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1.
PLoS One ; 16(9): e0257647, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34543329

RESUMO

INTRODUCTION: Despite the exalted status of sputum mycobacterial load for gauging pulmonary tuberculosis treatment and progress, Chest X-rays supplement valuable information for taking instantaneous therapeutic decisions, especially during the COVID-19 pandemic. Even though literature on individual parameters is overwhelming, few studies have explored the interaction between radiographic parameters denoting severity with mycobacterial burden signifying infectivity. By using a sophisticated approach of integrating Chest X-ray parameters with sputum mycobacterial characteristics, evaluated at all the three crucial time points of TB treatment namely pre-treatment, end of intensive phase and completion of treatment, utilizing the interactive Cox Proportional Hazards model, we aimed to precisely deduce predictors of unfavorable response to TB treatment. MATERIALS AND METHOD: We extracted de-identified data from well characterized clinical trial cohorts that recruited rifampicin-sensitive Pulmonary TB patients without any comorbidities, taking their first spell of anti-tuberculosis therapy under supervision and meticulous follow up for 24 months post treatment completion, to accurately predict TB outcomes. Radiographic data independently obtained, interpreted by two experienced pulmonologists was collated with demographic details and, sputum smear and culture grades of participants by an independent statistician and analyzed using the Cox Proportional Hazards model, to not only adjust for confounding factors including treatment effect, but also explore the interaction between radiological and bacteriological parameters for better therapeutic application. RESULTS: Of 667 TB patients with data available, cavitation, extent of involvement, lower zone involvement, smear and culture grade at baseline were significant parameters predisposing to an unfavorable TB treatment outcome in the univariate analysis. Reduction in radiological lesions in Chest X-ray by at least 50% at 2 months and 75% at the end of treatment helped in averting unfavorable responses. Smear and Culture conversion at the end of 2 months was highly significant as a predictor (p<0.001). In the multivariate analysis, the adjusted hazards ratios (HR) for an unfavorable response to TB therapy for extent of involvement, baseline cavitation and persistence (post treatment) were 1.21 (95% CI: 1.01-1.44), 1.73 (95% CI: 1.05-2.84) and 2.68 (95% CI: 1.4-5.12) respectively. A 3+ smear had an HR of 1.94 (95% CI: 0.81-4.64). Further probing into the interaction, among patients with 3+ and 2+ smears, HRs for cavitation were 3.26 (95% CI: 1.33-8.00) and 1.92 (95% CI: 0.80-4.60) while for >2 zones, were 3.05 (95% CI: 1.12-8.23) and 1.92 (95% CI: 0.72-5.08) respectively. Patients without cavitation, zonal involvement <2, and a smear grade less than 2+ had a better prognosis and constituted minimal disease. CONCLUSION: Baseline Cavitation, Opacities occupying >2 zones and 3+ smear grade individually and independently forecasted a poorer TB outcome. The interaction model revealed that Zonal involvement confined to 2 zones, without a cavity and smear grade up to 2+, constituting "minimal disease", had a better prognosis. Radiological clearance >50% along with smear conversion at the end of intensive phase of treatment, observed to be a reasonable alternative to culture conversion in predicting a successful outcome. These parameters may potentially take up key positions as stratification factors for future trials contemplating on shorter TB regimens.


Assuntos
Mycobacterium tuberculosis/fisiologia , Rifampina/uso terapêutico , Escarro/microbiologia , Tuberculose Pulmonar/diagnóstico por imagem , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Análise Multivariada , Modelos de Riscos Proporcionais , Rifampina/farmacologia , Resultado do Tratamento , Tuberculose Pulmonar/microbiologia , Adulto Jovem
3.
Dokl Biochem Biophys ; 499(1): 266-272, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34426925

RESUMO

The present study investigated Boerhaavia diffusa extract against Mycobacterium tuberculosis H37Rv (M.tb) infection in vitro and explored the underlying mechanism. The study demonstrated that Boerhaavia diffusa extract significantly (p < 0.05) reduced RAW 264.7 and A549 cell viability in concentration dependent manner. In BEAS-2B, NuLi-1 cells and splenocytes no significant (p > 0.05) reduction in viability was observed on treatment with 2.5 to 20 mg/L concentrations of Boerhaavia diffusa. The M. tb­induced increase in TNF­α expression was significantly (p < 0.05) reversed by Boerhaavia diffusa treatment in RAW 264.7 and BEAS-2B cells. Moreover, Boerhaavia diffusa treatment significantly (p < 0.05) inhibited M.tb­induced increase in IL-6 and IL­1ß expression in RAW 264.7 and BEAS-2B cells. Boerhaavia diffusa treatment of RAW 264.7 and BEAS-2B cells significantly (p < 0.05) reversed M.tb­induced increase in iNOS and COX­2 expression. Additionally, in Boerhaavia diffusa treated cells M.tb­induced increase in NO release was significantly (p < 0.05) reduced compared to untreated cells. In summary, Boerhaavia diffusa treatment inhibits pro-inflammatory cytokine production, NO release and regulate immunomodulatory mediators in M.tb­infected RAW 264.7 and BEAS-2B cells. Therefore, Boerhaavia diffusa may be developed as a therapeutic agent for treatment of M.tb­infection.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Nyctaginaceae/química , Extratos Vegetais/farmacologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Mycobacterium tuberculosis/fisiologia , Células RAW 264.7
4.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445098

RESUMO

Granulysin is an antimicrobial peptide (AMP) expressed by human T-lymphocytes and natural killer cells. Despite a remarkably broad antimicrobial spectrum, its implementation into clinical practice has been hampered by its large size and off-target effects. To circumvent these limitations, we synthesized a 29 amino acid fragment within the putative cytolytic site of Granulysin (termed "Gran1"). We evaluated the antimicrobial activity of Gran1 against the major human pathogen Mycobacterium tuberculosis (Mtb) and a panel of clinically relevant non-tuberculous mycobacteria which are notoriously difficult to treat. Gran1 efficiently inhibited the mycobacterial proliferation in the low micro molar range. Super-resolution fluorescence microscopy and scanning electron microscopy indicated that Gran1 interacts with the surface of Mtb, causing lethal distortions of the cell wall. Importantly, Gran1 showed no off-target effects (cytokine release, chemotaxis, cell death) in primary human cells or zebrafish embryos (cytotoxicity, developmental toxicity, neurotoxicity, cardiotoxicity). Gran1 was selectively internalized by macrophages, the major host cell of Mtb, and restricted the proliferation of the pathogen. Our results demonstrate that the hypothesis-driven design of AMPs is a powerful approach for the identification of small bioactive compounds with specific antimicrobial activity. Gran1 is a promising component for the design of AMP-containing nanoparticles with selective activity and favorable pharmacokinetics to be pushed forward into experimental in vivo models of infectious diseases, most notably tuberculosis.


Assuntos
Antígenos de Diferenciação de Linfócitos T/imunologia , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Animais , Antígenos de Diferenciação de Linfócitos T/química , Células Cultivadas , Interações Hospedeiro-Patógeno , Humanos , Macrófagos/microbiologia , Mycobacterium tuberculosis/fisiologia , Peptídeos/química , Peptídeos/imunologia , Tuberculose/microbiologia , Peixe-Zebra
5.
J Immunol ; 207(5): 1239-1249, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34389623

RESUMO

HIV-1 infection substantially increases the risk of developing tuberculosis (TB). Mechanisms such as defects in the Th1 response to Mycobacterium tuberculosis in HIV-infected persons have been widely reported. However, Th1-independent mechanisms also contribute to protection against TB. To identify a broader spectrum of defects in TB immunity during HIV infection, we examined IL-17A and IL-22 production in response to mycobacterial Ags in peripheral blood of persons with latent TB infection and HIV coinfection. Upon stimulating with mycobacterial Ags, we observed a distinct CD4+ Th lineage producing IL-22 in the absence of IL-17A and IFN-γ. Mycobacteria-specific Th22 cells were present at high frequencies in blood and contributed up to 50% to the CD4+ T cell response to mycobacteria, comparable in magnitude to the IFN-γ Th1 response (median 0.91% and 0.55%, respectively). Phenotypic characterization of Th22 cells revealed that their memory differentiation was similar to M. tuberculosis-specific Th1 cells (i.e., predominantly early differentiated CD45RO+CD27+ phenotype). Moreover, CCR6 and CXCR3 expression profiles of Th22 cells were similar to Th17 cells, whereas their CCR4 and CCR10 expression patterns displayed an intermediate phenotype between Th1 and Th17 cells. Strikingly, mycobacterial IL-22 responses were 3-fold lower in HIV-infected persons compared with uninfected persons, and the magnitude of responses correlated inversely with HIV viral load. These data provide important insights into mycobacteria-specific Th subsets in humans and suggest a potential role for IL-22 in protection against TB during HIV infection. Further studies are needed to fully elucidate the role of IL-22 in protective TB immunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Interleucinas/metabolismo , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/fisiologia , Subpopulações de Linfócitos T/imunologia , Adulto , Células Cultivadas , Coinfecção , Feminino , Soropositividade para HIV , Humanos , Interleucina-17/metabolismo , Masculino , África do Sul , Carga Viral , Adulto Jovem
6.
Nat Microbiol ; 6(8): 1082-1093, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34294904

RESUMO

Pathogenomic evidence suggests that Mycobacterium tuberculosis (MTB) evolved from an environmental ancestor similar to Mycobacterium canettii, a rare human pathogen. Although the adaptations responsible for this transition are poorly characterized, the ability to persist in humans seems to be important. We set out to identify the adaptations contributing to the evolution of persistence in MTB. We performed an experimental evolution of eight M. canettii populations in mice; four populations were derived from the isolate STB-K (phylogenomically furthest from MTB) and four from STB-D (closest to MTB), which were monitored for 15 and 6 cycles, respectively. We selected M. canettii mutants with enhanced persistence in vivo compared with the parental strains, which were phenotypically closer to MTB. Genome sequencing of 140 mutants and complementation analysis revealed that mutations in two loci were responsible for enhanced persistence. Most of the tested mutants were more resistant than their parental strains to nitric oxide, an important effector of immunity. Modern MTB were similarly more resistant to nitric oxide than M. canettii. Our findings demonstrate phenotypic convergence during experimental evolution of M. canettii, which mirrors natural evolution of MTB. Furthermore, they indicate that the ability to withstand host-induced stresses was key for the emergence of persistent MTB.


Assuntos
Evolução Biológica , Mycobacterium tuberculosis/fisiologia , Mycobacterium/fisiologia , Animais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Mutação , Mycobacterium/genética , Mycobacterium tuberculosis/genética , Estresse Fisiológico , Tuberculose/microbiologia
7.
Eur J Med Chem ; 223: 113657, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34217060

RESUMO

As a continuation of our research on antimycobacterial agents, a series of novel quinoxaline-1,4-di-N-oxides (QdNOs) containing various nitrogenous heterocyclic moieties at the R6 position were designed and synthesized. Antimycobacterial activities, as well as the cytotoxic effects, of the compounds were assayed. Four compounds (6b, 6f, 6n, and 6o), characterized by 2-carboxylate ethyl or benzyl ester, 6-imidazolyl or 1,2,4-triazolyl, and a 7-fluorine group, exhibited the most potent antimycobacterial activity against M.tb strain H37Rv (MIC ≤ 0.25 µg/mL) with low toxicity in VERO cells (SI = 169.3-412.1). Compound 6o also exhibited excellent antimycobacterial activity in an M.tb-infected macrophage model and was selected for further exploration of the mode of antimycobacterial action of QdNOs. The results showed that compound 6o was capable of disrupting membrane integrity and disturbing energy homeostasis in M.tb. Furthermore, compound 6o noticeably increased cellular ROS levels and, subsequently, induced autophagy in M.tb-infected macrophages, possibly indicating the pathways of QdNOs-mediated inhibition of intracellular M.tb replication. The in vivo pharmacokinetic (PK) profiles indicated that compounds 6o was acceptably safe and possesses favorable PK properties. Altogether, these findings suggest that compound 6o is a promising antimycobacterial candidate for further research.


Assuntos
Antituberculosos/farmacologia , Autofagia/efeitos dos fármacos , Macrófagos/microbiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Quinoxalinas/química , Animais , Antituberculosos/química , Antituberculosos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Testes de Sensibilidade Microbiana , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mycobacterium tuberculosis/fisiologia , Óxidos/química , Quinoxalinas/farmacocinética , Quinoxalinas/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Células Vero
8.
Int J Mol Sci ; 22(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299161

RESUMO

Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Currently, there are no reports on the mycobacterial components that regulate PGE2 production. Previously, we have reported that RpfE-treated dendritic cells (DCs) effectively expanded the Th1 and Th17 cell responses simultaneously; however, the mechanism underlying Th1 and Th17 cell differentiation is unclear. Here, we show that PGE2 produced by RpfE-activated DCs via the MAPK and cyclooxygenase 2 signaling pathways induces Th1 and Th17 cell responses mainly via the EP4 receptor. Furthermore, mice administered intranasally with PGE2 displayed RpfE-induced antigen-specific Th1 and Th17 responses with a significant reduction in bacterial load in the lungs. Furthermore, the addition of optimal PGE2 amount to IL-2-IL-6-IL-23p19-IL-1ß was essential for promoting differentiation into Th1/Th17 cells with strong bactericidal activity. These results suggest that RpfE-matured DCs produce PGE2 that induces Th1 and Th17 cell differentiation with potent anti-mycobacterial activity.


Assuntos
Proteínas de Bactérias/metabolismo , Diferenciação Celular , Células Dendríticas/metabolismo , Dinoprostona/metabolismo , Mycobacterium tuberculosis/fisiologia , Células Th1/citologia , Células Th17/citologia , Animais , Células Dendríticas/imunologia , Células Dendríticas/microbiologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Células Th1/imunologia , Células Th17/imunologia , Tuberculose/imunologia , Tuberculose/metabolismo , Tuberculose/microbiologia
9.
Front Immunol ; 12: 611673, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220793

RESUMO

In tuberculosis, T cell-mediated immunity is extensively studied whilst B cells received limited attention in human and mice. Of interest, Mycobacterium tuberculosis (Mtb) does increase IL-4 Receptor-alpha (IL4Rα) expression in murine B cells. To better understand the role of IL4Rα signalling in B cells, we compared wild type mice with B cell-specific IL4Rα deficient mice (mb1creIL-4Rα-/lox mice). Chronic Mtb aerosol infection in mb1creIL-4Rα-/lox mice reduced lung and spleen bacterial burdens, compared to littermate (IL-4Rα-/lox) control animals. Consequently, lung pathology, inflammation and inducible nitric oxide synthase (iNOS) expression were reduced in the lungs of mb1creIL-4Rα-/lox mice, which was also accompanied by increased lung IgA and decreased IgG1 levels. Furthermore, intratracheal adoptive transfer of wild-type B cells into B cell-specific IL4Rα deficient mice reversed the protective phenotype. Moreover, constitutively mCherry expressing Mtb showed decreased association with B cells from mb1creIL-4Rα-/lox mice ex vivo. In addition, supernatants from Mtb-exposed B cells of mb1creIL-4Rα-/lox mice also increased the ability of macrophages to produce nitric oxide, IL-1ß, IL-6 and TNF. Together, this demonstrates that IL-4-responsive B cells are detrimental during the chronic phase of tuberculosis in mice with perturbed antibody profiles, inflammatory cytokines and tnf and stat1 levels in the lungs.


Assuntos
Linfócitos B/imunologia , Imunoglobulina A/metabolismo , Interleucina-4/metabolismo , Pulmão/metabolismo , Macrófagos/patologia , Mycobacterium tuberculosis/fisiologia , Tuberculose/imunologia , Animais , Doença Crônica , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores de Superfície Celular/genética , Transdução de Sinais
10.
PLoS One ; 16(6): e0253169, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34143810

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created a remarkable and varying impact in every country, inciting calls for broad attention. Recently, the Bacillus Calmette-Guérin (BCG) vaccination has been regarded as a potential candidate to explain this difference. Herein, we hypothesised that the past epidemic of Mycobacterium tuberculosis (M. tuberculosis) may act as a latent explanatory factor for the worldwide differences seen in COVID-19 impact on mortality and incidence. We compared two indicators of past epidemic of M. tuberculosis, specifically, incidence (90 countries in 1990) and mortality (28 countries in 1950), with the mortality and incidence of COVID-19. We determined that an inverse relationship existed between the past epidemic indicators of M. tuberculosis and current COVID-19 impact. The rate ratio of the cumulative COVID-19 mortality per 1 million was 2.70 (95% confidence interval [CI]: 1.09-6.68) per 1 unit decrease in the incidence rate of tuberculosis (per 100,000 people). The rate ratio of the cumulative COVID-19 incidence per 1 million was 2.07 (95% CI: 1.30-3.30). This association existed even after adjusting for potential confounders (rate of people aged 65 over, diabetes prevalence, the mortality rate from cardiovascular disease, and gross domestic product per capita), leading to an adjusted rate ratio of COVID-19 mortality of 2.44, (95% CI: 1.32-4.52) and a COVID-19 incidence of 1.31 (95% CI: 0.97-1.78). After latent infection, Mycobacterium survives in the human body and may continue to stimulate trained immunity. This study suggests a possible mechanism underlying the region-based variation in the COVID-19 impact.


Assuntos
Vacina BCG/imunologia , COVID-19/prevenção & controle , Mycobacterium tuberculosis/imunologia , SARS-CoV-2/isolamento & purificação , Tuberculose/imunologia , COVID-19/epidemiologia , COVID-19/virologia , Epidemias , Humanos , Incidência , Modelos Teóricos , Mycobacterium tuberculosis/fisiologia , Prevalência , SARS-CoV-2/fisiologia , Taxa de Sobrevida , Tuberculose/epidemiologia , Tuberculose/microbiologia , Vacinação
11.
Front Immunol ; 12: 647019, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995365

RESUMO

Tuberculosis can occur during any stage of Human Immunodeficiency virus 1 (HIV) -infection including times when CD4+ T cell numbers have reconstituted and viral replication suppressed. We have previously shown that CD11b+CD33+CD14+HLA-DR-/lo monocytic myeloid-derived suppressor cells (MDSC) persist in HIV-infected individuals on combined anti-retroviral therapy (cART) and with virologic suppression. The response of MDSC to Mycobacterium tuberculosis (Mtb) is not known. In this study, we compared the anti-mycobacterial activity of MDSC isolated from HIV -infected individuals on cART with virologic suppression (HIV MDSC) and HIV-uninfected healthy controls (HIV (-) MDSC). Compared to HIV (-) MDSC, HIV MDSC produced significantly less quantities of anti-mycobacterial cytokines IL-12p70 and TNFα, and reactive oxygen species when cultured with infectious Mtb or Mtb antigens. Furthermore, HIV MDSC showed changes in the Toll-like receptor and IL-27 signaling, including reduced expression of MyD88 and higher levels of IL-27. Neutralizing IL-27 and overexpression of MyD88 synergistically controlled intracellular replication of Mtb in HIV MDSC. These results demonstrate that MDSC in fully suppressed HIV-infected individuals are permissive to Mtb and exhibit downregulated anti-mycobacterial innate immune activity through mechanisms involving IL-27 and TLR signaling. Our findings suggest MDSC as novel mediators of tuberculosis in HIV-Mtb co-infected individuals with virologic suppression.


Assuntos
Infecções por HIV/imunologia , Imunidade Inata/imunologia , Monócitos/imunologia , Mycobacterium tuberculosis/imunologia , Células Supressoras Mieloides/imunologia , Antivirais/uso terapêutico , Coinfecção/imunologia , Coinfecção/microbiologia , Coinfecção/virologia , Citocinas/imunologia , Citocinas/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , HIV-1/fisiologia , Humanos , Interleucina-27/imunologia , Interleucina-27/metabolismo , Monócitos/microbiologia , Monócitos/virologia , Mycobacterium tuberculosis/fisiologia , Fator 88 de Diferenciação Mieloide/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Células Supressoras Mieloides/microbiologia , Células Supressoras Mieloides/virologia , Transdução de Sinais/imunologia , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo , Tuberculose/imunologia , Tuberculose/microbiologia
12.
Nat Commun ; 12(1): 2899, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006838

RESUMO

There is urgent need for new drug regimens that more rapidly cure tuberculosis (TB). Existing TB drugs and regimens vary in treatment-shortening activity, but the molecular basis of these differences is unclear, and no existing assay directly quantifies the ability of a drug or regimen to shorten treatment. Here, we show that drugs historically classified as sterilizing and non-sterilizing have distinct impacts on a fundamental aspect of Mycobacterium tuberculosis physiology: ribosomal RNA (rRNA) synthesis. In culture, in mice, and in human studies, measurement of precursor rRNA reveals that sterilizing drugs and highly effective drug regimens profoundly suppress M. tuberculosis rRNA synthesis, whereas non-sterilizing drugs and weaker regimens do not. The rRNA synthesis ratio provides a readout of drug effect that is orthogonal to traditional measures of bacterial burden. We propose that this metric of drug activity may accelerate the development of shorter TB regimens.


Assuntos
Antituberculosos/administração & dosagem , Mycobacterium tuberculosis/efeitos dos fármacos , Precursores de RNA/metabolismo , RNA Ribossômico/metabolismo , Tuberculose/tratamento farmacológico , Animais , Modelos Animais de Doenças , Feminino , Humanos , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/fisiologia , Precursores de RNA/genética , RNA Bacteriano/genética , RNA Bacteriano/metabolismo , RNA Ribossômico/genética , Resultado do Tratamento , Tuberculose/diagnóstico , Tuberculose/microbiologia
13.
PLoS Pathog ; 17(5): e1009570, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33989345

RESUMO

Mycobacterium tuberculosis (Mtb) has complex and dynamic interactions with the human host, and subpopulations of Mtb that emerge during infection can influence disease outcomes. This study implicates zinc ion (Zn2+) availability as a likely driver of bacterial phenotypic heterogeneity in vivo. Zn2+ sequestration is part of "nutritional immunity", where the immune system limits micronutrients to control pathogen growth, but this defense mechanism seems to be ineffective in controlling Mtb infection. Nonetheless, Zn2+-limitation is an environmental cue sensed by Mtb, as calprotectin triggers the zinc uptake regulator (Zur) regulon response in vitro and co-localizes with Zn2+-limited Mtb in vivo. Prolonged Zn2+ limitation leads to numerous physiological changes in vitro, including differential expression of certain antigens, alterations in lipid metabolism and distinct cell surface morphology. Furthermore, Mtb enduring limited Zn2+ employ defensive measures to fight oxidative stress, by increasing expression of proteins involved in DNA repair and antioxidant activity, including well described virulence factors KatG and AhpC, along with altered utilization of redox cofactors. Here, we propose a model in which prolonged Zn2+ limitation defines a population of Mtb with anticipatory adaptations against impending immune attack, based on the evidence that Zn2+-limited Mtb are more resistant to oxidative stress and exhibit increased survival and induce more severe pulmonary granulomas in mice. Considering that extracellular Mtb may transit through the Zn2+-limited caseum before infecting naïve immune cells or upon host-to-host transmission, the resulting phenotypic heterogeneity driven by varied Zn2+ availability likely plays a key role during early interactions with host cells.


Assuntos
Granuloma/microbiologia , Lipidômica , Mycobacterium tuberculosis/fisiologia , Proteoma , Transcriptoma , Zinco/deficiência , Adaptação Fisiológica , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Granuloma/imunologia , Homeostase , Interações Hospedeiro-Patógeno , Humanos , Pulmão/microbiologia , Camundongos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Oxirredução , Estresse Oxidativo , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
14.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946542

RESUMO

Neutrophils readily infiltrate infection foci, phagocytose and usually destroy microbes. In tuberculosis (TB), a chronic pulmonary infection caused by Mycobacterium tuberculosis (Mtb), neutrophils harbor bacilli, are abundant in tissue lesions, and their abundances in blood correlate with poor disease outcomes in patients. The biology of these innate immune cells in TB is complex. Neutrophils have been assigned host-beneficial as well as deleterious roles. The short lifespan of neutrophils purified from blood poses challenges to cell biology studies, leaving intracellular biological processes and the precise consequences of Mtb-neutrophil interactions ill-defined. The phenotypic heterogeneity of neutrophils, and their propensity to engage in cellular cross-talk and to exert various functions during homeostasis and disease, have recently been reported, and such observations are newly emerging in TB. Here, we review the interactions of neutrophils with Mtb, including subcellular events and cell fate upon infection, and summarize the cross-talks between neutrophils and lung-residing and -recruited cells. We highlight the roles of neutrophils in TB pathophysiology, discussing recent findings from distinct models of pulmonary TB, and emphasize technical advances that could facilitate the discovery of novel neutrophil-related disease mechanisms and enrich our knowledge of TB pathogenesis.


Assuntos
Mycobacterium tuberculosis/imunologia , Neutrófilos/imunologia , Tuberculose/imunologia , Animais , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Mycobacterium tuberculosis/fisiologia , Neutrófilos/microbiologia , Neutrófilos/patologia , Fagocitose , Tuberculose/microbiologia , Tuberculose/patologia
15.
PLoS Med ; 18(4): e1003566, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33901173

RESUMO

BACKGROUND: Two weeks' isolation is widely recommended for people commencing treatment for pulmonary tuberculosis (TB). The evidence that this corresponds to clearance of potentially infectious tuberculous mycobacteria in sputum is not well established. This World Health Organization-commissioned review investigated sputum sterilisation dynamics during TB treatment. METHODS AND FINDINGS: For the main analysis, 2 systematic literature searches of OvidSP MEDLINE, Embase, and Global Health, and EBSCO CINAHL Plus were conducted to identify studies with data on TB infectiousness (all studies to search date, 1 December 2017) and all randomised controlled trials (RCTs) for drug-susceptible TB (from 1 January 1990 to search date, 20 February 2018). Included articles reported on patients receiving effective treatment for culture-confirmed drug-susceptible pulmonary TB. The outcome of interest was sputum bacteriological conversion: the proportion of patients having converted by a defined time point or a summary measure of time to conversion, assessed by smear or culture. Any study design with 10 or more particpants was considered. Record sifting and data extraction were performed in duplicate. Random effects meta-analyses were performed. A narrative summary additionally describes the results of a systematic search for data evaluating infectiousness from humans to experimental animals (PubMed, all studies to 27 March 2018). Other evidence on duration of infectiousness-including studies reporting on cough dynamics, human tuberculin skin test conversion, or early bactericidal activity of TB treatments-was outside the scope of this review. The literature search was repeated on 22 November 2020, at the request of the editors, to identify studies published after the previous censor date. Four small studies reporting 3 different outcome measures were identified, which included no data that would alter the findings of the review; they are not included in the meta-analyses. Of 5,290 identified records, 44 were included. Twenty-seven (61%) were RCTs and 17 (39%) were cohort studies. Thirteen studies (30%) reported data from Africa, 12 (27%) from Asia, 6 (14%) from South America, 5 (11%) from North America, and 4 (9%) from Europe. Four studies reported data from multiple continents. Summary estimates suggested smear conversion in 9% of patients at 2 weeks (95% CI 3%-24%, 1 single study [N = 1]), and 82% of patients at 2 months of treatment (95% CI 78%-86%, N = 10). Among baseline smear-positive patients, solid culture conversion occurred by 2 weeks in 5% (95% CI 0%-14%, N = 2), increasing to 88% at 2 months (95% CI 84%-92%, N = 20). At equivalent time points, liquid culture conversion was achieved in 3% (95% CI 1%-16%, N = 1) and 59% (95% CI 47%-70%, N = 8). Significant heterogeneity was observed. Further interrogation of the data to explain this heterogeneity was limited by the lack of disaggregation of results, including by factors such as HIV status, baseline smear status, and the presence or absence of lung cavitation. CONCLUSIONS: This systematic review found that most patients remained culture positive at 2 weeks of TB treatment, challenging the view that individuals are not infectious after this interval. Culture positivity is, however, only 1 component of infectiousness, with reduced cough frequency and aerosol generation after TB treatment initiation likely to also be important. Studies that integrate our findings with data on cough dynamics could provide a more complete perspective on potential transmission of Mycobacterium tuberculosis by individuals on treatment. TRIAL REGISTRATION: Systematic review registration: PROSPERO 85226.


Assuntos
Mycobacterium tuberculosis/fisiologia , Escarro/microbiologia , Tuberculose Pulmonar/terapia , Humanos
16.
Biochemistry (Mosc) ; 86(Suppl 1): S109-S119, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33827403

RESUMO

Mycobacterium tuberculosis possesses a significant arsenal of strategies to combat immune defense of the host organism. Small noncoding RNAs, which constitute the largest group of regulatory RNAs, play an important role in the host-pathogen interactions and represent one of the levels of the regulation of interactions of microbial cells with their environment. The regulatory role of small RNAs in pathogenic bacteria is essential when rapid adaptation to the changing environmental conditions with further synchronization of metabolic reactions are required to ensure microbial survival and infection progression. During the past few years, eight small RNAs from M. tuberculosis have been functionally characterized, and targets for four of them have been identified. Small RNAs from M. tuberculosis and other pathogenic microorganisms were found to be one of the most important functional factors in the adaptive response to changing environmental conditions.


Assuntos
Interações Hospedeiro-Patógeno , Mycobacterium tuberculosis/fisiologia , Pequeno RNA não Traduzido/fisiologia , Tuberculose/metabolismo , Humanos , Mycobacterium tuberculosis/metabolismo , RNA Bacteriano , Pequeno RNA não Traduzido/metabolismo , Tuberculose/etiologia , Tuberculose/microbiologia
17.
Int J Infect Dis ; 106: 370-375, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33845198

RESUMO

INTRODUCTION: To evaluate the performance of Xpert MTB/RIF Ultra (Xpert-Ultra) in testing pleural tissue and fluid collected by medical thoracoscopy among patients with unexplained exudative pleural effusion. METHODS: Patients with an undiagnosed exudative pleural effusion were prospectively and consecutively recruited. Pleural tissue and fluid were collected by medical thoracoscopy and subjected to culture, Xpert MTB/RIF (Xpert) and Xpert-Ultra assays. Histopathological examination was also performed with the tissue and used as the major reference. RESULTS: Sixty-one patients were enrolled, including: 27 tuberculosis (TB) pleurisy, 15 malignancy and 19 other chronic infection cases. The sensitivity, specificity, positive predictive value, and negative predictive value of Xpert-Ultra for TB diagnosis were 85.19% (23/27), 97.06% (33/34), 95.83% (23/24), and 89.19% (33/37), respectively. Xpert-Ultra testing with the biopsy tissue alone had an equivalent diagnostic capacity to that of pathological examination for the diagnosis of confirmed TB cases. By combining the pathological examination with Xpert-Ultra for biopsy, the percentage of confirmed TB cases greatly increased (i.e. 92.59% (25/27)). The "trace" positive outcome of Xpert-Ultra was highly supportive of TB diagnosis for both biopsy tissue and pleural fluid examinations. CONCLUSION: With the specimens collected by medical thoracoscopy, the Xpert-Ultra assay presented high value in identifying TB among pleurisy patients who had difficulties in etiological diagnosis.


Assuntos
Derrame Pleural/complicações , Rifamicinas/farmacologia , Toracoscopia , Tuberculose Pleural/diagnóstico , Tuberculose Pleural/patologia , Adulto , Biópsia , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/fisiologia , Valor Preditivo dos Testes , Estudos Prospectivos , Sensibilidade e Especificidade , Tuberculose Pleural/complicações , Adulto Jovem
18.
Front Immunol ; 12: 575519, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790886

RESUMO

Diagnosis of tuberculosis (TB) in children remains challenging due to unspecific clinical presentation and low bacillary load. In low TB incidence countries, most cases are diagnosed by a contact screening strategy after exposure to an index TB case. Due to the severity of TB in young children, the priority is to determine whether a child is infected or not, whereas differential diagnosis between active TB (aTB) and latent TB constitutes a second step. In Belgium, a low TB incidence country, we prospectively included 47 children with a defined M. tuberculosis infection status (12 children with aTB, 18 with latent TB, and 17 uninfected) (exploratory cohort), and determined the optimal combinations of cytokines secreted by their peripheral blood mononuclear cells in response to a 5-days in vitro stimulation with four different mycobacterial antigens, in an attempt to classify the children according to their infectious status. Correct identification of all infected children was obtained by several combinations of two purified protein derivative (PPD)-induced cytokines (IFN-γ and either GM-CSF, MIP-1α, sCD40L or TNF-α), or by combining PPD-induced IFN-γ with culture-filtrate protein-10 (CFP-10)-induced TNF-α. Alternatively, combining CFP-10-induced TNF-α and IP-10 with heparin-binding haemagglutinin (HBHA)-induced-IFN-γ was more effective in testing recently BCG-vaccinated children or those suspected to be infected with non-tuberculous mycobacteria, providing a correct classification of 97% of the M. tuberculosis-infected children. This combination also correctly classified 98% of the children from a validation cohort comprising 40 M. tuberculosis infected children and 20 non-infected children. Further differentiation between aTB and children with latent TB was more difficult. Combining ESAT-6-induced MIP1-α and IP-10, CFP-10-induced MIG, and HBHA-induced MIG provided a correct classification of 77% of the children from the exploratory cohort but only of 57.5% of those from the validation cohort. We conclude that combining the measurement of 2-4 cytokines induced by three different mycobacterial antigens allows an excellent identification of M. tuberculosis-infected children, whereas differentiating children with aTB from those with latent TB remains far from perfect.


Assuntos
Tuberculose Latente/imunologia , Mycobacterium tuberculosis/imunologia , Linfócitos T/imunologia , Tuberculose/imunologia , Adolescente , Bélgica/epidemiologia , Células Cultivadas , Criança , Pré-Escolar , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Incidência , Lactente , Recém-Nascido , Tuberculose Latente/diagnóstico , Tuberculose Latente/microbiologia , Masculino , Mycobacterium tuberculosis/fisiologia , Linfócitos T/metabolismo , Linfócitos T/microbiologia , Tuberculose/diagnóstico , Tuberculose/epidemiologia
19.
Int J Infect Dis ; 107: 86-91, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33823278

RESUMO

OBJECTIVES: Isoniazid-monoresistant tuberculosis (HR-TB) is the most prevalent form of drug-resistant TB worldwide and in France and is associated with poorer treatment outcomes compared with drug-susceptible TB (DS-TB). The objective of this study was to determine the characteristics of HR-TB patients in France and to compare outcomes and safety of treatment for HR-TB and DS-TB. METHODS: We performed a case-control multicenter study to identify risk factors associated with HR-TB and compare treatment outcomes and safety between HR-TB patients and DS-TB patients. RESULTS: Characteristics of 99 HR-TB patients diagnosed and treated in the university hospitals of Paris, Lille, Caen and Strasbourg were compared with 99 DS-TB patients. Female sex (OR = 2.2; 1.0-4.7), birth in the West-Pacific World Health Organization region (OR = 4.6; 1.1-18.7) and resistance to streptomycin (OR = 77.5; 10.1-594.4) were found to be independently associated with HR-TB. Rates of treatment success did not differ significantly between HR-TB and DS-TB. CONCLUSIONS: Factors associated with HR-TB are not significant enough to efficiently screen TB patients at risk of HR-TB. The systematic implementation of rapid molecular testing on clinical samples remains the only effective way to make the early diagnosis of HR-TB and adapt treatment.


Assuntos
Antituberculosos/efeitos adversos , Antituberculosos/uso terapêutico , Farmacorresistência Bacteriana , Isoniazida/efeitos adversos , Isoniazida/uso terapêutico , Tuberculose/tratamento farmacológico , Adulto , Estudos de Casos e Controles , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/fisiologia , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
20.
J Mol Biol ; 433(13): 166984, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-33845087

RESUMO

Tuberculosis (TB) disease remains a major health crisis. Infection with Mycobacterium tuberculosis (M.tb) cause a range of diseases ranging from latent infection to active TB disease. This active state of the disease is characterised by the formation of granulomas (a physical barrier in the lung), a structure thought to protect the host by controlling the infection through preventing the growth of the bacilli. Subsequently, the surviving bacteria become inactive and in most cases, TB reactivation is prevented by the immune response of the host. B-cells perform numerous immunological functions beyond antibody production to positively regulate the response to pathogenic assault. A subgroup of B-cells with regulatory functions express death-inducing ligands, such as Fas ligand (FasL). Expression and interaction of the Fas receptor-ligand promotes the induction of apoptosis and the induction of T-cell tolerance. Here, we focus on the significance of B-cells by addressing their FasL phenotype and regulatory functions during TB, with reference to disease in humans, non-human primates and mice.


Assuntos
Linfócitos B Reguladores/metabolismo , Proteína Ligante Fas/metabolismo , Mycobacterium tuberculosis/fisiologia , Tuberculose/imunologia , Tuberculose/microbiologia , Animais , Citocinas/biossíntese , Humanos , Modelos Biológicos
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