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1.
FASEB J ; 35(9): e21777, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403519

RESUMO

Mycobacterium bovis is the causative agent of bovine tuberculosis and also responsible for serious threat to public health. Koumiss is a fermented mare's milk product, used as traditional drink. Here, we explored the effect of koumiss on gut microbiota and the host immune response against M bovis infection. Therefore, mice were treated with koumiss and fresh mare milk for 14 days before M bovis infection and continue for 5 weeks after infection. The results showed a clear change in the intestinal flora of mice treated with koumiss, and the lungs of mice treated with koumiss showed severe edema, inflammatory infiltration, and pulmonary nodules in M bovis-infected mice. Notably, we found that the content of short-chain fatty acids was significantly lower in the koumiss-treated group compared with the control group. However, the expression of endoplasmic reticulum stress and apoptosis-related proteins in the lungs of koumiss-treated mice were significantly decreased. Collectively, these findings suggest that koumiss treatment disturb the intestinal flora of, which is associated with disease severity and the possible mechanism that induces lungs pathology. Our current findings can be exploited further to establish the "gut-lung" axis which might be a novel strategy for the control of tuberculosis.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Kumis/efeitos adversos , Mycobacterium bovis/efeitos dos fármacos , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Ácidos Graxos/análise , Fezes/química , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/imunologia , Cavalos , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium bovis/imunologia , Tuberculose Pulmonar/dietoterapia , Tuberculose Pulmonar/metabolismo
2.
Methods Mol Biol ; 2314: 365-383, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34235663

RESUMO

The utility of fluorescent proteins in bacterial research has long been appreciated, with extensive use in the Mycobacterium tuberculosis field. In more recent years, a new generation of fluorescent tools has been developed for use in M. tuberculosis research. These new fluorescent reporters exploit the immense genetic and transcriptional knowledge now available, and enable the use of the bacteria as direct reporters of the local environment during infection, as well as provide insight into bacterial replication status in situ. Here we describe methods for the construction of such fluorescent reporter M. tuberculosis strains, and their use in combination with confocal microscopy and flow cytometry approaches for single bacterium-level analyses of M. tuberculosis physiology and M. tuberculosis-host interactions.


Assuntos
Proteínas Luminescentes/metabolismo , Pulmão/microbiologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Tuberculose Pulmonar/microbiologia , Animais , Citometria de Fluxo , Interações Hospedeiro-Patógeno , Proteínas Luminescentes/genética , Pulmão/metabolismo , Pulmão/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/metabolismo , Tuberculose Pulmonar/patologia
3.
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
4.
Front Immunol ; 12: 623941, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777003

RESUMO

Host-directed therapies (HDTs) enhance the host response to tuberculosis (TB) infection to reduce disease severity. For instance, the manipulation of lipid mediator production diminishes the hyperactive immune response which is a known pathological feature of TB that generates lung tissue damage. Non-steroidal anti-inflammatory drugs (NSAIDs) and omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) are examples of such HDTs. In this mini-review, we recapitulate the literature available on the effects of NSAIDs and n-3 LCPUFA in TB as well as the immunological pathways underpinning these effects. Many NSAIDs have a great deal of data describing their effects and safety and in many jurisdictions are inexpensive, and sold over the counter in neighborhood convenience stores and supermarkets. The potential benefits of NSAIDs in TB are well-documented in pre-clinical studies. The reduction of pro-inflammatory lipid mediator production by inhibiting cyclooxygenase (COX) pathways with NSAIDs has been found to improve lung histopathology, bacterial control, and survival. Additionally, n-3 LCPUFA and its novel bioactive metabolites produced by COX and lipoxygenase (LOX) have been identified as safe and effective pro-resolving and antibacterial pharmaconutrients. Nevertheless, heterogeneous results have been reported in pre-clinical TB studies. Recently, the importance of the correct timing of NSAIDs and n-3 LCPUFA administration in TB has also been highlighted. This mini-review will provide a better understanding of the potential contribution of these therapies toward reducing inflammatory lung damage and improving bactericidal activity, especially during later stages of TB infection. It further highlights that clinical trials are required to confirm benefit and safety in TB patients.


Assuntos
Antituberculosos/uso terapêutico , Inibidores de Ciclo-Oxigenase/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Pulmonar/tratamento farmacológico , Animais , Interações Hospedeiro-Patógeno , Humanos , Inibidores de Lipoxigenase/uso terapêutico , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/microbiologia , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Resultado do Tratamento , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/metabolismo , Tuberculose Pulmonar/microbiologia
5.
Am J Respir Crit Care Med ; 204(3): 347-356, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33705666

RESUMO

Rationale: Patients with newly diagnosed tuberculosis often have inconsistent glycemic measurements during and after treatment. Distinct glycemic trajectories after the diagnosis of tuberculosis are not well characterized, and whether patients with stress hyperglycemia have poor treatment outcomes is not known.Objectives: To identify distinct glycemic trajectories from the point of tuberculosis diagnosis to the posttreatment period and to assess the relationship between glycemic trajectories and tuberculosis treatment outcomes.Methods: Patients with newly diagnosed, drug-susceptible tuberculosis and with at least three fasting plasma glucose tests at tuberculosis diagnosis and during the third and sixth month of treatment were identified and included from Jiangsu Province, China. Patients were also given an additional fasting plasma glucose test at 2 and 4 months after treatment.Measurements and Main Results: Several distinct glycemic trajectories from the point of tuberculosis diagnosis to the posttreatment period were found, including consistently normal glycemic testing results (43%), transient hyperglycemia (24%), erratic glycemic instability (12%), diabetes (16%), and consistent hyperglycemia without diabetes (6%). Compared with participants with a consistently normal glycemic trajectory, patients with transient hyperglycemia were more likely to experience treatment failure (adjusted odds ratio [AOR], 4.20; 95% confidence interval [CI], 1.57-11.25; P = 0.004) or erratic glycemic instability (AOR, 5.98; 95% CI, 2.00-17.87; P = 0.001). Patients living with diabetes also had a higher risk of experiencing treatment failure (AOR, 6.56; 95% CI, 2.22-19.35; P = 0.001), and this was modified by glycemic control and metformin use.Conclusions: Among patients with tuberculosis without diabetes, glycemic changes were common and may represent an important marker for patient response to tuberculosis treatment.


Assuntos
Antituberculosos/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus/epidemiologia , Hiperglicemia/epidemiologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/metabolismo , Adulto , China/epidemiologia , Estudos de Coortes , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Feminino , Humanos , Hiperglicemia/metabolismo , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Estudos Prospectivos , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Tuberculose/metabolismo , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia
6.
Front Immunol ; 12: 599641, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33732233

RESUMO

It remains undefined whether a subset of CD4+ T cells can function as fast-acting cells to control Mycobacterium tuberculosis (Mtb) infection. Here we show that the primary CD4+CD161+ T-cell subset, not CD4+CD161-, in unexposed healthy humans fast acted as unconventional T cells capable of inhibiting intracellular Mtb and BCG growth upon exposure to infected autologous and allogeneic macrophages or lung epithelial A549 cells. Such inhibition coincided with the ability of primary CD4+CD161+ T cells to rapidly express/secrete anti-TB cytokines including IFN-γ, TNF-α, IL-17, and perforin upon exposure to Mtb. Mechanistically, blockades of CD161 pathway, perforin or IFN-γ by blocking mAbs abrogated the ability of CD4+CD161+ T cells to inhibit intracellular mycobacterial growth. Pre-treatment of infected macrophages with inhibitors of autophagy also blocked the CD4+CD161+ T cell-mediated growth inhibition of mycobacteria. Furthermore, adoptive transfer of human CD4+CD161+ T cells conferred protective immunity against mycobacterial infection in SCID mice. Surprisingly, CD4+CD161+ T cells in TB patients exhibited a loss or reduction of their capabilities to produce perforin/IFN-γ and to inhibit intracellular growth of mycobacteria in infected macrophages. These immune dysfunctions were consistent with PD1/Tim3 up-regulation on CD4+CD161+ T cells in active tuberculosis patients, and the blockade of PD1/Tim3 on this subset cells enhanced the inhibition of intracellular mycobacteria survival. Thus, these findings suggest that a fast-acting primary CD4+CD161+T-cell subset in unexposed humans employs the CD161 pathway, perforin, and IFN-γ/autophagy to inhibit the growth of intracellular mycobacteria, thereby distinguishing them from the slow adaptive responses of conventional CD4+ T cells. The presence of fast-acting CD4+CD161+ T-cell that inhibit mycobacterial growth in unexposed humans but not TB patients also implicates the role of these cells in protective immunity against initial Mtb infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , Transdução de Sinais , Tuberculose/imunologia , Tuberculose/metabolismo , Transferência Adotiva , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/microbiologia , Células Epiteliais Alveolares/patologia , Animais , Autofagia/imunologia , Biomarcadores , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Imunofenotipagem , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Masculino , Camundongos , Viabilidade Microbiana/imunologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Tuberculose/microbiologia , Tuberculose/terapia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/metabolismo , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
7.
Aging (Albany NY) ; 13(6): 8228-8247, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33686954

RESUMO

Accurate diagnosis of complete inactivation of tuberculosis lesions is still a challenge with respect to sputum-negative tuberculosis. RNA-sequencing was conducted to uncover potential lncRNA indicators of metabolic activity in tuberculosis lesions. Lung tissues with high metabolic activity and low metabolic activity demonstrated by fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography were collected from five sputum-negative tuberculosis patients for RNA-sequencing. Differentially-expressed mRNAs and lncRNAs were identified. Their correlations were evaluated to construct lncRNA-mRNA co-expression network, in which lncRNAs and mRNAs with high degrees were confirmed by quantitative real-time PCR using samples collected from 11 patients. Prediction efficiencies of lncRNA indicators were assessed by receiver operating characteristic curve analysis. Bioinformatics analysis was performed for potential lncRNAs. 386 mRNAs and 44 lncRNAs were identified to be differentially expressed. Differentially-expressed mRNAs in lncRNA-mRNA co-expression network were significantly associated with fibrillar collagen, platelet-derived growth factor binding, and leukocyte migration involved in inflammatory response. Seven mRNAs (C1QB, CD68, CCL5, CCL19, MMP7, HLA-DMB, and CYBB) and two lncRNAs (ENST00000429730.1 and MSTRG.93125.4) were validated to be significantly up-regulated. The area under the curve of ENST00000429730.1 and MSTRG.93125.4 was 0.750 and 0.813, respectively. Two lncRNAs ENST00000429730.1 and MSTRG.93125.4 might be considered as potential indicators of metabolic activity in tuberculosis lesions for sputum-negative tuberculosis.


Assuntos
Biomarcadores/análise , RNA Longo não Codificante/análise , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/metabolismo , Adulto , Feminino , Humanos , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adulto Jovem
8.
Eur J Immunol ; 51(5): 1282-1284, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33554329

RESUMO

Microparticles (MPs) which circulate within the plasma are elevated in patients with active pulmonary tuberculosis infection. Circulating MPs isolated from the plasma of patients with active pulmonary tuberculosis infection modulate the cytokine production of immune cells in vitro.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Imunomodulação , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/metabolismo , Doença Aguda , Micropartículas Derivadas de Células/imunologia , Humanos , Imunidade , Tuberculose Pulmonar/patologia
9.
J Immunol Res ; 2021: 6625855, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33628846

RESUMO

ß-Catenin is a key molecule of canonical Wnt/ß-catenin pathway. Its roles and expression profiles in T cells of tuberculosis (TB) remain unclear. The aim of this study was to explore the role of ß-catenin in CD4+ T cells and its expression characteristics in patients with pulmonary tuberculosis (PTB). In this study, CD4+ T cell-specific ß-catenin conditional knockout mice (ß-CAT-cKO mice) were aerosol infected with Mycobacteria tuberculosis (Mtb) H37RV with wild-type mice as controls. Four weeks after infection, the mRNA expression of IFN-γ, TNF-α, and TCF-7 in the lungs of mice was measured. CD4, CD8, ß-catenin, IFN-γ, and TNF-α in mononuclear cells from the lungs and spleens were measured by flow cytometry, and the pathological changes of lungs were also observed. Patients with PTB were enrolled, with blood samples collected and PBMCs isolated. The expressions of ß-catenin, IFN-γ, TNF-α, and PD-1 in CD4+ and CD8+ T cells were measured by flow cytometry. Results showed a decreased frequency of and reduced IFN-γ/TNF-α mRNA expression and secretion by CD4+ T cells in the lungs of infected ß-CAT-cKO mice compared with infected wild-type controls, and only slightly more inflammatory changes were observed in the lungs. ß-catenin expressions in CD4+ and CD8+ T cells were significantly decreased in blood cells of patients with severe PTB compared with those in mild PTB. The stimulation of peripheral blood mononuclear cells (PBMCs) with lithium chloride (LiCl), a stimulant of ß-catenin, resulted in the increase in CD4+ T cell frequency, as well as their secretion of IFN-γ and TNF-α. ß-Catenin demonstrated a moderately positive correlation with PD-1 in CD4+ T cells. ß-Catenin along with PD-1 and IFN-γ in CD4+ T cells had a high correlation with those in CD8+ T cells. In conclusion, ß-catenin may be involved in the regulation of Th1 response and CD4+ T cell frequency in TB.


Assuntos
Modelos Animais de Doenças , Mycobacterium tuberculosis/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Transcriptoma , Tuberculose Pulmonar/etiologia , Tuberculose Pulmonar/metabolismo , beta Catenina/metabolismo , Adolescente , Adulto , Animais , Carga Bacteriana , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Antígenos O/imunologia , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto Jovem
10.
Biofactors ; 47(1): 6-18, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33249673

RESUMO

Specialized proresolving mediators (SPMs) are endogenous lipid metabolites of long-chain polyunsaturated fatty acids that are involved in promoting the resolution of inflammation. Many disease conditions characterized by excessive inflammation have impaired or altered SPM biosynthesis, which may lead to chronic, unresolved inflammation. Exogenous administration of SPMs in infectious conditions has been shown to be effective at improving infection clearance and survival in preclinical models. SPMs have also shown tremendous promise in the context of inflammatory lung conditions, such as acute respiratory distress syndrome and chronic obstructive pulmonary disease, mostly in preclinical settings. To date, SPMs have not been studied in the context of the novel Coronavirus, severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), however their preclinical efficacy in combatting infections and improving acute respiratory distress suggest they may be a valuable resource in the fight against Coronavirus disease-19 (COVID-19). Overall, while the research on SPMs is still evolving, they may offer a novel therapeutic option for inflammatory conditions.


Assuntos
Anti-Inflamatórios/uso terapêutico , COVID-19/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Lipoxinas/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Síndrome do Desconforto Respiratório/tratamento farmacológico , COVID-19/metabolismo , COVID-19/patologia , COVID-19/virologia , Herpes Simples/tratamento farmacológico , Herpes Simples/metabolismo , Herpes Simples/patologia , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/metabolismo , Influenza Humana/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Lesão Pulmonar/virologia , Periodontite/tratamento farmacológico , Periodontite/metabolismo , Periodontite/patologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/virologia , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/virologia , SARS-CoV-2/patogenicidade , Sepse/tratamento farmacológico , Sepse/metabolismo , Sepse/patologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/metabolismo , Tuberculose Pulmonar/patologia
11.
PLoS One ; 15(12): e0243542, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33306710

RESUMO

BACKGROUND: When evaluating symptomatic patients for tuberculosis (TB) without access to same-day diagnostic test results, clinicians often make empiric decisions about starting treatment. The number of TB symptoms and/or underweight status could help identify patients at highest risk for a positive result. We sought to evaluate the usefulness of BMI assessment and a count of characteristic TB symptoms for identifying patients at highest risk for TB. METHODS: We enrolled adult patients receiving pulmonary TB diagnoses and a representative sample with negative TB evaluations at four outpatient health facilities in Kampala, Uganda. We asked patients about symptoms of chronic cough, night sweats, chest pain, fever, hemoptysis, or weight loss; measured height and weight; and collected sputum for mycobacterial culture. We evaluated the diagnostic accuracy (for culture-positive TB) of two simple scoring systems: (a) number of TB symptoms, and (b) number of TB symptoms plus one or more additional points for underweight status (body mass index [BMI] ≤ 18.5 kg/m2). RESULTS: We included 121 patients with culture-positive TB and 370 patients with negative culture results (44 of whom had been recommended for TB treatment by evaluating clinicians). Of the six symptoms assessed, the median number of symptoms that patients reported was two (interquartile range [IQR]: 1, 3). The median BMI was 20.9 kg/m2 (IQR: 18.6, 24.0), and 118 (24%) patients were underweight. Counting the number of symptoms provided an area under the Receiver Operating Characteristic curve (c-statistic) of 0.77 (95% confidence interval, CI: 0.72, 0.81) for identifying culture-positive TB; adding two points for underweight status increased the c-statistic to 0.81 (95%CI: 0.76, 0.85). A cutoff of ≥3 symptoms had sensitivity and specificity of 65% and 74%, whereas a score of ≥4 on the combined score (≥2 symptoms if underweight, ≥4 symptoms if not underweight) gave higher sensitivity and specificity of 69% and 81% respectively. A sensitivity analysis defining TB by Xpert MTB/RIF status produced similar results. CONCLUSION: A count of patients' TB symptoms may be useful in clinical decision-making about TB diagnosis. Consideration of underweight status adds additional diagnostic value.


Assuntos
Magreza/fisiopatologia , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/fisiopatologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/patogenicidade , Pacientes Ambulatoriais , Fatores de Risco , Sensibilidade e Especificidade , Escarro/microbiologia , Magreza/metabolismo , Tuberculose/diagnóstico , Tuberculose Pulmonar/metabolismo , Uganda/epidemiologia
12.
Int J Mol Sci ; 21(24)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33322180

RESUMO

Tuberculosis (TB) is a chronic infectious disease in which prolonged, non-resolutive inflammation of the lung may lead to metabolic and neuroendocrine dysfunction. Previous studies have reported that individuals coursing pulmonary TB experience cognitive or behavioural changes; however, the pathogenic substrate of such manifestations have remained unknown. Here, using a mouse model of progressive pulmonary TB, we report that, even in the absence of brain infection, TB is associated with marked increased synthesis of both inflammatory and anti-inflammatory cytokines in discrete brain areas such as the hypothalamus, the hippocampal formation and cerebellum accompanied by substantial changes in the synthesis of neurotransmitters. Moreover, histopathological findings of neurodegeneration and neuronal death were found as infection progressed with activation of p38, JNK and reduction in the BDNF levels. Finally, we perform behavioural analysis in infected mice throughout the infection, and our data show that the cytokine and neurochemical changes were associated with a marked onset of cognitive impairment as well as depressive- and anxiety-like behaviour. Altogether, our results suggest that besides pulmonary damage, TB is accompanied by an extensive neuroinflammatory and neurodegenerative state which explains some of the behavioural abnormalities found in TB patients.


Assuntos
Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Citocinas/metabolismo , Inflamação/metabolismo , Mycobacterium tuberculosis/metabolismo , Neurônios/patologia , Tuberculose Pulmonar/metabolismo , Animais , Ansiedade/metabolismo , Ansiedade/microbiologia , Sintomas Comportamentais/microbiologia , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Encéfalo/citologia , Encéfalo/enzimologia , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Disfunção Cognitiva/microbiologia , Depressão/metabolismo , Depressão/microbiologia , Modelos Animais de Doenças , Regulação para Baixo , Hipocampo/citologia , Hipocampo/imunologia , Hipocampo/metabolismo , Hipocampo/patologia , Janus Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/patogenicidade , Neurônios/citologia , Neurotransmissores/metabolismo , Tuberculose Pulmonar/enzimologia , Tuberculose Pulmonar/patologia , Tuberculose Pulmonar/psicologia , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Elife ; 92020 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-33228849

RESUMO

We establish a murine lung-on-chip infection model and use time-lapse imaging to reveal the dynamics of host-Mycobacterium tuberculosis interactions at an air-liquid interface with a spatiotemporal resolution unattainable in animal models and to probe the direct role of pulmonary surfactant in early infection. Surfactant deficiency results in rapid and uncontrolled bacterial growth in both macrophages and alveolar epithelial cells. In contrast, under normal surfactant levels, a significant fraction of intracellular bacteria are non-growing. The surfactant-deficient phenotype is rescued by exogenous addition of surfactant replacement formulations, which have no effect on bacterial viability in the absence of host cells. Surfactant partially removes virulence-associated lipids and proteins from the bacterial cell surface. Consistent with this mechanism, the attenuation of bacteria lacking the ESX-1 secretion system is independent of surfactant levels. These findings may partly explain why smokers and elderly persons with compromised surfactant function are at increased risk of developing active tuberculosis.


Assuntos
Células Epiteliais Alveolares/microbiologia , Dispositivos Lab-On-A-Chip , Técnicas Analíticas Microfluídicas/instrumentação , Mycobacterium tuberculosis/crescimento & desenvolvimento , Proteínas Associadas a Surfactantes Pulmonares/metabolismo , Tuberculose Pulmonar/microbiologia , Células Epiteliais Alveolares/metabolismo , Animais , Carga Bacteriana , Proteínas de Bactérias/genética , Células Cultivadas , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Patógeno , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/microbiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Viabilidade Microbiana , Microscopia de Vídeo , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidade , Proteínas Associadas a Surfactantes Pulmonares/genética , Fatores de Tempo , Imagem com Lapso de Tempo , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/metabolismo , Virulência
14.
Front Immunol ; 11: 601534, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240287

RESUMO

Oxidized cholesterols have emerged as important signaling molecules of immune function, but little is known about the role of these oxysterols during mycobacterial infections. We found that expression of the oxysterol-receptor GPR183 was reduced in blood from patients with tuberculosis (TB) and type 2 diabetes (T2D) compared to TB patients without T2D and was associated with TB disease severity on chest x-ray. GPR183 activation by 7α,25-dihydroxycholesterol (7α,25-OHC) reduced growth of Mycobacterium tuberculosis (Mtb) and Mycobacterium bovis BCG in primary human monocytes, an effect abrogated by the GPR183 antagonist GSK682753. Growth inhibition was associated with reduced IFN-ß and IL-10 expression and enhanced autophagy. Mice lacking GPR183 had significantly increased lung Mtb burden and dysregulated IFNs during early infection. Together, our data demonstrate that GPR183 is an important regulator of intracellular mycobacterial growth and interferons during mycobacterial infection.


Assuntos
Autofagia , Interferons/metabolismo , Leucócitos Mononucleares/microbiologia , Pulmão/microbiologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Receptores Acoplados a Proteínas G/metabolismo , Tuberculose Pulmonar/microbiologia , Animais , Carga Bacteriana , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Patógeno , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium bovis/crescimento & desenvolvimento , Mycobacterium bovis/imunologia , Mycobacterium bovis/patogenicidade , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Receptores Acoplados a Proteínas G/genética , Índice de Gravidade de Doença , Transdução de Sinais , Células THP-1 , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/metabolismo
15.
Int J Mol Sci ; 21(22)2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33202583

RESUMO

The aim of this study is to explore the role of microRNAs (miR)-21/23a/146a/150/155 targeting the toll-like receptor pathway in active tuberculosis (TB) disease and latent TB infection (LTBI). Gene expression levels of the five miRs and predicted target genes were assessed in peripheral blood mononuclear cells from 46 patients with active pulmonary TB, 15 subjects with LTBI, and 17 non-infected healthy subjects (NIHS). THP-1 cell lines were transfected with miR-23a-3p mimics under stimuli with Mycobacterium TB-specific antigens. Both miR-155-5p and miR-150-5p gene expressions were decreased in the active TB group versus the NIHS group. Both miR-23a-3p and miR-146a-5p gene expressions were decreased in active TB patients with high bacterial burden versus those with low bacterial burden or control group (LTBI + NIHS). TLR2, TLR4, and interleukin (IL)10 gene expressions were all increased in active TB versus NIHS group. MiR-23a-3p mimic transfection reversed ESAT6-induced reduction of reactive oxygen species generation, and augmented ESAT6-induced late apoptosis and phagocytosis, in association with down-regulations of the predicted target genes, including tumor necrosis factor (TNF)-α, TLR4, TLR2, IL6, IL10, Notch1, IL6R, BCL2, TGF-ß1, SP1, and IRF1. In conclusion, the down-regulation of miR-23a-3p in active TB patients with high bacterial burden inhibited mononuclear cell function and phagocytosis through TLR4/TNF-α/TGF-ß1/IL-10 signaling via targeting IRF1/SP1.


Assuntos
Regulação para Baixo , Fator Regulador 1 de Interferon/metabolismo , Interleucina-10/metabolismo , MicroRNAs/biossíntese , Mycobacterium tuberculosis/metabolismo , Fagocitose , Transdução de Sinais , Fator de Transcrição Sp1/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Tuberculose Pulmonar/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Feminino , Humanos , Fator Regulador 1 de Interferon/genética , Interleucina-10/genética , Masculino , MicroRNAs/genética , Fator de Transcrição Sp1/genética , Células THP-1 , Receptor 4 Toll-Like/genética , Fator de Crescimento Transformador beta1/genética , Tuberculose Pulmonar/genética , Fator de Necrose Tumoral alfa/genética
16.
Sci Rep ; 10(1): 16257, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004826

RESUMO

Tuberculosis (TB) is a chronic inflammatory disease that is often associated with alterations in systemic and cellular metabolism that resolves following successful antimicrobial drug treatment. We hypothesized that altered systemic glucose metabolism as a consequence of Mycobacterium tuberculosis (Mtb) infection, contributes to TB pathogenesis, and when normalized with anti-glycemic drugs would improve clinical outcomes. To test this hypothesis, guinea pigs were treated daily with the anti-diabetic drug metformin starting 4 weeks prior or concurrent with aerosol exposure to the H37Rv strain of Mtb. In the chronic stages of infection, Mtb infected metformin-treated animals had restored systemic insulin sensitivity but remained glucose intolerant as determined by oral glucose tolerance testing. Despite persistent glucose intolerance, metformin-treated guinea pigs had a 2.8-fold reduction in lung lesion burden and a 0.7 log decrease in CFUs. An alternative hypothesis that metformin treatment improved clinical disease by having a direct effect on immune cell energy metabolism was tested using extracellular flux analysis and flow cytometry. The proinflammatory immune response to Mtb infection in untreated guinea pigs was associated with a marked increase in energy metabolism (glycolysis and mitochondrial respiration) of peripheral blood mononuclear cells (PBMCs), which was normalized in metformin-treated guinea pigs. Moreover, both CD4+ and CD8+ T lymphocytes from Mtb infected, metformin treated animals maintained a more normal mitochondrial membrane potential while those isolated from untreated animals had persistent mitochondrial hyperpolarization. These data suggest that metformin promotes natural host resistance to Mtb infection by maintaining immune cell metabolic homeostasis and function during the chronic stages of active TB disease.


Assuntos
Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Animais , Citocinas/metabolismo , Metabolismo Energético/efeitos dos fármacos , Glucose/metabolismo , Intolerância à Glucose/tratamento farmacológico , Cobaias , Resistência à Insulina , Pulmão/patologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Superóxidos/metabolismo , Linfócitos T/metabolismo , Tuberculose Pulmonar/metabolismo , Tuberculose Pulmonar/patologia
17.
Diabetes Metab Syndr ; 14(6): 1889-1894, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33002780

RESUMO

BACKGROUND AND AIMS: The link between diabetes and increased risk of infectious disease has long been recognized, but has re-entered sharp focus following the COVID-19 pandemic. METHODS: A literature search was conducted in PubMed for articles in English on diabetes and infection. RESULTS: Diabetes predisposes to infections through alterations in innate and acquired immune defenses. Outcomes of infection are worse in people with uncontrolled diabetes, and infection can worsen hyperglycemia in hitherto well controlled diabetes (bidirectional relationship). Diabetes does not increase the risk of infection with COVID-19 per se, but predisposes to severe disease and poor outcomes. COVID-19 has also been linked to deterioration of glycemic control as well as new-onset diabetes. CONCLUSIONS: Clinicians caring for people with diabetes should be aware of the increased risk of infections in this population, as well as the possibility of worsening hyperglycemia. A holistic approach with frequent monitoring of blood glucose levels and appropriate titration of medications, along with close attention to nutritional status, is essential to ensure the best possible outcomes.


Assuntos
COVID-19/epidemiologia , Diabetes Mellitus/epidemiologia , Tuberculose Pulmonar/epidemiologia , Imunidade Adaptativa/imunologia , Glicemia/metabolismo , COVID-19/imunologia , COVID-19/metabolismo , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Controle Glicêmico , Humanos , Imunidade Inata/imunologia , Índia/epidemiologia , Infecções/epidemiologia , Infecções/imunologia , Infecções/metabolismo , Infecções do Sistema Genital/epidemiologia , Infecções do Sistema Genital/imunologia , Infecções do Sistema Genital/metabolismo , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/metabolismo , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Dermatopatias Bacterianas/epidemiologia , Dermatopatias Bacterianas/imunologia , Dermatopatias Bacterianas/metabolismo , Infecções dos Tecidos Moles/epidemiologia , Infecções dos Tecidos Moles/imunologia , Infecções dos Tecidos Moles/metabolismo , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/metabolismo , Infecções Urinárias/epidemiologia , Infecções Urinárias/imunologia , Infecções Urinárias/metabolismo
18.
Front Immunol ; 11: 575504, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33117374

RESUMO

Bacillus Calmette-Guerin (BCG) is the only licensed vaccine to prevent children from tuberculosis (TB), whereas it cannot provide effective protection for adults. Our previous work showed a novel vaccine candidate, liposomal adjuvant DMT emulsified with a multistage antigen CMFO, could protect mice against primary progressive TB, latency, and reactivation. To develop a more effective vaccine against adult TB, we aimed to further understand the role of pattern recognition receptor (PRR) agonists monophosphoryl lipid A (MPLA) and trehalose-6,6'-dibehenate (TDB) of the liposomal adjuvant DMT in the CMFO subunit vaccine-induced protection. Using C57BL/6 mouse models, the current study prepared different dimethyldioctadecylammonium (DDA)-based liposomal adjuvants with MPLA, TDB, or both (DMT), and then compared the immunogenicity and the protective efficacy among different liposomal adjuvanted CMFO subunit vaccines. Our study demonstrated that CMFO/DMT provided stronger and longer-lasting protective efficacy than the CMFO emulsified with adjuvants DDA or DDA/TDB. In addition, DDA/MPLA adjuvanted CMFO conferred a comparable protection in the lung as CMFO/DMT did. Higher levels of IFN-γ, IL-2, TNF-α, and IL-17A secreted by splenocytes were related with a more powerful and durable protection induced by CMFO/DMT through a putative synergistic effect of both MPLA and TDB via binding to TLR4 and Mincle. IL-2+ CD4+ T cells, especially IL-2+ CD4+ TCM cells, in the lung after infection were significantly associated with the vaccine-induced protection, whereas stronger IL-10 response and lower IL-2+ CD4+ T cells also contributed to the inferior protection of the DDA/TDB adjuvanted CMFO subunit vaccine. Given their crucial roles in vaccine-induced protection, combinational different PRR agonists in adjuvant formulation represent a promising strategy for the development of next-generation TB vaccine.


Assuntos
Adjuvantes Imunológicos/farmacologia , Glicolipídeos/farmacologia , Imunogenicidade da Vacina , Lipídeo A/análogos & derivados , Pulmão/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade , Compostos de Amônio Quaternário/farmacologia , Receptores de Reconhecimento de Padrão/agonistas , Vacinas contra a Tuberculose/farmacologia , Tuberculose Pulmonar/prevenção & controle , Adjuvantes Imunológicos/química , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/microbiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Composição de Medicamentos , Feminino , Glicolipídeos/química , Interações Hospedeiro-Patógeno , Lipídeo A/química , Lipídeo A/farmacologia , Lipossomos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/microbiologia , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/imunologia , Compostos de Amônio Quaternário/química , Receptores de Reconhecimento de Padrão/metabolismo , Fatores de Tempo , Vacinas contra a Tuberculose/química , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/metabolismo , Tuberculose Pulmonar/microbiologia , Vacinação , Vacinas de Subunidades/química , Vacinas de Subunidades/farmacologia , Virulência
19.
Commun Biol ; 3(1): 604, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097805

RESUMO

Previous reports have suggested a link between pulmonary tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), and the development of lung adenocarcinoma (LUAD) and sarcoidosis. Furthermore, these lung diseases share certain clinical similarities that can challenge differential diagnosis in some cases. Here, through comparison of lung transcriptome-derived molecular signatures of TB, LUAD and sarcoidosis patients, we identify certain shared disease-related expression patterns. We also demonstrate that MKI67, an over-expressed gene shared by TB and LUAD, is a key mediator in Mtb-promoted tumor cell proliferation, migration, and invasion. Moreover, we reveal a distinct ossification-related TB lung signature, which may be associated with the activation of the BMP/SMAD/RUNX2 pathway in Mtb-infected macrophages that can restrain mycobacterial survival and promote osteogenic differentiation of mesenchymal stem cells. Taken together, these findings provide novel pathogenic links and potential molecular markers for better understanding and differential diagnosis of pulmonary TB, LUAD and sarcoidosis.


Assuntos
Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Sarcoidose/genética , Transcriptoma/genética , Tuberculose Pulmonar/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Biomarcadores , Diagnóstico Diferencial , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Sarcoidose/diagnóstico , Sarcoidose/metabolismo , Sarcoidose/patologia , Transdução de Sinais/genética , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/metabolismo , Tuberculose Pulmonar/patologia
20.
J Cell Mol Med ; 24(23): 13763-13774, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33089914

RESUMO

Type 2 diabetes mellitus (T2DM) is a risk factor for pulmonary tuberculosis (PTB) and increased mortality. This work focused on the functions of phosphorylated STAT3 in lung injury in mouse with T2DM-associated PTB and the molecules involved. A mouse model with T2DM-PTB was induced by administrations of streptozotocin, nicotinamide and mycobacterium tuberculosis (Mtb). A pSTAT3-specific inhibitor AG-490 was given into mice and then the lung injury in mice was observed. The molecules involved in AG-490-mediated events were screened out. Altered expression of miR-19b, miR-1281 and NFAT5 was introduced to identify their involvements and roles in lung injury and PTB severity in the mouse model. Consequently, pSTAT3 expression in mice with T2DM-associated PTB was increased. Down-regulation of pSTAT3 by AG-490 prolonged the lifetime of mice and improved the histopathologic conditions, and inhibited the fibrosis, inflammation, Mtb content and number of apoptotic epithelial cells in mouse lung tissues. pSTAT3 transcriptionally suppressed miR-19b/1281 expression to up-regulate NFAT5. Inhibition of miR-19b/1281 or up-regulation of NFAT5 blocked the protective roles of AG-490 in mouse lung tissues. To conclude, this study evidenced that pSTAT3 promotes NFAT5 expression by suppressing miR-19b/1281 transcription, leading to lung injury aggravation and severity in mice with T2DM-associated PTB.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Regulação da Expressão Gênica , MicroRNAs/genética , Fator de Transcrição STAT3/metabolismo , Tuberculose Pulmonar/etiologia , Tuberculose Pulmonar/metabolismo , Animais , Apoptose/genética , Biomarcadores , Biópsia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Genes Reporter , Imuno-Histoquímica , Camundongos , Fosforilação , Tuberculose Pulmonar/patologia
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