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1.
Front Microbiol ; 15: 1392782, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38881671

RESUMEN

Introduction: The proteolytic activity of A Disintegrin and Metalloproteinase 17 (ADAM17) regulates the release of tumor necrosis factor (TNF) and TNF receptors (TNFRs) from cell surfaces. These molecules play important roles in tuberculosis (TB) shaping innate immune reactions and granuloma formation. Methods: Here, we investigated whether single nucleotide polymorphisms (SNPs) of ADAM17 influence TNF and TNFRs levels in 224 patients with active TB (ATB) and 118 healthy close contacts. Also, we looked for significant associations between SNPs of ADAM17 and ATB status. TNF, TNFR1, and TNFR2 levels were measured in plasma samples by ELISA. Four SNPs of ADAM17 (rs12692386, rs1524668, rs11684747, and rs55790676) were analyzed in DNA isolated from peripheral blood leucocytes. The association between ATB status, genotype, and cytokines was analyzed by multiple regression models. Results: Our results showed a higher frequency of rs11684747 and rs55790676 in close contacts than ATB patients. Coincidentally, heterozygous to these SNPs of ADAM17 showed higher plasma levels of TNF compared to homozygous to their respective ancestral alleles. Strikingly, the levels of TNF and TNFRs distinguished participant groups, with ATB patients displaying lower TNF and higher TNFR1/TNFR2 levels compared to their close contacts. Conclusion: These findings suggest a role for SNPs of ADAM17 in genetic susceptibility to ATB.

2.
Tuberculosis (Edinb) ; 143: 102418, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37813014

RESUMEN

Pulmonary tuberculosis (TB) inflammation is an underestimated disease complication which anti-inflammatory drugs may alleviate. This study explored the potential use of the COX-2 inhibitors acetylsalicylic acid (ASA) and celecoxib in 12 TB patients and 12 healthy controls using a whole-blood ex vivo model where TNFα, PGE2, and LTB4 plasma levels were quantitated by ELISA; we also measured COX-2, 5-LOX, 12-LOX, and 15-LOX gene expression. We observed a significant TNFα production in response to stimulation with LPS or M. tuberculosis (Mtb). Celecoxib, but not ASA, reduced TNFα and PGE2 production, while increasing LTB4 in patients after infection with Mtb. Gene expression of COX-2 and 5-LOX was higher in controls, while 12-LOX was significantly higher in patients. 15-LOX expression was similar in both groups. We concluded that COX-2 inhibitors downregulate inflammation after Mtb infection, and our methodology offers a straightforward time-efficient approach for evaluating different drugs in this context. Further research is warranted to elucidate the underlying mechanisms and assess the potential clinical benefit.


Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Humanos , Celecoxib/farmacología , Celecoxib/uso terapéutico , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Dinoprostona , Inmunidad , Inflamación/metabolismo , Leucotrieno B4/metabolismo , Mycobacterium tuberculosis/metabolismo , Tuberculosis/tratamiento farmacológico , Factor de Necrosis Tumoral alfa
3.
Front Immunol ; 14: 1241121, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37753080

RESUMEN

Introduction: Pulmonary dysfunction is an underestimated complication in tuberculosis (TB) infection, affecting quality of life (QoL). Although respiratory function tests objectively reflect lung disturbances in a specific moment, predictors of illness severity at the time of diagnosis are still lacking. Methods: We measured serum pro-inflammatory cytokines (TNF-α and IL-8), eicosanoids (PGE2, LTB4, RvD1, Mar1, and LXA4), a marker of tissue damage (cell-free nucleosomes), and indicators of redox status (malonaldehyde, 8-isoprostane, total oxidants, and antioxidants), as well as a score of radiological abnormalities (SRA) and a QoL questionnaire, in 25 patients with pulmonary TB at the time of diagnosis (t0) and two months after the initiation of treatment (t2). Results: We found higher antioxidant levels in the patients with the worst QoL at t0, and all the indicators of the prooxidant state were significantly reduced at t2, while the total antioxidant levels increased. LTB4, a pro-inflammatory eicosanoid, was diminished at t2, while all the pro-resolutory lipids decreased substantially. Significant correlations between the SRA and the QoL scores were observed, the latter showing a substantial reduction at t2, ranking it as a reliable tool for monitoring disease evolution during TB treatment. Discussion: These results suggest that evaluating a combination of these markers might be a valuable predictor of QoL improvement and a treatment response indicator; in particular, the oxidation metabolites and eicosanoid ratios could also be proposed as a future target for adjuvant therapies to reduce inflammation-associated lung injury in TB disease.


Asunto(s)
Tuberculosis Latente , Tuberculosis Pulmonar , Humanos , Calidad de Vida , Antioxidantes , Leucotrieno B4 , Tuberculosis Pulmonar/tratamiento farmacológico , Cognición
4.
Int J Infect Dis ; 130 Suppl 1: S12-S15, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36918080

RESUMEN

In December 2022 World Health Organization released a new treatment for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) guideline. The main novelty of this update is two new recommendations (i) a 6-month treatment regimen composed of bedaquiline, pretomanid, linezolid (600 mg), and moxifloxacin (BPaLM) is recommended in place of the 9-month or longer (18-month) regimens in MDR/RR-TB patients, now including extensive pulmonary TB and extrapulmonary TB (except TB involving central nervous system, miliary TB and osteoarticular TB); (ii) the use of the 9-month all-oral regimen rather than longer (18-months) regimen is suggested in patients with MDR/RR-TB and in whom resistance to fluoroquinolones has been excluded. Longer (18-month) treatments remain a valid option in all cases in which shorter regimens cannot be implemented due to intolerance, drug-drug interactions, extensively drug-resistant tuberculosis, extensive forms of extrapulmonary TB, or previous failure. The new guidelines represent a milestone in MDR/RR-TB treatment landscape, setting the basis for a shorter, all-oral, more acceptable, equitable, and patient-centered model for MDR/RR-TB management. However, some challenges remain to be addressed to allow full implementation of the new recommendations.


Asunto(s)
Tuberculosis Extensivamente Resistente a Drogas , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis Pulmonar , Humanos , Antituberculosos/farmacología , Tuberculosis Extensivamente Resistente a Drogas/tratamiento farmacológico , Rifampin/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Pulmonar/tratamiento farmacológico
5.
Microbiol Spectr ; 10(5): e0125222, 2022 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-36102651

RESUMEN

Tuberculosis (TB) remains one of the most important infectious diseases globally. Establishing a resistance profile from the initial TB diagnosis is a priority. Rapid molecular tests evaluate only the most common genetic variants responsible for resistance to certain drugs, and Whole Genome Sequencing (WGS) needs culture prior to next-generation sequencing (NGS), limiting their clinical value. Targeted sequencing (TS) from clinical samples avoids these drawbacks, providing a signature of genetic markers that can be associated with drug resistance and phylogeny. In this study, a proof-of-concept protocol was developed for detecting genomic variants associated with drug resistance and for the phylogenetic classification of Mycobacterium Tuberculosis (Mtb) in sputum samples. Initially, a set of Mtb reference strains from the WHO were sequenced (WGS and TS). The results from the protocol agreed >95% with WHO reported data and phenotypic drug susceptibility testing (pDST). Lineage genetics results were 100% concordant with those derived from WGS. After that, the TS protocol was applied to sputum samples from TB patients to detect resistance to first- and second-line drugs and derive phylogeny. The accuracy was >90% for all evaluated drugs, except Eto/Pto (77.8%), and 100% were phylogenetically classified. The results indicate that the described protocol, which affords the complete drug resistance profile and phylogeny of Mtb from sputum, could be useful in the clinical area, advancing toward more personalized and more effective treatments in the near future. IMPORTANCE The COVID-19 pandemic negatively affected the progress in accessing essential Tuberculosis (TB) services and reducing the burden of TB disease, resulting in a decreased detection of new cases and increased deaths. Generating molecular diagnostic tests with faster results without losing reliability is considered a priority. Specifically, developing an antimicrobial resistance profile from the initial stages of TB diagnosis is essential to ensure appropriate treatment. Currently available rapid molecular tests evaluate only the most common genetic variants responsible for resistance to certain drugs, limiting their clinical value. In this work, targeted sequencing on sputum samples from TB patients was used to identify Mycobacterium tuberculosis mutations in genes associated with drug resistance and to derive a phylogeny of the infecting strain. This protocol constitutes a proof-of-concept toward the goal of helping clinicians select a timely and appropriate treatment by providing them with actionable information beyond current molecular approaches.


Asunto(s)
COVID-19 , Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis , Humanos , Esputo , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Filogenia , Pruebas de Sensibilidad Microbiana , Reproducibilidad de los Resultados , Marcadores Genéticos , Pandemias , Tuberculosis/microbiología , Resistencia a Medicamentos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico
6.
J Bras Pneumol ; 48(2): e20210515, 2022.
Artículo en Inglés, Portugués | MEDLINE | ID: mdl-35584466

RESUMEN

OBJECTIVE: To evaluate lung function in a cohort of patients with a history of pulmonary tuberculosis in Brazil, as well as to evaluate the decline in lung function over time and compare it with that observed in similar cohorts in Mexico and Italy. METHODS: The three cohorts were compared in terms of age, smoking status, pulmonary function test results, six-minute walk test results, and arterial blood gas results. In the Brazilian cohort, pulmonary function test results, six-minute walk test results, and arterial blood gas results right after the end of tuberculosis treatment were compared with those obtained at the end of the follow-up period. RESULTS: The three cohorts were very different regarding pulmonary function test results. The most common ventilatory patterns in the Brazilian, Italian, and Mexican cohorts were an obstructive pattern, a mixed pattern, and a normal pattern (in 58 patients [50.9%], in 18 patients [41.9%], and in 26 patients [44.1%], respectively). Only 2 multidrug-resistant tuberculosis cases were included in the Brazilian cohort, whereas, in the Mexican cohort, 27 cases were included (45.8%). Mean PaO2 and mean SaO2 were lower in the Mexican cohort than in the Brazilian cohort (p < 0.0001 and p < 0.002 for PaO2 and SaO2, respectively). In the Brazilian cohort, almost all functional parameters deteriorated over time. CONCLUSIONS: This study reinforces the importance of early and effective treatment of drug-susceptible tuberculosis patients, because multidrug-resistant tuberculosis increases lung damage. When patients complete their tuberculosis treatment, they should be evaluated as early as possible, and, if post-tuberculosis lung disease is diagnosed, they should be managed and offered pulmonary rehabilitation because there is evidence that it is effective in these patients.


Asunto(s)
Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis Pulmonar , Tuberculosis , Brasil/epidemiología , Humanos , Pulmón , México/epidemiología , Oxígeno , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/epidemiología
7.
Biomolecules ; 12(4)2022 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-35454079

RESUMEN

There is a sex bias in tuberculosis's severity, prevalence, and pathogenesis, and the rates are higher in men. Immunological and physiological factors are fundamental contributors to the development of the disease, and sex-related factors could play an essential role in making women more resistant to severe forms of the disease. In this study, we evaluated sex-dependent differences in inflammatory markers. Serum samples were collected from 34 patients diagnosed with pulmonary TB (19 male and 15 female) and 27 healthy controls (18 male and 9 female). Cytokines IL2, IL4, IL6, IL8, IL10, IFNγ, TNFα, and GM-CSF, and eicosanoids PGE2, LTB4, RvD1, and Mar1 were measured using commercially available immunoassays. The MDA, a product of lipidic peroxidation, was measured by detecting thiobarbituric-acid-reactive substances (TBARS). Differential inflammation patterns between men and women were observed. Men had higher levels of IL6, IL8, and TNFα than women. PGE2 and LTB4 levels were higher in patients than healthy controls, but there were no differences for RvD1 and Mar1. Women had higher RvD1/PGE2 and RvD1/LTB4 ratios among patients. RvD1 plays a vital role in resolving the inflammatory process of TB in women. Men are the major contributors to the typical pro-inflammatory profile observed in the serum of tuberculosis patients.


Asunto(s)
Tuberculosis Pulmonar , Tuberculosis , Dinoprostona , Eicosanoides , Femenino , Humanos , Inflamación/complicaciones , Interleucina-6 , Interleucina-8 , Leucotrieno B4 , Masculino , Tuberculosis/complicaciones , Tuberculosis Pulmonar/complicaciones , Factor de Necrosis Tumoral alfa
8.
Int J Infect Dis ; 124 Suppl 1: S90-S103, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35245659

RESUMEN

INTRODUCTION: Multidrug-resistant tuberculosis (MDR-TB) is a life-threatening condition needing long poly-chemotherapy regimens. As no systematic reviews/meta-analysis is available to comprehensively evaluate the role of delamanid (DLM), we evaluated its effectiveness and safety. METHODS: We reviewed the relevant scientific literature published up to January 20, 2022. The pooled success treatment rate with 95% confidence intervals (CI) was assessed using a random-effect model. We assessed studies for quality and bias, and considered P<0.05 to be statistically significant. RESULTS: After reviewing 626 records, we identified 25 studies that met the inclusion criteria, 22 observational and 3 experimental, with 1276 and 411 patients, respectively. In observational studies the overall pooled treatment success rate of DLM-containing regimens was 80.9% (95% CI 72.6-87.2) with no evidence of publication bias (Begg's test; P >0.05). The overall pooled treatment success rate in DLM and bedaquiline-containing regimens was 75.2% (95% CI 68.1-81.1) with no evidence of publication bias (Begg's test; P >0.05). In experimental studies the pooled treatment success rate of DLM-containing regimens was 72.5 (95% CI 44.2-89.8, P <0.001, I2: 95.1%) with no evidence of publication bias (Begg's test; P >0.05). CONCLUSIONS: In MDR-TB patients receiving DLM, culture conversion and treatment success rates were high despite extensive resistance with limited adverse events.


Asunto(s)
Nitroimidazoles , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Antituberculosos/uso terapéutico , Nitroimidazoles/uso terapéutico , Oxazoles/efectos adversos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Diarilquinolinas/uso terapéutico , Resultado del Tratamiento
9.
J. bras. pneumol ; 48(2): e20210515, 2022. tab
Artículo en Inglés | LILACS-Express | LILACS | ID: biblio-1375737

RESUMEN

ABSTRACT Objective: To evaluate lung function in a cohort of patients with a history of pulmonary tuberculosis in Brazil, as well as to evaluate the decline in lung function over time and compare it with that observed in similar cohorts in Mexico and Italy. Methods: The three cohorts were compared in terms of age, smoking status, pulmonary function test results, six-minute walk test results, and arterial blood gas results. In the Brazilian cohort, pulmonary function test results, six-minute walk test results, and arterial blood gas results right after the end of tuberculosis treatment were compared with those obtained at the end of the follow-up period. Results: The three cohorts were very different regarding pulmonary function test results. The most common ventilatory patterns in the Brazilian, Italian, and Mexican cohorts were an obstructive pattern, a mixed pattern, and a normal pattern (in 58 patients [50.9%], in 18 patients [41.9%], and in 26 patients [44.1%], respectively). Only 2 multidrug-resistant tuberculosis cases were included in the Brazilian cohort, whereas, in the Mexican cohort, 27 cases were included (45.8%). Mean PaO2 and mean SaO2 were lower in the Mexican cohort than in the Brazilian cohort (p < 0.0001 and p < 0.002 for PaO2 and SaO2, respectively). In the Brazilian cohort, almost all functional parameters deteriorated over time. Conclusions: This study reinforces the importance of early and effective treatment of drug-susceptible tuberculosis patients, because multidrug-resistant tuberculosis increases lung damage. When patients complete their tuberculosis treatment, they should be evaluated as early as possible, and, if post-tuberculosis lung disease is diagnosed, they should be managed and offered pulmonary rehabilitation because there is evidence that it is effective in these patients.


RESUMO Objetivo: Avaliar a função pulmonar em uma coorte de pacientes com história de tuberculose pulmonar no Brasil, bem como avaliar o declínio da função pulmonar ao longo do tempo e compará-lo com o observado em coortes semelhantes no México e Itália. Métodos: As três coortes foram comparadas quanto à idade, tabagismo, testes de função pulmonar, teste de caminhada de seis minutos e gasometria arterial. Na coorte brasileira, os resultados dos testes de função pulmonar, do teste de caminhada de seis minutos e da gasometria arterial logo após o término do tratamento da tuberculose foram comparados com os obtidos no fim do período de acompanhamento. Resultados: As três coortes foram muito diferentes quanto aos resultados dos testes de função pulmonar. Os padrões ventilatórios mais comuns nas coortes brasileira, italiana e mexicana foram o padrão obstrutivo, o padrão misto e o padrão normal [em 58 pacientes (50,9%), em 18 pacientes (41,9%) e em 26 pacientes (44,1%), respectivamente]. Apenas 2 casos de tuberculose multirresistente foram incluídos na coorte brasileira, ao passo que na coorte mexicana foram incluídos 27 casos (45,8%). As médias da PaO2 e SaO2 foram mais baixas na coorte mexicana do que na brasileira (p < 0,0001 e p < 0,002 para PaO2 e SaO2, respectivamente). Na coorte brasileira, quase todos os parâmetros funcionais se deterioraram ao longo do tempo. Conclusões: Este estudo reforça a importância do tratamento precoce e eficaz de pacientes com tuberculose sensível, pois a tuberculose multirresistente aumenta o dano pulmonar. Quando o tratamento da tuberculose é concluído, os pacientes devem ser avaliados o quanto antes e, caso se estabeleça o diagnóstico de sequelas pulmonares da tuberculose, é preciso tratá-los e oferecer-lhes reabilitação pulmonar, pois há evidências de que ela é eficaz nesses pacientes.

10.
Antibiotics (Basel) ; 10(11)2021 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-34827293

RESUMEN

Tuberculosis (TB) does not respect borders, and migration confounds global TB control and elimination. Systematic screening of immigrants from TB high burden settings and-to a lesser degree TB infection (TBI)-is recommended in most countries with a low incidence of TB. The aim of the study was to evaluate the views of a diverse group of international health professionals on TB management among migrants. Participants expressed their level of agreement using a six-point Likert scale with different statements in an online survey available in English, French, Mandarin, Spanish, Portuguese and Russian. The survey consisted of eight sections, covering TB and TBI screening and treatment in migrants. A total of 1055 respondents from 80 countries and territories participated between November 2019 and April 2020. The largest professional groups were pulmonologists (16.8%), other clinicians (30.4%), and nurses (11.8%). Participants generally supported infection control and TB surveillance established practices (administrative interventions, personal protection, etc.), while they disagreed on how to diagnose and manage both TB and TBI, particularly on which TBI regimens to use and when patients should be hospitalised. The results of this first knowledge, attitude and practice study on TB screening and treatment in migrants will inform public health policy and educational resources.

11.
Antioxidants (Basel) ; 10(10)2021 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-34679707

RESUMEN

Tuberculosis (TB) is one of the highest infectious burdens worldwide. An excess of inflammation and inadequate antioxidant defense mechanisms are believed to lead to chronic inflammation and lung damage in tuberculosis (TB). However, circulating metabolites do not always replicate lung-associated biomarkers that define the pathobiology of the disease. The objective of this study was to determine the utility of exhaled breath condensate (EBC), a non-invasive and straightforward sample, to evaluate alveolar space-derived metabolites of redox state and inflammation. We assessed the levels of exhaled oxidant/antioxidant parameters (8-isoprostane, MDA, GSH), inflammatory markers, such as nucleosomes, cytokines (IL-2, IL-4, IL-6 and IL-8, IL-10, GM-CSF, TNF-α, and IFN-γ) and lipid mediators (PGE2, LTB4, RvD1, and Mar1), in patients with recently diagnosed pulmonary TB and healthy controls' EBC and serum. The TB patients showed 36% lower GSH levels, and 2-, 1.4-, 1.1-, and 50-fold higher levels of 8-isoprostanes, nucleosomes, IL-6, and LTB4, respectively, in EBC. There was no correlation between EBC and serum, highlighting the importance of measuring local biomarkers. Quantitation of local inflammatory molecules and redox states in EBC would help find biomarkers useful for pharmacological and follow-up studies in pulmonary tuberculosis.

12.
PLoS One ; 16(10): e0258774, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34699523

RESUMEN

Next-Generation Sequencing (NGS) is widely used to investigate genomic variation. In several studies, the genetic variation of Mycobacterium tuberculosis has been analyzed in sputum samples without previous culture, using target enrichment methodologies for NGS. Alignments obtained by different programs generally map the sequences under default parameters, and from these results, it is assumed that only Mycobacterium reads will be obtained. However, variants of interest microorganism in clinical samples can be confused with a vast collection of reads from other bacteria, viruses, and human DNA. Currently, there are no standardized pipelines, and the cleaning success is never verified since there is a lack of rigorous controls to identify and remove reads from other sputum-microorganisms genetically similar to M. tuberculosis. Therefore, we designed a bioinformatic pipeline to process NGS data from sputum samples, including several filters and quality control points to identify and eliminate non-M. tuberculosis reads to obtain a reliable genetic variant report. Our proposal uses the SURPI software as a taxonomic classifier to filter input sequences and perform a mapping that provides the highest percentage of Mycobacterium reads, minimizing the reads from other microorganisms. We then use the filtered sequences to perform variant calling with the GATK software, ensuring the mapping quality, realignment, recalibration, hard-filtering, and post-filter to increase the reliability of the reported variants. Using default mapping parameters, we identified reads of contaminant bacteria, such as Streptococcus, Rhotia, Actinomyces, and Veillonella. Our final mapping strategy allowed a sequence identity of 97.8% between the input reads and the whole M. tuberculosis reference genome H37Rv using a genomic edit distance of three, thus removing 98.8% of the off-target sequences with a Mycobacterium reads loss of 1.7%. Finally, more than 200 unreliable genetic variants were removed during the variant calling, increasing the report's reliability.


Asunto(s)
Biología Computacional/métodos , ADN Bacteriano/genética , Mycobacterium tuberculosis/genética , Tuberculosis/microbiología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mycobacterium tuberculosis/clasificación , Mycobacterium tuberculosis/aislamiento & purificación , Análisis de Secuencia de ADN , Programas Informáticos , Esputo/microbiología
13.
Immunohorizons ; 5(9): 752-759, 2021 09 24.
Artículo en Inglés | MEDLINE | ID: mdl-34561226

RESUMEN

CXCL17 is a novel mucosal chemokine that mediates myeloid cell recruitment and bactericidal activity and highly expressed in the respiratory tract. However, its role in tuberculosis (TB) immunopathogenesis or protection remains unknown. In this study, we evaluated the function of CXCL17 in a mouse model of aerosol infection with the clinical W-Beijing lineage Mycobacterium tuberculosis hypervirulent HN878 strain. Our results show that CXCL17 production increases in the lung of M. tuberculosis-infected mice during acute and chronic stages of infection. Moreover, in vitro M. tuberculosis infection of epithelial cells and myeloid cells induces production of CXCL17. In humans, lower serum CXCL17 levels are observed among active pulmonary TB patients when compared with subjects with latent TB infection and healthy controls, suggesting a protective role. However, mice treated with rCXCL17 show similar lung bacterial burden and inflammation compared with control animals, despite an increased lung myeloid cell accumulation. Finally, CXCL17-/- mice are not more susceptible to TB than wild-type animals. These findings suggest that CXCL17 is induced in both murine epithelial and myeloid cells upon M. tuberculosis infection and increased expression during human latent TB infection. However, CXCL17 may have a dispensable role during pulmonary TB.


Asunto(s)
Quimiocinas CXC/metabolismo , Tuberculosis Latente/inmunología , Pulmón/patología , Mycobacterium tuberculosis/inmunología , Tuberculosis Pulmonar/inmunología , Animales , Estudios de Casos y Controles , Quimiocinas CXC/administración & dosificación , Quimiocinas CXC/genética , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Voluntarios Sanos , Humanos , Exposición por Inhalación/efectos adversos , Tuberculosis Latente/sangre , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/microbiología , Pulmón/diagnóstico por imagen , Pulmón/inmunología , Pulmón/microbiología , Ratones , Ratones Noqueados , Mycobacterium tuberculosis/patogenicidad , Células Mieloides/inmunología , Células Mieloides/metabolismo , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/patología
14.
Microorganisms ; 9(8)2021 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-34442841

RESUMEN

Mycobacterium tuberculosis infection has three discernible outcomes: active tuberculosis, latent tuberculosis, or clearance of the bacterium. The outcome of the infection depends on the interaction of the bacterium, the immune system, and the microbiome of the host. The current study uses 16S rRNA sequencing to determine the diversity and composition of the respiratory microbiome of drug-resistant and drug-sensitive tuberculosis patients as well as healthy volunteers. Tuberculosis patients exhibited increased microbial diversity and differentially abundant bacteria than healthy volunteers. Compositional differences were also observed when comparing drug-sensitive or -resistant tuberculosis patients. Finally, we defined and assessed the differences in the core sputum microbiota between tuberculosis patients and healthy volunteers. Our observations collectively suggest that in sputum, Mycobacterium tuberculosis infection is related to altered bacterial diversity and compositional differences of core members of the microbiome, with potential implications for the bacterial pulmonary ecosystem's stability and function.

15.
Mol Med ; 27(1): 76, 2021 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-34261449

RESUMEN

BACKGROUND: Tuberculosis (TB) is an infectious disease. During TB, regulatory T cells (Treg) are related to poor prognosis. However, information about conventional and unconventional Treg (cTreg and uTreg, respectively) is limited. The tumour necrosis factor (TNF) and its receptors (TNFR1 and TNFR2) are necessary for mycobacterial infection, and TNFR2 signalling is required to maintain Treg. METHODS: A blood sample of drug-susceptible (DS-TB) and drug-resistant tuberculosis (DR-TB) patients was obtained before (basal) and after 2 and 6 months of anti-TB therapy. Expression of TNF, TNFR1, and TNFR2 (transmembrane form, tm) on cTreg, uTreg, activated CD4+ (actCD4+), and CD4+ CD25- (CD4+) T cell subpopulations were evaluated. The main objective was to identify immunological changes associated with sensitive/resistant Mtb strains and with the use of anti-TB therapy. RESULTS: We found that after 6 months of anti-TB therapy, both DS- and DR-TB patients have decreased the frequency of cTreg tmTNF+, CD4+ tmTNFR1+ and CD4+ tmTNFR2+. Nevertheless, after 6 months of therapy, only DR-TB patients decreased the frequency of actCD4+ tmTNF+ and actCD4+ tmTNFR2+, exhibited a systemic inflammatory status (high levels of TNF, IFN-γ and IL-12), and their purified CD4+ T cells showed that TNF and TNFR2 are up-regulated at the transcriptional level. Moreover, DS- and DR-TB down-regulated TNFR1 and other proteins associated with Treg (FOXP3 and TGFß1) in response to the anti-TB therapy. CONCLUSION: These results partially explain the differences in the immune response of DS-TB vs DR-TB. The frequency of actCD4+ tmTNFR2+ cells and inflammatory status should be considered in the follow-up of therapy in DR-TB patients.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Mycobacterium tuberculosis/inmunología , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Tuberculosis/etiología , Tuberculosis/metabolismo , Adulto , Anciano , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Biomarcadores , Recuento de Linfocito CD4 , Citocinas/metabolismo , Susceptibilidad a Enfermedades/inmunología , Femenino , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunofenotipificación , Mediadores de Inflamación/metabolismo , Masculino , Persona de Mediana Edad , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Tuberculosis/diagnóstico , Tuberculosis/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/etiología , Tuberculosis Resistente a Múltiples Medicamentos/metabolismo
16.
J Immunol Res ; 2021: 5517856, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34007850

RESUMEN

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


Asunto(s)
Células Asesinas Naturales/inmunología , Tuberculosis Latente/inmunología , Mycobacterium tuberculosis/inmunología , Tuberculosis Meníngea/inmunología , Tuberculosis Pulmonar/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Citocinas/metabolismo , Femenino , Humanos , Inmunidad Innata , Inmunofenotipificación , Células Asesinas Naturales/metabolismo , Tuberculosis Latente/sangre , Tuberculosis Latente/microbiología , Masculino , México , Persona de Mediana Edad , Estudios Prospectivos , Tuberculosis Meníngea/sangre , Tuberculosis Meníngea/microbiología , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/microbiología , Adulto Joven
17.
J Infect Dev Ctries ; 15(3): 310-319, 2021 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-33839703

RESUMEN

Mycobacterium tuberculosis (M.tb) is the causative agent of tuberculosis (TB), an infectious disease that leads to numerous deaths worldwide. Malnutrition, smoking, alcohol abuse, Human Immunodeficiency Virus infection, and diabetes are some of the most important risk factors associated with TB development. At present, it is necessary to conduct studies on risk factors to establish new effective strategies and combat this disease. Malnutrition has been established as a risk factor since several years ago; although there is in vitro experimental evidence that reveals the importance of micronutrients in activating the immune response against M.tb, evidence from clinical trials is controversial. Currently, nutritional assessment is recommended in all TB patients upon diagnosis. However, there is insufficient evidence to indicate micronutrient supplementation as adjuvant therapy or prophylactic to prevent micronutrient depletion. Strengthening the interaction between basic and clinical research is necessary to carry out studies that will help establish adjuvant therapies to improve outcomes in TB patients. In this review, we discuss the experimental evidence, provided by basic research, regarding micronutrients in the TB field. However, when these studies are applied to clinical trials, the data are inconsistent, indicating that still missing mechanisms are necessary to propose alternatives to the treatment of TB patients.


Asunto(s)
Desnutrición/complicaciones , Micronutrientes/inmunología , Tuberculosis/etiología , Países en Desarrollo/estadística & datos numéricos , Humanos , Desnutrición/epidemiología , Desnutrición/prevención & control , Micronutrientes/deficiencia , Mycobacterium tuberculosis/inmunología , Factores de Riesgo , Tuberculosis/prevención & control
18.
J Infect Dis ; 224(1): 21-30, 2021 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-33668070

RESUMEN

The differentiation between influenza and coronavirus disease 2019 (COVID-19) could constitute a diagnostic challenge during the ongoing winter owing to their clinical similitude. Thus, novel biomarkers are required to enable making this distinction. Here, we evaluated whether the surfactant protein D (SP-D), a collectin produced at the alveolar epithelium with known immune properties, was useful to differentiate pandemic influenza A(H1N1) from COVID-19 in critically ill patients. Our results revealed high serum SP-D levels in patients with severe pandemic influenza but not those with COVID-19. This finding was validated in a separate cohort of mechanically ventilated patients with COVID-19 who also showed low plasma SP-D levels. However, plasma SP-D levels did not distinguish seasonal influenza from COVID-19 in mild-to-moderate disease. Finally, we found that high serum SP-D levels were associated with death and renal failure among severe pandemic influenza cases. Thus, our studies have identified SP-D as a unique biomarker expressed during severe pandemic influenza but not COVID-19.


Asunto(s)
COVID-19/genética , Expresión Génica , Interacciones Huésped-Patógeno/genética , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana/genética , Proteína D Asociada a Surfactante Pulmonar/genética , SARS-CoV-2 , Adulto , Anciano , Biomarcadores , COVID-19/sangre , COVID-19/diagnóstico , COVID-19/virología , Coinfección , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Gripe Humana/diagnóstico , Gripe Humana/virología , Masculino , Persona de Mediana Edad , Pronóstico , Proteína D Asociada a Surfactante Pulmonar/sangre , Índice de Severidad de la Enfermedad , Evaluación de Síntomas , Adulto Joven
19.
Front Immunol ; 11: 582414, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33117393

RESUMEN

Natural killer (NK) cells participate in immunity against several pathogens by exerting cytotoxic and cytokine-production activities. Some NK cell subsets also mediate recall responses that resemble memory of adaptive lymphocytes against antigenic and non-antigenic stimuli. The C-X-C motif chemokine receptor 6 (CXCR6) is crucial for the development and maintenance of memory-like responses in murine NK cells. In humans, several subsets of tissue-resident and circulating NK cells with different functional properties express CXCR6. However, the role of CXCR6+ NK cells in immunity against relevant human pathogens is unknown. Here, we addressed whether murine and human CXCR6+ NK cells respond to antigens of Mycobacterium tuberculosis (Mtb). For this purpose, we evaluated the immunophenotype of hepatic and splenic CXCR6+ NK cells in mice exposed to a cell-wall (CW) extract of Mtb strain H37Rv. Also, we characterized the expression of CXCR6 in peripheral NK cells from active pulmonary tuberculosis (ATB) patients, individuals with latent TB infection (LTBI), and healthy volunteer donors (HD). Furthermore, we evaluated the responses of CXCR6+ NK cells from HD, LTBI, and ATB subjects to the in vitro exposure to CW preparations of Mtb H37Rv and Mtb HN878. Our results showed that murine hepatic CXCR6+ NK cells expand in vivo after consecutive administrations of Mtb H37Rv CW to mice. Remarkably, pooled hepatic and splenic, but not isolated splenic NK cells from treated mice, enhance their cytokine production capacity after an in vitro re-challenge with H37Rv CW. In humans, CXCR6+ NK cells were barely detected in the peripheral blood, although slightly significative increments in the percentage of CXCR6+, CXCR6+CD49a-, CXCR6+CD49a+, and CXCR6+CD69+ NK cells were observed in ATB patients as compared to HD and LTBI individuals. In contrast, the expansion of CXCR6+CD49a- and CXCR6+CD69+ NK cells in response to the in vitro stimulation with Mtb H37Rv was higher in LTBI individuals than in ATB patients. Finally, we found that Mtb HN878 CW generates IFN-γ-producing CXCR6+CD49a+ NK cells. Our results demonstrate that antigens of both laboratory-adapted and clinical Mtb strains are stimulating factors for murine and human CXCR6+ NK cells. Future studies evaluating the role of CXCR6+ NK cells during TB are warranted.


Asunto(s)
Antígenos Bacterianos/inmunología , Células Asesinas Naturales/inmunología , Tuberculosis Latente/inmunología , Mycobacterium tuberculosis/fisiología , Tuberculosis Pulmonar/inmunología , Animales , Células Cultivadas , Femenino , Humanos , Inmunofenotipificación , Interferón gamma/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Receptores CXCR6/metabolismo
20.
Emerg Infect Dis ; 26(11): 2709-2712, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32917293

RESUMEN

Coronavirus disease has disrupted tuberculosis services globally. Data from 33 centers in 16 countries on 5 continents showed that attendance at tuberculosis centers was lower during the first 4 months of the pandemic in 2020 than for the same period in 2019. Resources are needed to ensure tuberculosis care continuity during the pandemic.


Asunto(s)
Continuidad de la Atención al Paciente/tendencias , Infecciones por Coronavirus/epidemiología , Utilización de Instalaciones y Servicios/tendencias , Salud Global/tendencias , Neumonía Viral/epidemiología , Tuberculosis/terapia , Betacoronavirus , COVID-19 , Humanos , Pandemias , SARS-CoV-2 , Tuberculosis/epidemiología
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