenção & controle , Vacinação/estatística & dados numéricos , Vacina BCG/administração & dosagem , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Processamento Eletrônico de Dados , Feminino , Humanos , Programas de Imunização/estatística & dados numéricos , Lactente , Recém-Nascido , Masculino , Sarampo/epidemiologia , Sarampo/imunologia , Vacina contra Sarampo/administração & dosagem , Paquistão/epidemiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Sistema de Registros , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , População Rural , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/imunologia , População Urbana , Vacinação/psicologia , Cobertura Vacinal/estatística & dados numéricos , Vacinas Atenuadas/administração & dosagem
5.
Am J Trop Med Hyg ; 103(4): 1597-1599, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32815513

RESUMO

COVID-19, designated as SARS-CoV-2, has caused millions of infections worldwide, including in patients with concomitant infections. Here, we report two unusual cases of patients with triple infections of SARS-CoV-2, Mycobacterium tuberculosis, and HIV. Both cases were confirmed through microbiological and immunological studies. The acute respiratory phase in both patients was treated with supplemental oxygen. Antituberculosis and antiretroviral therapies were started simultaneously. In 2 weeks, both patients demonstrated clinical improvement and recovery from COVID-19. Our findings suggest that even in cases of triple infection, clinical management together with respiratory therapy contributes to patient survival.


Assuntos
Antituberculosos/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/terapia , Infecções por HIV/terapia , Heparina/uso terapêutico , Hidroxicloroquina/uso terapêutico , Pneumonia Viral/terapia , Tuberculose Pulmonar/terapia , Adulto , Betacoronavirus/patogenicidade , Coinfecção , Convalescença , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/microbiologia , Infecções por Coronavirus/virologia , HIV/patogenicidade , Infecções por HIV/imunologia , Infecções por HIV/microbiologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/patogenicidade , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/microbiologia , Pneumonia Viral/virologia , Respiração com Pressão Positiva/métodos , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/virologia
6.
Am J Trop Med Hyg ; 103(4): 1593-1596, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32815515

RESUMO

Coinfection of SARS-CoV-2/Mycobacterium tuberculosis (MTB) in patients with HIV/AIDS has not been previously reported. Here, we present two cases of coinfection of SARS-CoV-2 and MTB in patients with HIV. The first case is a 39-year-old patient who was admitted with a 7-day history of fever, myalgia, headache, and cough. The second patient is a 43-year-old man who had a 1-month history of cough with hemoptoic sputum, evolving to mild respiratory distress in the last 7 days. Both patients already had pulmonary tuberculosis and subsequently developed SARS-CoV-2 infection during the 2020 pandemic. Nonadherence to antiretroviral treatment may have been a factor in the clinical worsening of the patients.


Assuntos
Infecções por Coronavirus/microbiologia , Tosse/microbiologia , Infecções por HIV/microbiologia , Cooperação do Paciente/psicologia , Pneumonia Viral/microbiologia , Síndrome do Desconforto Respiratório do Adulto/microbiologia , Tuberculose Pulmonar/microbiologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Betacoronavirus/patogenicidade , Coinfecção , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Tosse/tratamento farmacológico , Tosse/imunologia , Tosse/virologia , HIV/patogenicidade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Mycobacterium tuberculosis/patogenicidade , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/virologia , Tomografia Computadorizada por Raios X , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/virologia
7.
PLoS One ; 15(8): e0237062, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760105

RESUMO

Nutritional status contributes to the regulation of immune responses against pathogens, and malnutrition has been considered as a risk factor for tuberculosis (TB). Mycobacterium tuberculosis (Mtb), the causative agent of TB, can modulate host lipid metabolism and induce lipid accumulation in macrophages, where the bacilli adopt a dormant phenotype. In addition, serum lipid components play dual roles in the regulation of and protection from Mtb infection. We analyzed the relationship between nutritional status and the humoral immune response in TB patients. We found that serum HDL levels are positively correlated with the serum IgA specific for Mtb antigens. Analysis of the relationship between serum nutritional parameters and clinical parameters in TB patients showed that serum albumin and CRP levels were negatively correlated before treatment. We also observed reduced serum LDL levels in TB patients following treatment. These findings may provide insight into the role of serum lipids in host immune responses against Mtb infection. Furthermore, improving the nutritional status may enhance vaccination efficacy.


Assuntos
Imunidade Humoral , Mycobacterium tuberculosis/imunologia , Estado Nutricional/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Idoso , Anticorpos Antibacterianos/sangue , Proteína C-Reativa/metabolismo , Progressão da Doença , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Albumina Sérica Humana/metabolismo , Vacinas contra a Tuberculose/imunologia , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/tratamento farmacológico
8.
Int J Infect Dis ; 98: 261-267, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32623087

RESUMO

OBJECTIVE: The influence of tuberculosis (TB)-immune reconstitution inflammatory syndrome (IRIS) on TB treatment outcomes and its risk factors were investigated among people with human immunodeficiency virus (HIV) and co-infected with TB. METHODS: Newly diagnosed, culture-confirmed, pulmonary TB patients with HIV and enrolled in a clinical trial (NCT00933790) were retrospectively analysed for IRIS occurrence. Risk factors and TB outcomes (up to 18 months after initiation of anti-TB treatment [ATT]) were compared between people who experienced IRIS (IRIS group) and those who did not (non-IRIS group). RESULTS: TB-IRIS occurred in 82 of 292 (28%) participants. Significant baseline risk factors predisposing to TB-IRIS occurrence in univariate analysis were: lower CD4+ T-cell count, CD4/CD8 ratio, haemoglobin levels, presence of extra-pulmonary TB focus, and higher HIV viral load; the last two retained significance in the multivariate analysis. After 2 months of ATT commencement, sputum smear conversion was documented in 45 of 80 (56.2%) vs. 124 of 194 (63.9%) (p=0.23), culture conversion was in 75 of 80 (93.7%) vs. 178 of 194 (91.7%) (p=0.57) and the median decline in viral load (log10copies/mm3) was 2.7 in the IRIS vs. 1.1 in the non-IRIS groups (p<0.0001), respectively. An unfavourable response to TB therapy was detected in 17 of 82 (20.7%) and 28 of 210 (13.3%) in the IRIS and non-IRIS groups, respectively (p=0.14). CONCLUSIONS: TB-IRIS frequently occurred in people with advanced HIV infection and in those who presented with extra-pulmonary TB lesions, without influencing subsequent TB treatment outcomes.


Assuntos
Infecções por HIV/complicações , Síndrome Inflamatória da Reconstituição Imune/etiologia , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Antituberculosos/administração & dosagem , Feminino , Humanos , Síndrome Inflamatória da Reconstituição Imune/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Tuberculose Pulmonar/etiologia , Tuberculose Pulmonar/imunologia , Carga Viral
9.
Am J Respir Crit Care Med ; 202(5): 730-744, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32421376

RESUMO

Rationale: Platelets are generated in the capillaries of the lung, control hemostasis, and display immunological functions. Tuberculosis primarily affects the lung, and patients show platelet changes and hemoptysis. A role of platelets in immunopathology of pulmonary tuberculosis requires careful assessment.Objectives: To identify the dynamics and interaction partners of platelets in the respiratory tissue and establish their impact on the outcome of pulmonary tuberculosis.Methods: Investigations were primarily performed in murine models of primary progressive pulmonary tuberculosis, by analysis of mouse strains with variable susceptibility to Mycobacterium tuberculosis infection using platelet depletion and delivery of antiplatelet drugs.Measurements and Main Results: Platelets were present at the site of infection and formed aggregates with different myeloid subsets during experimental tuberculosis. Such aggregates were also detected in patients with tuberculosis. Platelets were detrimental during the early phase of infection, and this effect was uncoupled from their canonical activation. Platelets left lung cell dynamics and patterns of antimycobacterial T-cell responses unchanged but hampered antimicrobial defense by restricting production of reactive oxygen species in lung-residing myeloid cells.Conclusions: Platelets are detrimental in primary progressive pulmonary tuberculosis, orchestrate lung immunity by modulating innate immune responsiveness, and may be amenable to new interventions for this deadly disease.


Assuntos
Plaquetas/metabolismo , Mycobacterium tuberculosis/imunologia , Fagócitos/patologia , Explosão Respiratória/fisiologia , Linfócitos T/imunologia , Tuberculose Pulmonar/metabolismo , Animais , Modelos Animais de Doenças , Progressão da Doença , Feminino , Citometria de Fluxo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fagócitos/metabolismo , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia
10.
PLoS Pathog ; 16(5): e1008585, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32433713

RESUMO

Mucosal-associated invariant T (MAIT) cells can recognize and respond to some bacterially infected cells. Several in vitro and in vivo models of Mycobacterium tuberculosis (Mtb) infection suggest that MAIT cells can contribute to control of Mtb, but these studies are often cross-sectional and use peripheral blood cells. Whether MAIT cells are recruited to Mtb-affected granulomas and lymph nodes (LNs) during early Mtb infection and what purpose they might serve there is less well understood. Furthermore, whether HIV/SIV infection impairs MAIT cell frequency or function at the sites of Mtb replication has not been determined. Using Mauritian cynomolgus macaques (MCM), we phenotyped MAIT cells in the peripheral blood and bronchoalveolar lavage (BAL) before and during infection with SIVmac239. To test the hypothesis that SIV co-infection impairs MAIT cell frequency and function within granulomas, SIV+ and -naïve MCM were infected with a low dose of Mtb Erdman, and necropsied at 6 weeks post Mtb-challenge. MAIT cell frequency and function were examined within the peripheral blood, BAL, and Mtb-affected lymph nodes (LN) and granulomas. MAIT cells did not express markers indicative of T cell activation in response to Mtb in vivo within granulomas in animals infected with Mtb alone. SIV and Mtb co-infection led to increased expression of the activation/exhaustion markers PD-1 and TIGIT, and decreased ability to secrete TNFα when compared to SIV-naïve MCM. Our study provides evidence that SIV infection does not prohibit the recruitment of MAIT cells to sites of Mtb infection, but does functionally impair those MAIT cells. Their impaired function could have impacts, either direct or indirect, on the long-term containment of TB disease.


Assuntos
Coinfecção/imunologia , Células T Invariáveis Associadas à Mucosa/imunologia , Mycobacterium tuberculosis/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Tuberculose Pulmonar/imunologia , Animais , Coinfecção/patologia , Granuloma/imunologia , Granuloma/patologia , Linfonodos/imunologia , Linfonodos/patologia , Macaca fascicularis , Células T Invariáveis Associadas à Mucosa/patologia , Receptor de Morte Celular Programada 1/imunologia , Receptores Imunológicos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Tuberculose Pulmonar/patologia
11.
PLoS Pathog ; 16(5): e1008356, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32437421

RESUMO

Tuberculosis (TB) is one of the deadliest diseases, claiming ~2 million deaths annually worldwide. The majority of people in TB endemic regions are vaccinated with Bacillus Calmette Guerin (BCG), which is the only usable vaccine available. BCG is efficacious against meningeal and disseminated TB in children, but protective responses are relatively short-lived and fail to protect against adult pulmonary TB. The longevity of vaccine efficacy critically depends on the magnitude of long-lasting central memory T (TCM) cells, a major source of which is stem cell-like memory T (TSM) cells. These TSM cells exhibit enhanced self-renewal capacity as well as to rapidly respond to antigen and generate protective poly-functional T cells producing IFN-γ, TNF-α, IL-2 and IL-17. It is now evident that T helper Th 1 and Th17 cells are essential for host protection against TB. Recent reports have indicated that Th17 cells preserve the molecular signature for TSM cells, which eventually differentiate into IFN-γ-producing effector cells. BCG is ineffective in inducing Th17 cell responses, which might explain its inadequate vaccine efficacy. Here, we show that revaccination with BCG along with clofazimine treatment promotes TSM differentiation, which continuously restores TCM and T effector memory (TEM) cells and drastically increases vaccine efficacy in BCG-primed animals. Analyses of these TSM cells revealed that they are predominantly precursors to host protective Th1 and Th17 cells. Taken together, these findings revealed that clofazimine treatment at the time of BCG revaccination provides superior host protection against TB by increasing long-lasting TSM cells.


Assuntos
Vacina BCG/imunologia , Vacina BCG/metabolismo , Clofazimina/farmacologia , Memória Imunológica/imunologia , Animais , Vacina BCG/farmacologia , Clofazimina/metabolismo , Quimioterapia Combinada/métodos , Feminino , Imunização Secundária/métodos , Imunogenicidade da Vacina/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Células-Tronco/imunologia , Células Th1/imunologia , Células Th17/imunologia , Tuberculose/imunologia , Tuberculose Pulmonar/imunologia
12.
Medicine (Baltimore) ; 99(16): e19567, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32311924

RESUMO

OBJECTIVE: To evaluate the differences between traditional Chinese medicine combined with western medicine and western medicine alone for the treatment of secondary tuberculosis and its impact on the evaluation of clinical efficacy and safety of patients in randomized controlled trials. METHODS: A literature search of all major academic databases was conducted (PubMed, CNKI, Wanfang, VIP). Meta-analysis was conducted using RevMan 5.3 and Stata 12.0 software for those studies that satisfied the inclusion criteria. Ethical approval was not necessary because no people or animals were selected as subjects in this meta-analysis. RESULTS: Twenty-three randomized controlled trials were included in this meta-analysis. The following indicators in the treatment group (traditional Chinese medicine decoction combined with western medicine chemotherapy) improved in comparison with those in the control group:focus absorption rate (RR:1.18; 95% CI: 1.15-1.22);sputum smear negative rate (RR: 1.17; 95% CI: 1.09-1.27);comprehensive clinical effective rate (RR: 1.18; 95% CI: 1.14-1.22);cavity closure rate (RR: 1.37; 95% CI: 1.12-1.67).The difference of Immune function indicator likes CD4+ level (SMD: 0.76; 95% CI: -0.25 to 1.76) between the treatment group and the control group was not significant. In addition, safety evaluation indicators like the decrease rate of white blood cell (WBC) and platelets (PLT) and the elevation rate of alanine aminotransferase (ALT) and uric acid (UA) in the treatment group were reduced compared with those in the control group (P < .05). CONCLUSIONS: The curative effect of combining traditional Chinese and western medicine for the treatment of secondary tuberculosis is better than that of western medicine alone and is conducive to reducing the incidence of adverse reactions.


Assuntos
Antituberculosos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Alanina Transaminase/sangue , Antituberculosos/efeitos adversos , Contagem de Linfócito CD4 , Quimioterapia Combinada , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Fitoterapia , Contagem de Plaquetas , Ensaios Clínicos Controlados Aleatórios como Assunto , Escarro/microbiologia , Resultado do Tratamento , Tuberculose Pulmonar/diagnóstico por imagem , Tuberculose Pulmonar/imunologia , Ácido Úrico/sangue
13.
Nat Commun ; 11(1): 1949, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327653

RESUMO

Genetic diversity of Mycobacterium tuberculosis affects immune responses and clinical outcomes of tuberculosis (TB). However, how bacterial diversity orchestrates immune responses to direct distinct TB severities is unknown. Here we study 681 patients with pulmonary TB and show that M. tuberculosis isolates from cases with mild disease consistently induce robust cytokine responses in macrophages across multiple donors. By contrast, bacteria from patients with severe TB do not do so. Secretion of IL-1ß is a good surrogate of the differences observed, and thus to classify strains as probable drivers of different TB severities. Furthermore, we demonstrate that M. tuberculosis isolates that induce low levels of IL-1ß production can evade macrophage cytosolic surveillance systems, including cGAS and the inflammasome. Isolates exhibiting this evasion strategy carry candidate mutations, generating sigA recognition boxes or affecting components of the ESX-1 secretion system. Therefore, we provide evidence that M. tuberculosis strains manipulate host-pathogen interactions to drive variable TB severities.


Assuntos
Citosol/imunologia , Interleucina-1beta/metabolismo , Mycobacterium tuberculosis/patogenicidade , Transdução de Sinais/imunologia , Tuberculose Pulmonar/imunologia , Animais , Proteínas de Bactérias/genética , Células Cultivadas , Citocinas/metabolismo , Feminino , Genoma Bacteriano/genética , Humanos , Evasão da Resposta Imune , Imunomodulação , Inflamassomos/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Mutação , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Filogenia , Polimorfismo de Nucleotídeo Único , Tuberculose Pulmonar/microbiologia , Virulência/genética
14.
Int J Infect Dis ; 96: 240-243, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32339714

RESUMO

OBJECTIVES: Between-person variability in T-cell-specific interferon-gamma release assay (IGRA) responses and discordance between IGRA test formats are poorly understood. METHODS: We evaluated the IFN-γ responses (QuantiFERON-TB Gold-In-Tube [QFT-GIT] and TSPOT-TB) stratified according to the Mycobacterium tuberculosis spoligotype of the culture isolate obtained from the same patients with confirmed active tuberculosis (n = 91). We further analysed differences within the RD-1-encoding ESX-1 region between the different strain types using whole genome sequencing. RESULTS: In HIV-uninfected patients, TSPOT.TB and QFT-GIT IFN-γ responses were 5-fold (p < 0.01) and 2-fold higher (p < 0.05) for those infected with family 33 compared to the LAM strain (additionally, TSPOT.TB responses were 5.6-fold [p < 0.05] and 2.6-fold higher [p < 0.05] for the patients infected with the family 33 versus the X strain and Beijing versus the LAM strain, respectively). Multivariate analysis revealed that strain type (determined by spoligotyping) was independently associated with the magnitude of the IGRA response (varied by IGRA test type) and this is likely explained by variability in the ESX-1 region of Mycobacteriumtuberculosis (determined by next-generation sequencing). CONCLUSIONS: These data have implications for the understanding of between-person heterogeneity in IGRA responses, Mycobateriumtuberculosis-specific host immunity, and the discordance between different IGRA test formats.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Interferon gama/metabolismo , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Pequim , Feminino , Genótipo , Humanos , Testes de Liberação de Interferon-gama , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Linfócitos T/imunologia
15.
Sci Rep ; 10(1): 5142, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32198367

RESUMO

Tuberculosis prevalence is significantly higher among men than women. We have previously revealed an increased susceptibility of male C57BL/6 mice towards Mycobacterium tuberculosis (Mtb) H37Rv. In the current study, we confirm the male bias for infection with the Beijing strain HN878. Males succumbed to HN878 infection significantly earlier than females. In both models, premature death of males was associated with smaller B cell follicles in the lungs. Analysis of homeostatic chemokines and their receptors revealed differences between H37Rv and HN878 infected animals, indicating different immune requirements for follicle formation in both models. However, expression of IL-23, which is involved in long-term containment of Mtb and lymphoid follicle formation, was reduced in male compared to female lungs in both models. Our study reveals sex differences in the formation of B cell follicles in the Mtb infected lung and we propose that impaired follicle formation is responsible for accelerated disease progression in males.


Assuntos
Linfócitos B/imunologia , Suscetibilidade a Doenças/imunologia , Mycobacterium tuberculosis/imunologia , Estruturas Linfoides Terciárias/imunologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia , Animais , Feminino , Subunidade p19 da Interleucina-23/metabolismo , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores Sexuais , Tuberculose Pulmonar/mortalidade
16.
Eur J Immunol ; 50(5): 736-747, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32113187

RESUMO

Prolonged therapy, drug toxicity, noncompliance, immune suppression, and alarming emergence of drug resistance necessitate the search for therapeutic vaccine strategies for tuberculosis (TB). Such strategies ought to elicit not only IFN-γ, but polyfunctional response including TNF-α, which is essential for protective granuloma formation. Here, we investigated the impact of PD-1 inhibition in facilitating protective polyfunctional T cells (PFTs), bacillary clearance, and disease resolution. We have observed PD-1 inhibition preferentially rescued the suppressed PFTs in active tuberculosis patients. In addition, polyfunctional cytokine milieu favored apoptosis of infected MDMs over necrosis with markedly reduced bacillary growth (≪CFU) in our in vitro monocyte-derived macrophages (MDMs) infection model. Furthermore, the animal study revealed a significant decline in the bacterial burden in the lungs and spleen of infected mice after in vivo administration of α-PD-1 along with antitubercular treatment. Our findings suggest that rescuing polyfunctional immune response by PD-1 inhibition works synergistically with antituberculosis chemotherapy to confer improved control over bacillary growth and dissemination. In summary, our data strongly indicate the therapeutic potential of α-PD-1 as adjunct immunotherapy that can rejuvenate suppressed host immunity and enhance the efficacy of candidate therapeutic vaccine(s).


Assuntos
Anticorpos/farmacologia , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Tuberculose Pulmonar/tratamento farmacológico , Adolescente , Adulto , Animais , Carga Bacteriana/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Terapia Combinada/métodos , Feminino , Humanos , Interferon gama/genética , Interferon gama/imunologia , Isoniazida/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/microbiologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Cultura Primária de Células , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Rifampina/farmacologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/microbiologia , Resultado do Tratamento , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
18.
Sci Adv ; 6(10): eaaz1767, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32181361

RESUMO

Tuberculosis (TB) is the deadliest infectious disease worldwide. Bacille-Calmette-Guérin (BCG), the only licensed TB vaccine, affords variable protection against TB but remains the gold standard. BCG improvement is focused around three strategies: recombinant BCG strains, heterologous routes of administration, and booster vaccination. It is currently unknown whether combining these strategies is beneficial. The preclinical evaluation for new TB vaccines is heavily skewed toward immunogenicity and efficacy; however, safety and efficacy are the dominant considerations in human use. To facilitate stage gating of TB vaccines, we developed a simple empirical model to systematically rank vaccination strategies by integrating multiple measurements of safety, immunogenicity, and efficacy. We assessed 24 vaccination regimens, composed of three BCG strains and eight combinations of delivery. The model presented here highlights that mucosal booster vaccination may cause adverse outcomes and provides a much needed strategy to evaluate and rank data obtained from TB vaccine studies using different routes, strains, or animal models.


Assuntos
Vacina BCG/administração & dosagem , Imunização Secundária/métodos , Imunogenicidade da Vacina , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Pulmonar/prevenção & controle , Vacinação/métodos , Animais , Feminino , Humanos , Esquemas de Imunização , Injeções Espinhais , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Segurança do Paciente , Projetos de Pesquisa , Resultado do Tratamento , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Vacinas Sintéticas
19.
Mol Immunol ; 120: 187-195, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32179338

RESUMO

BACKGROUND: To facilitate better discrimination between patients with active tuberculosis (TB) and latent TB infection (LTBI), whole blood transcriptomic studies have been performed to identify novel candidate host biomarkers. SERPING1, which encodes C1-inhibitor (C1-INH), the natural inhibitor of the C1-complex has emerged as candidate biomarker. Here we collated and analysed SERPING1 expression data and subsequently determined C1-INH protein levels in four cohorts of patients with TB. METHODS: SERPING1 expression data were extracted from online deposited datasets. C1-INH protein levels were determined by ELISA in sera from individuals with active TB, LTBI as well as other disease controls in geographically diverse cohorts. FINDINGS: SERPING1 expression was increased in patients with active TB compared to healthy controls (8/11 cohorts), LTBI (13/14 cohorts) and patients with other (non-TB) lung-diseases (7/7 cohorts). Serum levels of C1-INH were significantly increased in The Gambia and Italy in patients with active TB relative to the endemic controls but not in South Africa or Korea. In the largest cohort (n = 50), with samples collected longitudinally, normalization of C1-INH levels following successful TB treatment was observed. This cohort, also showed the most abundant increase in C1-INH, and a positive correlation between C1q and C1-INH levels. Combined presence of increased levels of both C1q and C1-INH had high specificity for active TB (96 %) but only very modest sensitivity 38 % compared to the endemic controls. INTERPRETATION: SERPING1 transcript expression is increased in TB patients, while serum protein levels of C1-INH were increased in half of the cohorts analysed.


Assuntos
Proteína Inibidora do Complemento C1/biossíntese , Proteína Inibidora do Complemento C1/genética , Tuberculose Latente/genética , Tuberculose Latente/imunologia , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos de Coortes , Proteína Inibidora do Complemento C1/metabolismo , Complemento C1q/metabolismo , Feminino , Expressão Gênica , Humanos , Tuberculose Latente/sangue , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Tuberculose Pulmonar/sangue , Adulto Jovem
20.
PLoS One ; 15(3): e0230376, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32182274

RESUMO

INTRODUCTION: Household contacts of patients with active pulmonary tuberculosis (TB) often have latent TB infection, and are at risk of progression to disease. We set out to investigate whether index TB case HIV status was linked to a higher probability of latent TB infection among household contacts. MATERIALS AND METHODS: Data were collected prospectively from participants in the intervention arm of a household cluster-randomised trial in two South Africa provinces (Mangaung, Free State, and Capricorn, Limpopo). In intervention group households, TB contacts underwent HIV testing and tuberculin skin testing (TST). TST induration was estimated at two cut-offs (≥5mm, ≥10mm). Multilevel Bayesian regression models estimated posterior distributions of the percentage of household contacts with TST induration ≥5mm and ≥10mm by age group, and compared the odds of latent TB infection by key risk factors including HIV status index case age and study province. RESULTS: A total of 2,985 household contacts of 924 index cases were assessed, with most 2,725 (91.3%) undergoing TST. HIV prevalence in household contacts was 14% and 10% in Mangaung and Capricorn respectively. Overall, 16.8% (458/2,725) had TST induration of ≥5mm and 13.1% (359/2,725) ≥10mm. In Mangaung, children aged 0-4 years had a high TST positivity prevalence compared to their peers in Capricorn (22.0% vs. 7.6%, and 20.5% vs. 2.3%, using TST thresholds of ≥5mm and ≥10mm respectively). Compared to contacts from Capricorn, household contacts living in Mangaung were more likely to have TST induration ≥5mm (odds ratio [OR]: 3.08, 95% credibility interval [CI]: 2.13-4.58) and ≥10mm (OR: 4.52, 95% CI: 3.03-6.97). There was a 90% and 92% posterior probability that the odds of TST induration ≥5mm (OR: 0.79, 95% CI: 0.56-1.14) and ≥10mm (OR: 0.77, 95% CI: 0.53-1.10) respectively were lower in household contacts of HIV-positive compared to HIV-negative index cases. CONCLUSIONS: High TST induration positivity, especially among young children and people living in Mangaung indicates considerable TB transmission despite high antiretroviral therapy coverage. Household contact of HIV-positive index TB cases were less likely to have evidence of latent TB infection than contacts of HIV-negative index cases.


Assuntos
Busca de Comunicante/estatística & dados numéricos , Infecções por HIV/epidemiologia , Tuberculose Latente/epidemiologia , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Pulmonar/transmissão , Adulto , Características da Família , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Tuberculose Latente/diagnóstico , Tuberculose Latente/imunologia , Tuberculose Latente/microbiologia , Masculino , Mycobacterium tuberculosis/imunologia , Prevalência , Fatores de Risco , África do Sul/epidemiologia , Teste Tuberculínico , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia
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