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1.
Biomed Res Int ; 2021: 9970817, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34527747

RESUMO

Objective: To investigate the diagnostic accuracy of metagenomic next-generation sequencing (mNGS) in bronchoalveolar lavage fluid (BALF) samples or lung biopsy specimens from which suspected pulmonary tuberculosis (PTB) patients have no sputum or negative smear. Materials and Methods: Sputum-scarce or smear-negative cases with suspected PTB (n = 107) were analyzed from January 2018 to June 2020. We collected BALF or lung tissue biopsy samples with these cases of suspected TB during hospitalization. The diagnostic accuracy of mNGS for these samples was compared with those of conventional tests or the T-SPOT.TB assay. Results: 46 cases of PTB patients and 61 cases of non-PTB patients were finally enrolled and analyzed. mNGS exhibited a sensitivity of 89.13%, which was higher than conventional tests (67.39%) but equivalent to those of the T-SPOT.TB assay alone (76.09%) or T-SPOT.TB assay in combination with conventional tests (91.30%). The specificity of mNGS was 98.36%, similar to conventional tests (95.08%) but significantly higher than those of the T-SPOT.TB assay alone (65.57%) or the T-SPOT.TB assay in combination with conventional tests (63.93%). There was no significant difference in the diagnostic accuracy of mNGS in BALF samples and lung biopsy tissue specimens. Conclusion: Our findings demonstrate that mNGS could offer improved detection of Mycobacterium tuberculosis in BALF or lung tissue biopsy samples in sputum-scarce or smear-negative cases with suspected PTB.


Assuntos
Genoma Bacteriano , Sequenciamento de Nucleotídeos em Larga Escala/normas , Pulmão/microbiologia , Metagenoma , Mycobacterium tuberculosis/genética , Tuberculose Pulmonar/diagnóstico , Adulto , Idoso , Biópsia , Líquido da Lavagem Broncoalveolar/microbiologia , Estudos de Casos e Controles , Reações Falso-Negativas , Feminino , Humanos , Pulmão/patologia , Masculino , Microscopia , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Estudos Retrospectivos , Sensibilidade e Especificidade , Escarro/microbiologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
2.
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
3.
FASEB J ; 35(9): e21853, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34416038

RESUMO

We highlight the ability of the tuberculosis (TB) causing bacterial pathogen, Mycobacterium tuberculosis (Mtb), to induce key characteristics that are associated with established IARC classified Group 1 and Group 2A carcinogenic agents. There is sufficient evidence from epidemiological case-control, cohort and meta-analysis studies of increased lung cancer (LC) risk in pre-existing/active/old TB cases. Similar to carcinogens and other pathogenic infectious agents, exposure to aerosol-containing Mtb sprays in mice produce malignant transformation of cells that result in squamous cell carcinoma. Convincing, mechanistic data show several characteristics shared between TB and LC which include chronic inflammation, genomic instability and replicative immortality, just to name a few cancer hallmarks. These hallmarks of cancer may serve as precursors to malignant transformation. Together, these findings form the basis of our postulate that Mtb is a complete human pulmonary carcinogen. We also discuss how Mtb may act as both an initiating agent and promoter of tumor growth. Forthcoming experimental studies will not only serve as proof-of-concept but will also pivot our understanding of how to manage/treat TB cases as well as offer solutions to clinical conundrums of TB lesions masquerading as tumors. Clinical validation of our concept may also help pave the way for next generation personalized medicine for the management of pulmonary TB/cancer particularly for cases that are not responding well to conventional chemotherapy or TB drugs.


Assuntos
Transformação Celular Neoplásica , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/microbiologia , Pulmão/microbiologia , Pulmão/patologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/microbiologia , Adolescente , Adulto , Idoso , Células Epiteliais Alveolares/citologia , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Carcinógenos , Transformação Celular Neoplásica/genética , Criança , Estudos de Coortes , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Mycobacterium tuberculosis/genética , Metástase Neoplásica/genética , Células-Tronco Neoplásicas/patologia , Fatores de Risco , Tuberculose Pulmonar/patologia , Adulto Jovem
4.
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
5.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206086

RESUMO

Tuberculosis (TB) is an important infectious disease and a public health problem. The organs most frequently affected by TB are the lungs; despite this, it has been reported that TB patients suffer from depression and anxiety, which have been attributed to social factors. In previous experimental work, we observed that the extensive pulmonary inflammation characteristic of TB with high cytokine production induces neuroinflammation, neuronal death and behavioral abnormalities in the absence of brain infection. The objective of the present work was to reduce this neuroinflammation and avoid the psycho-affective disorders showed during pulmonary TB. Glucocorticoids (GCs) are the first-line treatment for neuroinflammation; however, their systemic administration generates various side effects, mostly aggravating pulmonary TB due to immunosuppression of cellular immunity. Intranasal administration is a route that allows drugs to be released directly in the brain through the olfactory nerve, reducing their doses and side effects. In the present work, dexamethasone's (DEX) intranasal administration was evaluated in TB BALB /c mice comparing three different doses (0.05, 0.25 and 2.5 mg/kg BW) on lung disease evolution, neuroinflammation and behavioral alterations. Low doses of dexamethasone significantly decreased neuroinflammation, improving behavioral status without aggravating lung disease.


Assuntos
Encéfalo/efeitos dos fármacos , Dexametasona/farmacologia , Inflamação/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Administração Intranasal , Animais , Ansiedade/complicações , Ansiedade/tratamento farmacológico , Ansiedade/patologia , Encéfalo/patologia , Depressão/complicações , Depressão/tratamento farmacológico , Depressão/patologia , Modelos Animais de Doenças , Glucocorticoides/farmacologia , Humanos , Inflamação/complicações , Inflamação/microbiologia , Inflamação/patologia , Camundongos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
6.
J Clin Invest ; 131(15)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34128839

RESUMO

Tuberculosis (TB) is a persistent global pandemic, and standard treatment for it has not changed for 30 years. Mycobacterium tuberculosis (Mtb) has undergone prolonged coevolution with humans, and patients can control Mtb even after extensive infection, demonstrating the fine balance between protective and pathological host responses within infected granulomas. We hypothesized that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a noninfectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared 3 primary human cell culture models at the whole transcriptome level and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified 12 intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.


Assuntos
Granuloma do Sistema Respiratório/metabolismo , Pulmão/metabolismo , Modelos Biológicos , Mycobacterium tuberculosis/metabolismo , RNA-Seq , Tuberculose Pulmonar/metabolismo , Adulto , Idoso , Feminino , Granuloma do Sistema Respiratório/genética , Granuloma do Sistema Respiratório/microbiologia , Granuloma do Sistema Respiratório/patologia , Humanos , Pulmão/microbiologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/patologia
7.
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
9.
Nat Commun ; 12(1): 2716, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976135

RESUMO

Polyclonal infections occur when at least two unrelated strains of the same pathogen are detected in an individual. This has been linked to worse clinical outcomes in tuberculosis, as undetected strains with different antibiotic resistance profiles can lead to treatment failure. Here, we examine the amount of polyclonal infections in sputum and surgical resections from patients with tuberculosis in the country of Georgia. For this purpose, we sequence and analyse the genomes of Mycobacterium tuberculosis isolated from the samples, acquired through an observational clinical study (NCT02715271). Access to the lung enhanced the detection of multiple strains (40% of surgery cases) as opposed to just using a sputum sample (0-5% in the general population). We show that polyclonal infections often involve genetically distant strains and can be associated with reversion of the patient's drug susceptibility profile over time. In addition, we find different patterns of genetic diversity within lesions and across patients, including mutational signatures known to be associated with oxidative damage; this suggests that reactive oxygen species may be acting as a selective pressure in the granuloma environment. Our results support the idea that the magnitude of polyclonal infections in high-burden tuberculosis settings is underestimated when only testing sputum samples.


Assuntos
Farmacorresistência Bacteriana Múltipla/genética , Genoma Bacteriano , Granuloma/patologia , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/patologia , Tuberculose Pulmonar/patologia , Antituberculosos/uso terapêutico , Biópsia , Células Clonais , Estudos de Coortes , Variação Genética , República da Geórgia , Granuloma/tratamento farmacológico , Granuloma/microbiologia , Granuloma/cirurgia , Humanos , Pulmão/microbiologia , Pulmão/patologia , Pulmão/cirurgia , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade , Espécies Reativas de Oxigênio/metabolismo , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/cirurgia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/cirurgia
10.
Medicine (Baltimore) ; 100(20): e25821, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011045

RESUMO

BACKGROUND: To evaluate the value of interleukin (IL)-27 measured in serum and bronchoalveolar lavage fluid (BALF) for the diagnosis of smear-negative pulmonary tuberculosis (TB). METHODS: This was a prospective study of patients planned to undergo bronchoscopy at Wuxi No.5 People's Hospital between January 2017 and September 2018. The patients were grouped as the TB and control groups. BALF and serum IL-27 were measured by ELISA. Receiver operating characteristic (ROC) curves were used to assess the diagnostic value and calculate the optimal cutoff values. RESULTS: There were 40 patients in the control group and 87 in the TB group. In the TB group, 20 had positive sputum smear results and 67 were negative. The area under the ROC curve (AUC) of BALF IL-27 for pulmonary TB was 0.897 (95% CI: 0.830-0.944) (P < .001). The AUC of serum IL-27 for pulmonary TB was 0.703 (95% CI: 0.616-0.781) (P < .001). In patients with negative sputum smear results, the AUCs of BALF IL-27 and serum IL-27 for pulmonary TB was 0.882 (95% confidence interval [CI]: 0.805-0.936) (P < .001) and 0.679 (95% CI: 0.601-0.782) (P < .001), respectively. CONCLUSIONS: BALF IL-27 can be used for the diagnosis of pulmonary TB, particularly in those with a negative sputum smear result. Serum IL-27 could be an auxiliary method for TB screening.


Assuntos
Líquido da Lavagem Broncoalveolar/química , Interleucina-27/análise , Interleucinas/análise , Programas de Rastreamento/métodos , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Pulmonar/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Biópsia , Broncoscopia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Estudos de Viabilidade , Feminino , Humanos , Pulmão/microbiologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Escarro/microbiologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Adulto Jovem
11.
Epidemiol Infect ; 149: e117, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33902774

RESUMO

No previous studies have examined Mycobacterium avium complex pulmonary disease (MAC-PD) in only elderly patients ⩾75 years old. Here, we investigated the exacerbating factors of MAC-PD in elderly patients and clarified cases that can be followed up without MAC medication. From April 2011 to March 2019, 126 advanced aged patients at our institute were newly diagnosed with MAC-PD, and could be observed based on radiological findings for over a year. Their medical records were retrospectively examined for clinical and radiological findings at the time of diagnosis and 1 year later. To identify the predictors of exacerbation, clinical characteristics of 109 treatment-naïve patients were compared between exacerbated and unchanged groups. Additionally, the unchanged group was followed for one more year. In the current study, positive acid-fast bacilli smears from the sputum test, the presence of cavitary lesions and extensive radiological findings, particularly abnormal shadows in ⩾3 lobes, were predictive of exacerbation among treatment-naïve elderly MAC-PD patients. In the unchanged group, <10% showed exacerbation of radiological findings within the subsequent year. In conclusion, if the sputum smear is negative, no cavitary lesions are present, and abnormal shadows are restricted to ⩽2 lobes, elderly patients with MAC-PD may remain untreated for a few years.


Assuntos
Complexo Mycobacterium avium/isolamento & purificação , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Tuberculose Pulmonar/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Infecção por Mycobacterium avium-intracellulare/microbiologia , Infecção por Mycobacterium avium-intracellulare/patologia , Infecção por Mycobacterium avium-intracellulare/terapia , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Escarro/microbiologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Tuberculose Pulmonar/terapia
12.
Front Immunol ; 12: 641065, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868272

RESUMO

Novel tuberculosis (TB) prevention and control strategies are urgently required. Utilising specimens from the Improving Retreatment Success (NCT02114684) trial we assessed the associations between inflammatory markers, measured during active TB, with treatment response and disease severity in HIV-infected and uninfected individuals. Multiplex immunoassays and ELISA were used to measure plasma expression of 24 cytokines/chemokines. Cytokines were log transformed to adjust for skewness. We conducted a nested, un-matched, case (n= 31) - control (n=101) study with cases defined as those participants who failed to sputum culture convert within 8-weeks of TB treatment initiation. Additionally, we examined the association between the measured cytokines and time to culture conversion and presence of lung cavitation using cox proportional hazards and logistic regression models, respectively. Multivariable analyses adjusted for a wide range of baseline clinical and demographic variables. IP-10 expression during active TB was associated with increased odds of sputum culture conversion by 8-weeks overall (aOR 4.255, 95% CI 1.025 - 17.544, p=0.046)) and among HIV-infected individuals (OR 10.204, 95% CI 1.247 - 83.333, p=0.030). Increased MCP-3 (aHR 1.723, 95% CI 1.040 - 2.855, p=0.035) and IL-6 (aHR 1.409, 95% CI 1.045 - 1.899, p=0.024) expression was associated with a shorter time to culture conversion in the total cohort. Higher plasma expression of IL-6 (aHR 1.783, 95% CI 1.128 - 2.820, p=0.013), IL-1RA (aHR 2.595, 95% CI 1.136 - 5.926, p=0.024), IP-10 (aHR 2.068, 95% CI 1.034 - 4.137, p=0.040) and IL-1α (aHR 2.008, 95% CI 1.053 - 3.831, p=0.035) were significantly associated with shorter time to culture conversion among HIV-infected individuals. Increased IL-6 and IL-1RA expression was significantly associated with the presence of lung cavitation during active TB in the total cohort (OR 2.543, 95% CI 1.254 - 5.160, p=0.010), (OR 4.639, 95% CI 1.203 - 21.031, p=0.047) and in HIV-infected individuals (OR 2.644, 95% CI 1.062 - 6.585, p=0.037), (OR 7.795, 95% CI 1.177 - 51.611, p=0.033) respectively. Our results indicate that inflammatory cytokines/chemokines play an important role in TB disease outcome. Importantly, the observed associations were stronger in multivariable models highlighting the impact of behavioural and clinical variables on the expression of immune markers as well as their potential effects on TB outcome.


Assuntos
Biomarcadores/sangue , Coinfecção , Citocinas/sangue , Infecções por HIV , Tuberculose Pulmonar/imunologia , Adulto , Antibióticos Antituberculose/uso terapêutico , Estudos de Casos e Controles , Citocinas/imunologia , Feminino , Humanos , Inflamação/imunologia , Masculino , Rifampina/uso terapêutico , África do Sul , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/patologia
13.
PLoS One ; 16(4): e0249301, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33793598

RESUMO

We evaluated in this cohort study the predictive ability of 23 peripheral blood parameters and ratios for treatment outcomes after the 2-month intensive phase in patients with PTB. In 63 patients out of 90 that turned culture negative, a significant decrease in white blood cell count, neutrophils, monocyte, hemoglobin, platelet, plateletcrit, erythrocyte sedimentation rate, MLR, NLR, PLR and SII values after anti-TB therapy compared to pretreatment was observed (p <0.001). Logistic regression analysis generated a model of predictors consisting of nine covariates. Spearman's correlation analysis revealed significant positive correlations between NLR with NEU (r = 0.79, p<0.01), SII with NEU (r = 0.846, p<0.01), PLT with SII (r = 0.831, p<0.01), PLT with PCT (r = 0.71, p<0.01) and MPV with P-LCR (r = 0,897, p<0.01) in 63 patients out of 90 that turned culture negative after 2 months of treatment. ROC curve analysis indicated that all areas under the curve (AUC) revealed no statistically significant results, except lymphocyte for culture conversion. In summary, here we observed a set of hematological parameters that declined significantly as the disease was treated in patients that turned culture negative. Despite some limitations, our findings are useful for further studies aiming to identify hematological profiles that could predict the treatment outcome.


Assuntos
Contagem de Células Sanguíneas , Hematócrito , Tuberculose Pulmonar/patologia , Adulto , Antituberculosos/uso terapêutico , Área Sob a Curva , Plaquetas/citologia , Feminino , Humanos , Modelos Logísticos , Linfócitos/citologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Prognóstico , Curva ROC , Estudos Retrospectivos , Romênia , Tuberculose Pulmonar/tratamento farmacológico
14.
Indian J Tuberc ; 68(2): 261-265, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33845962

RESUMO

BACKGROUND: Bronchiectasis severity Index (BSI) score which predicts the severity of the disease along with future exacerbations and mortality rate has been well validated in European patients; however there is paucity of data evaluating its validity in Indian patients. The authors therefore decided to evaluate the utility of BSI to predict exacerbations and mortality rate in patients with post tubercular bronchiectasis presenting to our facility. METHODS: The study was a retrospective observational study done in patients with bronchiectasis secondary to tuberculosis. These patients were followed up for 4 years. BSI was calculated from different variables and descriptive statistics along with regression analysis were used to evaluate utility of BSI. RESULTS: A total of 48 patients of post tubercular bronchiectasis were included in the study. Majority of our patients belonged to severe bronchiectasis group seen in 23 patients (48%) while those with mild and moderate bronchiectasis were seen in 13 (27%) and 12 (25%) patients respectively. The exacerbation rate in mild group was comparable to the predicted BSI exacerbation at 1 year while the predicted and observed rates were statistically significant for moderate and severe bronchiectasis group (p value < 0.05). Mortality rates at 1 year were comparable in all the groups of bronchiectasis while it was comparable only in mild and moderate group bronchiectasis at 4 years. CONCLUSION: Bronchiectasis severity index seems to predict mortality at 1 year in post tuberculosis bronchiectasis. However, it under predicts 1 year and 4 year exacerbation rates. Hence BSI may not be useful as a prognostic tool in Indian patients with bronchiectasis. Larger multi-centred studies may be required to further evaluate the clinical utility of BSI among Indian population.


Assuntos
Bronquiectasia/diagnóstico , Índice de Gravidade de Doença , Tuberculose Pulmonar/diagnóstico , Bronquiectasia/mortalidade , Bronquiectasia/patologia , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Centros de Atenção Terciária , Tuberculose Pulmonar/mortalidade , Tuberculose Pulmonar/patologia
15.
J Clin Invest ; 131(10)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33848273

RESUMO

T cell immunity is essential for the control of tuberculosis (TB), an important disease of the lung, and is generally studied in humans using peripheral blood cells. Mounting evidence, however, indicates that tissue-resident memory T cells (Trms) are superior at controlling many pathogens, including Mycobacterium tuberculosis (M. tuberculosis), and can be quite different from those in circulation. Using freshly resected lung tissue, from individuals with active or previous TB, we identified distinct CD4+ and CD8+ Trm-like clusters within TB-diseased lung tissue that were functional and enriched for IL-17-producing cells. M. tuberculosis-specific CD4+ T cells producing TNF-α, IL-2, and IL-17 were highly expanded in the lung compared with matched blood samples, in which IL-17+ cells were largely absent. Strikingly, the frequency of M. tuberculosis-specific lung T cells making IL-17, but not other cytokines, inversely correlated with the plasma IL-1ß levels, suggesting a potential link with disease severity. Using a human granuloma model, we showed the addition of either exogenous IL-17 or IL-2 enhanced immune control of M. tuberculosis and was associated with increased NO production. Taken together, these data support an important role for M. tuberculosis-specific Trm-like, IL-17-producing cells in the immune control of M. tuberculosis in the human lung.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucina-17/imunologia , Pulmão/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Linfócitos T CD4-Positivos/patologia , Feminino , Humanos , Interleucina-1beta/imunologia , Interleucina-2/imunologia , Pulmão/patologia , Masculino , Óxido Nítrico/imunologia , Tuberculose Pulmonar/patologia
16.
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
17.
PLoS One ; 16(3): e0248493, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33750959

RESUMO

OBJECTIVES: To determine: i) the emergency department (ED) utilization history of pulmonary tuberculosis (PTB) patients, and ii) the potential individual and public health consequences of a missed diagnosis of PTB in this setting. DESIGN: Retrospective observational cohort study. PARTICIPANTS: Patients with PTB aged >16 years diagnosed between April 1, 2010 and December 31, 2016 in the Province of Alberta, Canada. METHODS: We identified valid new cases of PTB from a provincial registry and linked them to ED attendees in administrative databases. Visits are considered 'PTB', pulmonary 'other', and non-pulmonary based on the most responsible discharge diagnosis. Individual consequences of a missed diagnosis included health system delay and PTB-related death; public health consequences included nosocomial ED exposure time and secondary cases. RESULTS: Of 711 PTB patients, 378 (53%) made 845 ED visits in the six months immediately preceding the date of diagnosis. The most responsible ED discharge diagnosis was PTB in 92 (10.9%), pulmonary 'other' in 273 (32%) and non-pulmonary in 480 (56.8%). ED attendees had a median (IQR) health system delay of 27 (7,180) days and, compared to non-ED attendees were more likely to die a TB-related death 5.9% vs 1.2%, p = 0.001. Emergency attendees generated 3812 hours of ED nosocomial exposure time, and 31 secondary cases (60.8% of all secondary cases reported). Mycobacterium tuberculosis isolates from ED-attendees were more likely than non-attendees to be clustered-i.e., have an identical DNA fingerprint with another isolate (27% vs. 21%, p = 0.037). CONCLUSIONS: ED utilization by PTB patients, and related consequences, are substantial. EDs are a potential resource for earlier PTB diagnosis.


Assuntos
Serviço Hospitalar de Emergência , Diagnóstico Ausente , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Pulmonar/diagnóstico , Adolescente , Adulto , Alberta/epidemiologia , Estudos de Coortes , Gerenciamento de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/patogenicidade , Saúde Pública , Estudos Retrospectivos , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/patologia , Adulto Jovem
18.
PLoS Negl Trop Dis ; 15(3): e0009194, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33651797

RESUMO

Both Mycobacterium tuberculosis infection and helminths may affect innate immune mechanisms such as differential effects on monocytes towards the non-classical and intermediate subsets that favor bacterial persistence. Our aim, was to investigate helminth species specific effects on the frequency and functional activity of monocyte subsets in patients with active tuberculosis and healthy subjects. HIV-negative patients with active pulmonary tuberculosis (PTB) and community controls (CCs) in Gondar, Ethiopia were screened for helminth infection by stool microscopy. Flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) and ex vivo stimulation with purified protein derivative (PPD) and helminth antigens were used to characterize the distribution of monocyte subsets and their function. A total of 74 PTB patients and 57 CCs with and without helminth infection were included. Non-classical monocytes were increased in PTB patients with Ascaris and hookworm infection but not in Schistosoma-infected patients. Ascaris had the strongest effect in increasing the frequency of non-classical monocytes in both PTB patients and CCs, whereas PTB without helminth infection did not affect the frequency of monocyte subsets. There was a helminth specific increase in the frequency of TNF-α producing non-classical monocytes in hookworm infected PTB patients, both with and without PPD-stimulation. Low-to-intermediate TB disease severity associated with increased frequency of non-classical monocytes only for helminth-positive PTB patients, and the frequency of TNF-α producing monocytes were significantly higher in intermediate and non-classical monocytes of helminth positive PTB patients with an intermediate disease score. Helminth infection affected the frequency of monocyte subsets and function both in TB patients and controls which was helminth species dependent in TB patients. The clinical role of this potential immunomodulatory effect needs further study and may affect the response and protection to tuberculosis in areas where helminth infections are endemic.


Assuntos
Helmintíase/patologia , Leucócitos Mononucleares/metabolismo , Tuberculose Pulmonar/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Animais , Antígenos de Helmintos , Estudos de Casos e Controles , Coinfecção , Etiópia , Feminino , Helmintíase/imunologia , Helmintos/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Ovos de Parasitas , Tuberculose Pulmonar/patologia
19.
Nat Commun ; 12(1): 1606, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33707445

RESUMO

Tuberculosis is a chronic disease that displays several features commonly associated with biofilm-associated infections: immune system evasion, antibiotic treatment failures, and recurrence of infection. However, although Mycobacterium tuberculosis (Mtb) can form cellulose-containing biofilms in vitro, it remains unclear whether biofilms are formed during infection in vivo. Here, we demonstrate the formation of Mtb biofilms in animal models of infection and in patients, and that biofilm formation can contribute to drug tolerance. First, we show that cellulose is also a structural component of the extracellular matrix of in vitro biofilms of fast and slow-growing nontuberculous mycobacteria. Then, we use cellulose as a biomarker to detect Mtb biofilms in the lungs of experimentally infected mice and non-human primates, as well as in lung tissue sections obtained from patients with tuberculosis. Mtb strains defective in biofilm formation are attenuated for survival in mice, suggesting that biofilms protect bacilli from the host immune system. Furthermore, the administration of nebulized cellulase enhances the antimycobacterial activity of isoniazid and rifampicin in infected mice, supporting a role for biofilms in phenotypic drug tolerance. Our findings thus indicate that Mtb biofilms are relevant to human tuberculosis.


Assuntos
Biofilmes/crescimento & desenvolvimento , Celulose/metabolismo , Farmacorresistência Bacteriana Múltipla/fisiologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/metabolismo , Animais , Celulase/farmacologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Isoniazida/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium abscessus/crescimento & desenvolvimento , Mycobacterium avium/crescimento & desenvolvimento , Mycobacterium fortuitum/crescimento & desenvolvimento , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/farmacologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/patologia
20.
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
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