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1.
Front Immunol ; 12: 687044, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630380

RESUMO

Phagosome-lysosome fusion in innate immune cells like macrophages and neutrophils marshal an essential role in eliminating intracellular microorganisms. In microbe-challenged macrophages, phagosome-lysosome fusion occurs 4 to 6 h after the phagocytic uptake of the microbe. However, live pathogenic mycobacteria hinder the transfer of phagosomes to lysosomes, up to 20 h post-phagocytic uptake. This period is required to evade pro-inflammatory response and upregulate the acid-stress tolerant proteins. The exact sequence of events through which mycobacteria retards phagolysosome formation remains an enigma. The macrophage coat protein Coronin1(Cor1) is recruited and retained by mycobacteria on the phagosome membrane to retard its maturation by hindering the access of phagosome maturation factors. Mycobacteria-infected macrophages exhibit an increased cAMP level, and based on receptor stimulus, Cor1 expressing cells show a higher level of cAMP than non-Cor1 expressing cells. Here we have shown that infection of bone marrow-derived macrophages with H37Rv causes a Cor1 dependent rise of intracellular cAMP levels at the vicinity of the phagosomes. This increased cAMP fuels cytoskeletal protein Cofilin1 to depolymerize F-actin around the mycobacteria-containing phagosome. Owing to reduced F-actin levels, the movement of the phagosome toward the lysosomes is hindered, thus contributing to the retarded phagosome maturation process. Additionally, Cor1 mediated upregulation of Cofilin1 also contributes to the prevention of phagosomal acidification, which further aids in the retardation of phagosome maturation. Overall, our study provides first-hand information on Cor1 mediated retardation of phagosome maturation, which can be utilized in developing novel peptidomimetics as part of host-directed therapeutics against tuberculosis.


Assuntos
Cofilina 1/metabolismo , AMP Cíclico/metabolismo , Macrófagos/microbiologia , Proteínas dos Microfilamentos/metabolismo , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium bovis/patogenicidade , Mycobacterium smegmatis/patogenicidade , Mycobacterium tuberculosis/patogenicidade , Fagossomos/microbiologia , Tuberculose/microbiologia , Animais , Linhagem Celular , Interações Hospedeiro-Patógeno , Concentração de Íons de Hidrogênio , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Proteínas dos Microfilamentos/genética , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/metabolismo , Mycobacterium bovis/imunologia , Mycobacterium smegmatis/imunologia , Mycobacterium tuberculosis/imunologia , Fagossomos/imunologia , Fagossomos/metabolismo , Sistemas do Segundo Mensageiro , Tuberculose/imunologia , Tuberculose/metabolismo
2.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502407

RESUMO

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a successful intracellular pathogen that is responsible for the highest mortality rate among diseases caused by bacterial infections. During early interaction with the host innate cells, M. tuberculosis cell surface antigens interact with Toll like receptor 4 (TLR4) to activate the nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3 (NLRP3) canonical, and non-canonical inflammasome pathways. NLRP3 inflammasome activation in the alveoli has been reported to contribute to the early inflammatory response that is needed for an effective anti-TB response through production of pro-inflammatory cytokines, including those of the Interleukin 1 (IL1) family. However, overstimulation of the alveolar NLRP3 inflammasomes can induce excessive inflammation that is pathological to the host. Several studies have explored the use of medicinal plants and/or their active derivatives to inhibit excessive stimulation of the inflammasomes and its associated factors, thus reducing immunopathological response in the host. This review describes the molecular mechanism of the NLRP3 inflammasome activation in the alveoli during M. tuberculosis infection. Furthermore, the mechanisms of inflammasome inhibition using medicinal plant and their derivatives will also be explored, thus offering a novel perspective on the alternative control strategies of M. tuberculosis-induced immunopathology.


Assuntos
Macrófagos Alveolares/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Tuberculose/tratamento farmacológico , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Citocinas/metabolismo , Humanos , Inflamassomos/metabolismo , Inflamação , Interleucina-1beta/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Plantas Medicinais , Alvéolos Pulmonares/patologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Tuberculose/metabolismo
3.
Sci Rep ; 11(1): 16254, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376753

RESUMO

The association between the total cholesterol level and tuberculosis (TB) risk has been controversial. Our study aimed to evaluate whether total cholesterol level can predict the risk of TB. Data from 5,000,566 subjects who participated in a health screening exam in 2009 were investigated using the Korean National Health Insurance Service database (2009-2018). Cox hazard regression analyses were used to evaluate TB risk according to the quartile of total cholesterol levels. During an average of 8.2 years of follow-up, 32,078 cases of TB occurred. There was a significant inverse association between the total cholesterol level and TB risk. Compared with subjects in the highest quartile, those in the lowest quartile had a 1.35-fold increased TB risk (95% confidence interval = 1.31-1.39). The association between total cholesterol level and TB risk was more apparent in young subjects (age < 65 years), those without diabetes mellitus (DM), and those without obesity (p for interaction < 0.001 for age group, DM, and body mass index). Although there was a significant inverse association between total cholesterol level and TB risk in subjects who did not use a statin, no significant association was observed between the total cholesterol level and TB risk in subjects who used a statin. A low total cholesterol level was significantly associated with an increased risk of TB, even after adjusting for confounders, especially in patients younger than 65 years, those without DM or obesity, and those who did not use a statin.


Assuntos
Colesterol/metabolismo , Bases de Dados Factuais , Tuberculose/epidemiologia , Idoso , Estudos de Casos e Controles , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , República da Coreia/epidemiologia , Fatores de Risco , Tuberculose/metabolismo , Tuberculose/microbiologia
4.
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
5.
Methods Mol Biol ; 2314: 649-702, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34235675

RESUMO

Mycobacterium tuberculosis is able to colonize, persist, and massively replicate in host cells, such as phagocytes and epithelial cells. The intracellular stage of the bacteria is critical to the development of tuberculosis pathogenesis. The detailed mechanisms of intracellular trafficking of the bacillus are not fully understood and require further investigations. Therefore, increasing the knowledge of this process will help to develop therapeutic tools that will lower the burden of tuberculosis. M. tuberculosis is genetically tractable and tolerates the expression of heterologous fluorescent proteins. Thus, the intracellular distribution of the bacteria expressing fluorescent tracers can be easily defined using confocal microscopy. Advances in imaging techniques and images-based analysis allow the rapid quantification of biological objects in complex environments. In this chapter, we detailed high-content / high-throughput imaging methods to track the bacillus within host cell settings.


Assuntos
Células Dendríticas/microbiologia , Células Epiteliais/microbiologia , Ensaios de Triagem em Larga Escala/métodos , Macrófagos/microbiologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Fagócitos/microbiologia , Tuberculose/microbiologia , Animais , Células Dendríticas/metabolismo , Testes Diagnósticos de Rotina , Células Epiteliais/metabolismo , Humanos , Macrófagos/metabolismo , Camundongos , Mycobacterium tuberculosis/patogenicidade , Estresse Oxidativo , Fagócitos/metabolismo , Espécies Reativas de Oxigênio , Tuberculose/metabolismo
6.
PLoS One ; 16(7): e0254198, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34214138

RESUMO

INTRODUCTION: The pathogenesis of consumptive syndrome of tuberculosis (TB) is largely unknown. Leptin concentrations may be high because of the host's inflammatory response, contributing to weight loss in patients with TB. The receptor for advanced glycation end products (RAGE) is also associated with weight loss in patients with TB and is related to enhanced mortality. The objective of this study was to evaluate the association between leptin and AGE/RAGE. METHODS: Case-control study. Leptin, AGE (carboxymethyl lysine, CML) and soluble RAGE (sRAGE) were measured from blood samples by ELISA. RESULTS: We included in the study 34 patients with TB and 34 controls. We found an inverse correlation between serum leptin levels and sRAGE, only in cases (r = -0.609, p < 0.0001). sRAGE levels were lower in patients with TB who died as compared with patients who survive (21.90 ± 4.24 pg/mL vs 66.14 ± 29.49 pg/mL; p = 0.045). Leptin levels were higher in patients with TB who died as compared with patients who survive (14.11 [7.48-14.11] ng/mL vs 3.08 [0.54-6.34] ng/mL; p = 0.028). CONCLUSIONS: We identified lower sRAGE levels and higher leptin levels in patients with TB who died as compared with patients who survive. In addition, an inverse and significant correlation between serum leptin and sRAGE levels was demonstrated. Future studies, with a larger sample size and in different settings, including not only hospitalized patients, are needed to confirm these findings.


Assuntos
Antígenos de Neoplasias/metabolismo , Leptina/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Tuberculose/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Estudos Prospectivos , Perda de Peso/fisiologia
7.
PLoS Pathog ; 17(7): e1009712, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34324582

RESUMO

Mycobacterium tuberculosis (Mtb) has evolved to evade host innate immunity by interfering with macrophage functions. Interleukin-1ß (IL-1ß) is secreted by macrophages after the activation of the inflammasome complex and is crucial for host defense against Mtb infections. We have previously shown that Mtb is able to inhibit activation of the AIM2 inflammasome and subsequent pyroptosis. Here we show that Mtb is also able to inhibit host cell NLRP3 inflammasome activation and pyroptosis. We identified the serine/threonine kinase PknF as one protein of Mtb involved in the NLRP3 inflammasome inhibition, since the pknF deletion mutant of Mtb induces increased production of IL-1ß in bone marrow-derived macrophages (BMDMs). The increased production of IL-1ß was dependent on NLRP3, the adaptor protein ASC and the protease caspase-1, as revealed by studies performed in gene-deficient BMDMs. Additionally, infection of BMDMs with the pknF deletion mutant resulted in increased pyroptosis, while the IL-6 production remained unchanged compared to Mtb-infected cells, suggesting that the mutant did not affect the priming step of inflammasome activation. In contrast, the activation step was affected since potassium efflux, chloride efflux and the generation of reactive oxygen species played a significant role in inflammasome activation and subsequent pyroptosis mediated by the Mtb pknF mutant strain. In conclusion, we reveal here that the serine/threonine kinase PknF of Mtb plays an important role in innate immune evasion through inhibition of the NLRP3 inflammasome.


Assuntos
Evasão da Resposta Imune/imunologia , Inflamassomos/imunologia , Mycobacterium tuberculosis/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Tuberculose/imunologia , Animais , Interações Hospedeiro-Patógeno/imunologia , Camundongos , Mycobacterium tuberculosis/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Tuberculose/metabolismo
8.
Front Immunol ; 12: 687962, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248974

RESUMO

Non-coding RNAs have emerged as critical regulators of the immune response to infection. MicroRNAs (miRNAs) are small non-coding RNAs which regulate host defense mechanisms against viruses, bacteria and fungi. They are involved in the delicate interplay between Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), and its host, which dictates the course of infection. Differential expression of miRNAs upon infection with M. tuberculosis, regulates host signaling pathways linked to inflammation, autophagy, apoptosis and polarization of macrophages. Experimental evidence suggests that virulent M. tuberculosis often utilize host miRNAs to promote pathogenicity by restricting host-mediated antibacterial signaling pathways. At the same time, host- induced miRNAs augment antibacterial processes such as autophagy, to limit bacterial proliferation. Targeting miRNAs is an emerging option for host-directed therapies. Recent studies have explored the role of long non-coding RNA (lncRNAs) in the regulation of the host response to mycobacterial infection. Among other functions, lncRNAs interact with chromatin remodelers to regulate gene expression and also function as miRNA sponges. In this review we attempt to summarize recent literature on how miRNAs and lncRNAs are differentially expressed during the course of M. tuberculosis infection, and how they influence the outcome of infection. We also discuss the potential use of non-coding RNAs as biomarkers of active and latent tuberculosis. Comprehensive understanding of the role of these non-coding RNAs is the first step towards developing RNA-based therapeutics and diagnostic tools for the treatment of TB.


Assuntos
Imunidade Inata , MicroRNAs/imunologia , Mycobacterium tuberculosis/imunologia , RNA Longo não Codificante/imunologia , Tuberculose/imunologia , Animais , Apoptose , Autofagia , Proteína DEAD-box 58/imunologia , Proteína DEAD-box 58/metabolismo , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Mycobacterium tuberculosis/patogenicidade , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo , Tuberculose/genética , Tuberculose/metabolismo , Tuberculose/microbiologia
9.
Front Immunol ; 12: 668060, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276658

RESUMO

Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, kills 1.5 to 1.7 million people every year. Macrophages are Mtb's main host cells and their inflammatory response is an essential component of the host defense against Mtb. However, Mtb is able to circumvent the macrophages' defenses by triggering an inappropriate inflammatory response. The ability of Mtb to hinder phagolysosome maturation and acidification, and to escape the phagosome into the cytosol, is closely linked to its virulence. The modulation of the host inflammatory response relies on Mtb virulence factors, but remains poorly studied. Understanding macrophage interactions with Mtb is crucial to develop strategies to control tuberculosis. The present study aims to determine the inflammatory response transcriptome and miRNome of human macrophages infected with the virulent H37Rv Mtb strain, to identify macrophage genetic networks specifically modulated by Mtb virulence. Using human macrophages infected with two different live strains of mycobacteria (live or heat-inactivated Mtb H37Rv and M. marinum), we quantified and analyzed 184 inflammatory mRNAs and 765 micro(mi)RNAs. Transcripts and miRNAs differently modulated by H37Rv in comparison with the two other conditions were analyzed using in silico approaches. We identified 30 host inflammatory response genes and 37 miRNAs specific for H37Rv virulence, and highlight evidence suggesting that Mtb intracellular-linked virulence depends on the inhibition of IL-1ß-dependent pro-inflammatory response, the repression of apoptosis and the delay of the recruitment and activation of adaptive immune cells. Our findings provide new potential targets for the development of macrophage-based therapeutic strategies against TB.


Assuntos
Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Pulmão/microbiologia , Macrófagos/microbiologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose/microbiologia , Imunidade Adaptativa , Apoptose , Citocinas/genética , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Pulmão/imunologia , Pulmão/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/metabolismo , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium marinum/imunologia , Mycobacterium marinum/patogenicidade , Mycobacterium tuberculosis/imunologia , Transdução de Sinais , Células THP-1 , Transcriptoma , Tuberculose/genética , Tuberculose/imunologia , Tuberculose/metabolismo , Virulência
10.
Front Immunol ; 12: 678354, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149713

RESUMO

Hypoxia-inducible factor (HIF) is a key oxygen sensor that controls gene expression patterns to adapt cellular metabolism to hypoxia. Pharmacological inhibition of prolyl-hydroxylases stabilizes HIFs and mimics hypoxia, leading to increased expression of more than 300 genes. Whether the genetic program initialized by HIFs affects immune responses against microbial pathogens, is not well studied. Recently we showed that hypoxia enhances antimicrobial activity against Mycobacterium tuberculosis (Mtb) in human macrophages. The objective of this study was to evaluate whether the oxygen sensor HIF is involved in hypoxia-mediated antimycobacterial activity. Treatment of Mtb-infected macrophages with the prolyl-hydroxylase inhibitor Molidustat reduced the release of TNFα and IL-10, two key cytokines involved in the immune response in tuberculosis. Molidustat also interferes with the p38 MAP kinase pathway. HIF-stabilization by Molidustat also induced the upregulation of the Vitamin D receptor and human ß defensin 2, which define an antimicrobial effector pathway in human macrophages. Consequently, these immunological effects resulted in reduced proliferation of virulent Mtb in human macrophages. Therefore, HIFs may be attractive new candidates for host-directed therapies against infectious diseases caused by intracellular bacteria, including tuberculosis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Interações Hospedeiro-Patógeno , Macrófagos/imunologia , Macrófagos/metabolismo , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Tuberculose/metabolismo , Citocinas/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Modelos Biológicos , Estabilidade Proteica/efeitos dos fármacos , Pirazóis/farmacologia , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Triazóis/farmacologia , Tuberculose/microbiologia
11.
Front Immunol ; 12: 685237, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34140955

RESUMO

Tuberculosis (TB) is the leading cause of death from infection with a single bacterial pathogen. Host macrophages are the primary cell type infected with Mycobacterium tuberculosis (Mtb), the organism that causes TB. Macrophage response pathways are regulated by various factors, including microRNAs (miRNAs) and epigenetic changes that can shape the outcome of infection. Although dysregulation of both miRNAs and DNA methylation have been studied in the context of Mtb infection, studies have not yet investigated how these two processes may jointly co-regulate critical anti-TB pathways in primary human macrophages. In the current study, we integrated genome-wide analyses of miRNA abundance and DNA methylation status with mRNA transcriptomics in Mtb-infected primary human macrophages to decipher which macrophage functions may be subject to control by these two types of regulation. Using in vitro macrophage infection models and next generation sequencing, we found that miRNAs and methylation changes co-regulate important macrophage response processes, including immune cell activation, macrophage metabolism, and AMPK pathway signaling.


Assuntos
Metilação de DNA , Macrófagos/microbiologia , MicroRNAs/genética , Mycobacterium tuberculosis/patogenicidade , Tuberculose/genética , Tuberculose/microbiologia , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla , Interações Hospedeiro-Patógeno , Humanos , Macrófagos/metabolismo , Masculino , Transdução de Sinais , Tuberculose/metabolismo
12.
Cells ; 10(5)2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065319

RESUMO

As a very successful pathogen with outstanding adaptive properties, Mycobacterium tuberculosis (Mtb) has developed a plethora of sophisticated mechanisms to subvert host defenses and effectively enter and replicate in the harmful environment inside professional phagocytes, namely, macrophages. Here, we demonstrated the binding interaction of Mtb with a major human acute phase protein, namely, serum amyloid A (SAA1), and identified AtpA (Rv1308), ABC (Rv2477c), EspB (Rv3881c), TB 18.6 (Rv2140c), and ThiC (Rv0423c) membrane proteins as mycobacterial effectors responsible for the pathogen-host protein interplay. SAA1-opsonization of Mtb prior to the infection of human macrophages favored bacterial entry into target phagocytes accompanied by a substantial increase in the load of intracellularly multiplying and surviving bacteria. Furthermore, binding of human SAA1 by Mtb resulted in the up- or downregulation of the transcriptional response of tubercle bacilli. The most substantial changes were related to the increased expression level of the genes of two operons encoding mycobacterial transporter systems, namely, mmpL5/mmpS5 (rv0676c), and rv1217c, rv1218c. Therefore, we postulate that during infection, Mtb-SAA1 binding promotes the infection of host macrophages by tubercle bacilli and modulates the functional response of the pathogen.


Assuntos
Proteínas de Bactérias/metabolismo , Interações Hospedeiro-Patógeno , Macrófagos/microbiologia , Mycobacterium tuberculosis/fisiologia , Proteína Amiloide A Sérica/metabolismo , Transcriptoma , Tuberculose/microbiologia , Proteínas de Bactérias/genética , Humanos , Macrófagos/metabolismo , Tuberculose/metabolismo
13.
EBioMedicine ; 67: 103388, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34000621

RESUMO

BACKGROUND: Machine learning sustains successful application to many diagnostic and prognostic problems in computational histopathology. Yet, few efforts have been made to model gene expression from histopathology. This study proposes a methodology which predicts selected gene expression values (microarray) from haematoxylin and eosin whole-slide images as an intermediate data modality to identify fulminant-like pulmonary tuberculosis ('supersusceptible') in an experimentally infected cohort of Diversity Outbred mice (n=77). METHODS: Gradient-boosted trees were utilized as a novel feature selector to identify gene transcripts predictive of fulminant-like pulmonary tuberculosis. A novel attention-based multiple instance learning model for regression was used to predict selected genes' expression from whole-slide images. Gene expression predictions were shown to be sufficiently replicated to identify supersusceptible mice using gradient-boosted trees trained on ground truth gene expression data. FINDINGS: The model was accurate, showing high positive correlations with ground truth gene expression on both cross-validation (n = 77, 0.63 ≤ ρ ≤ 0.84) and external testing sets (n = 33, 0.65 ≤ ρ ≤ 0.84). The sensitivity and specificity for gene expression predictions to identify supersusceptible mice (n=77) were 0.88 and 0.95, respectively, and for an external set of mice (n=33) 0.88 and 0.93, respectively. IMPLICATIONS: Our methodology maps histopathology to gene expression with sufficient accuracy to predict a clinical outcome. The proposed methodology exemplifies a computational template for gene expression panels, in which relatively inexpensive and widely available tissue histopathology may be mapped to specific genes' expression to serve as a diagnostic or prognostic tool. FUNDING: National Institutes of Health and American Lung Association.


Assuntos
Predisposição Genética para Doença , Aprendizado de Máquina , Transcriptoma , Tuberculose/genética , Animais , Feminino , Hibridização Genética , Camundongos , Tuberculose/metabolismo , Tuberculose/patologia
14.
BMC Infect Dis ; 21(1): 461, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34016046

RESUMO

BACKGROUND: Tuberculosis (TB) and type 2 diabetes mellitus (DM) are global health diseases with high morbidity and mortality. Few studies have focused on platelet indices in TB-DM coinfection patients. The objective of this work was to analyze the platelet indices in TB, DM and TB-DM patients to assess the predictive value of the platelet index for the risk of these diseases. METHODS: In total, 246 patients admitted to our hospital were distributed into three groups (113 TB, 59 DM and 74 TB + DM). A total of 133 individuals were also recruited as healthy controls (HC). Platelet indices, namely, platelet count (PC), mean platelet volume (MPV), plateletcrit (PCT) and platelet distribution width (PDW), were compared among the four groups, and the relationship with inflammatory markers was explored by using statistical software. RESULTS: Our study discovered that MPV and PCT were significantly downregulated in TB + DM patients (9.95 ± 1.25 fL, 0.20 ± 0.05%, P < 0.0001, P = 0.0121, separately) compared with DM individuals (10.92 ± 1.17 fL, 0.22 ± 0.04%). Moreover, the changes in MPV were significantly higher in TB + DM patients (9.95 ± 1.25 fL, P = 0.0041) than in TB patients (9.42 ± 1.01 fL). No differences were found in PLT and PDW among the four groups (P > 0.05). The sensitivity and specificity of MPV in the differential diagnosis of DM patients vs TB + DM patients were 64.9 and 66.1% (P < 0.0001), respectively, and the sensitivity and specificity of MPV between TB patients and TB + DM patients was 60.8 and 66.4%, respectively (P = 0.003). MPV improved the diagnosis sensitivity when it was combined with clinical parameters, such as fasting blood glucose in DM and Mycobacterium tuberculosis culture result in TB (76.3% vs 64.9, 72.6% vs 60.8%, P < 0.0001, P = 0.001, respectively). In addition, the sensitivity and specificity of PCT in the differential diagnosis of DM patients vs TB + DM patients were 69.5 and 59.4%, respectively (P = 0.008). PCT improved the diagnosis sensitivity when combined with fasting blood glucose in DM (72.9% vs 64.9%, P = 0.004). In addition, MPV was linked to CRP (C-reactive protein) and ESR (erythrocyte sedimentation rate) in the TB + DM patients (r = 0.3203, P = 0.0054, r = 0.2504, P = 0.0307) but PCT was not (r = 0.1905, r = 0.008675, P > 0.05, respectively). CONCLUSIONS: Our research shows that MPV and PCT might be good clinical laboratory markers to distinguish TB + DM patients from TB or DM individuals, thus providing support for earlier clinical diagnosis, prevention, and therapy.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Volume Plaquetário Médio , Tuberculose/epidemiologia , Adulto , Biomarcadores/sangue , Plaquetas/metabolismo , Sedimentação Sanguínea , Comorbidade , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Valor Preditivo dos Testes , Tuberculose/sangue , Tuberculose/metabolismo
15.
Future Med Chem ; 13(10): 911-926, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33845594

RESUMO

The spectacular success of the mycobacterial F1F0-ATP synthase inhibitor bedaquiline for the treatment of drug-resistant tuberculosis has generated wide interest in the development of other inhibitors of this enzyme. Work in this realm has included close analogues of bedaquiline with better safety profiles and 'bedaquiline-like' compounds, some of which show potent antibacterial activity in vitro although none have yet progressed to clinical trials. The search has lately extended to a range of new scaffolds as potential inhibitors, including squaramides, diaminoquinazolines, chloroquinolines, dihydropyrazolo[1,5-a]pyrazin-4-ones, thiazolidinediones, diaminopyrimidines and tetrahydroquinolines. Because of the ubiquitous expression of ATP synthase enzymes, there has also been interest in inhibitors of other bacterial ATP synthases, as well as inhibitors of human mitochondrial ATP synthase for cancer therapy. The latter encompass both complex natural products and simpler small molecules. The review seeks to demonstrate the breadth of the structural types of molecules able to effectively inhibit the function of variants of this intriguing enzyme.


Assuntos
Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Inibidores Enzimáticos/farmacologia , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Tuberculose/tratamento farmacológico , Antineoplásicos/química , Antituberculosos/química , Inibidores Enzimáticos/química , Humanos , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Neoplasias/metabolismo , Tuberculose/metabolismo
16.
Front Immunol ; 12: 598601, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815361

RESUMO

Cryptococcal meningitis (CM) is the leading cause of mortality among patients infected with human immunodeficiency virus (HIV). Although treatment strategies for CM are continually being developed, the mortality rate is still high. Therefore, we need to explore more therapeutic strategies that are aimed at hindering its pathogenic mechanism. In the field of CM, several studies have observed rapid iron accumulation and lipid peroxidation within the brain, all of which are hallmarks of ferroptosis, which is a type of programmed cell death that is characterized by iron dependence and lipid peroxidation. In recent years, many studies have confirmed the involvement of ferroptosis in many diseases, including infectious diseases such as Mycobacterium tuberculosis infection and coronavirus disease-2019 (COVID-19). Furthermore, ferroptosis is considered as immunogenic and pro-inflammatory as the ferroptotic cells release damage-associated molecular pattern molecules (DAMPs) and alarmin, both of which regulate immunity and pro-inflammatory activity. Hence, we hypothesize that there might be a relationship between this unique cell death modality and CM. Herein, we review the evidence of ferroptosis in CM and consider the hypothesis that ferroptotic cell death may be involved in the cell death of CM.


Assuntos
COVID-19/metabolismo , Ferroptose , Ferro/metabolismo , Peroxidação de Lipídeos , Meningite Criptocócica/metabolismo , Tuberculose/metabolismo , COVID-19/imunologia , COVID-19/patologia , Ferroptose/imunologia , Glutationa/metabolismo , Humanos , Inflamação/imunologia , Metabolismo dos Lipídeos , Meningite Criptocócica/imunologia , Meningite Criptocócica/patologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Tuberculose/imunologia , Tuberculose/patologia
17.
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
18.
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
19.
Front Immunol ; 12: 639965, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717192

RESUMO

The risk of progression from Mycobacterium tuberculosis (M.tb) infection to active tuberculosis (TB) disease varies markedly with age. TB disease is significantly less likely in pre-adolescent children above 4 years of age than in very young children or post-pubescent adolescents and young adults. We hypothesized that pro-inflammatory responses to M.tb in pre-adolescent children are either less pronounced or more regulated, than in young adults. Inflammatory and antimicrobial mediators, measured by microfluidic RT-qPCR and protein bead arrays, or by analyzing published microarray data from TB patients and controls, were compared in pre-adolescent children and adults. Multivariate analysis revealed that M.tb-uninfected 8-year-old children had lower levels of myeloid-associated pro-inflammatory mediators than uninfected 18-year-old young adults. Relative to uninfected children, those with M.tb-infection had higher levels of similar myeloid inflammatory responses. These inflammatory mediators were also expressed after in vitro stimulation of whole blood from uninfected children with live M.tb. Our findings suggest that myeloid inflammation is intrinsically lower in pre-pubescent children than in young adults. The lower or more regulated pro-inflammatory responses may play a role in the lower risk of TB disease in this age group.


Assuntos
Inflamação/metabolismo , Inflamação/patologia , Tuberculose/metabolismo , Tuberculose/patologia , Adolescente , Antígenos de Bactérias/metabolismo , Criança , Estudos Transversais , Citocinas/metabolismo , Feminino , Humanos , Inflamação/microbiologia , Mediadores da Inflamação/metabolismo , Masculino , Mycobacterium tuberculosis/patogenicidade , Tuberculose/microbiologia
20.
Am J Respir Crit Care Med ; 204(3): 347-356, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33705666

RESUMO

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


Assuntos
Antituberculosos/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus/epidemiologia , Hiperglicemia/epidemiologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/metabolismo , Adulto , China/epidemiologia , Estudos de Coortes , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Feminino , Humanos , Hiperglicemia/metabolismo , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Estudos Prospectivos , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Tuberculose/metabolismo , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia
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