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1.
Neurol India ; 70(2): 775-777, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35532658

RESUMO

A 39-year-old female presented with complaints of occipital headaches, diplopia, numbness over left half of face and deviation of face to the right. On examination she had hypoesthesia over left half of face, associated with bilateral abductor and left facial palsy. Neuroradiology showed a well-defined lytic lesion involving the clivus and adjacent sphenoid sinus and sella. The patient underwent an endoscopic transnasal decompression of the clival lesion. Intraoperative squash preparation was reported to show tuberculous granulation, which was confirmed on postoperative histology. The patient was advised anti-tubercular therapy. At 12 months follow up neuroradiology showed a near total resolution of the clival lesion. The patient had completely recovered from her cranial nerve deficits. Tuberculous involvement of spheno-clival region is rare and the authors' literature search has yielded only three previous similar case reports. A surgical decompression followed by anti-tubercular therapy is the recommended approach for management of clival tuberculosis. The relevant literature on the subject is presented.


Assuntos
Fossa Craniana Posterior , Tuberculose , Adulto , Fossa Craniana Posterior/diagnóstico por imagem , Fossa Craniana Posterior/patologia , Fossa Craniana Posterior/cirurgia , Diplopia , Endoscopia , Feminino , Humanos , Seio Esfenoidal/cirurgia , Tuberculose/patologia
2.
Int J Mycobacteriol ; 11(1): 75-82, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35295027

RESUMO

Background: In tuberculosis (TB) endemic areas, other pyogenic causes of spine involvement may be missed. The study aimed to describe TB and non-TB causes of spine involvement and identify features that can help in differentiating them. Methods: A retrospective cohort study was conducted to screen the clinical records of all admitted patients (Kasturba Hospital, Manipal) in 2018-20 for a diagnosis of spondylitis and/or sacroiliitis. The clinical features, radiological findings, laboratory parameters, treatment details, and outcomes were compared among those diagnosed with confirmed TB, confirmed brucellosis, or confirmed pyogenic infection. A scoring system was also developed to differentiate spondylodiscitis due to tuberculous and pyogenic causes. The qualitative variables were compared using the Chi-square test, while quantitative variables were compared using the one-way analysis of variance test. Results: Of 120 patients with spine infections, a total of 85 patients were confirmed with the microbiological diagnosis of interest. Involvement of the thoracic spine, longer duration of illness, and caseous granulomatous reaction on histopathology was more common in TB patients. Male gender, involvement of lumbar vertebra, and neutrophilic infiltrate on histopathology were more common in brucellosis patients. Male gender, diabetes mellitus, involvement of lumbar vertebra, neutrophilic infiltrate on histopathology, leukocytosis, and increased C-reactive protein were more commonly seen in patients with pyogenic infection. The scoring system had a sensitivity and specificity of 75% and 91%, respectively, when used to differentiate TB from pyogenic infection. Conclusions: In resource-limited settings, suggestive findings can be used to decide empiric therapy.


Assuntos
Brucelose , Discite , Espondilite , Tuberculose , Brucelose/complicações , Brucelose/diagnóstico , Brucelose/tratamento farmacológico , Discite/diagnóstico , Discite/microbiologia , Discite/patologia , Humanos , Masculino , Estudos Retrospectivos , Coluna Vertebral , Espondilite/diagnóstico , Espondilite/tratamento farmacológico , Espondilite/microbiologia , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Tuberculose/patologia
3.
Pediatr Infect Dis J ; 41(5): e246-e248, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35195567

RESUMO

A 6-year-old boy with autistic spectrum disorder was diagnosed with tuberculosis infection following contact tracing of his mother who had isoniazid-resistant pulmonary tuberculosis. He progressed to develop mediastinal lymphadenopathy causing a persistent cough. He was too small to undergo endobronchial ultrasound-guided biopsy. As an alternative, he underwent esophageal endoscopic ultrasound-guided biopsy, leading to confirmation of the diagnosis. We believe this approach to diagnostic biopsy is underrecognized in pediatric practice, and highlight its utility with this case and a brief literature review.


Assuntos
Neoplasias Pulmonares , Tuberculose , Broncoscopia , Criança , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Humanos , Neoplasias Pulmonares/patologia , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Masculino , Mediastino/diagnóstico por imagem , Mediastino/patologia , Tuberculose/patologia , Ultrassonografia
4.
J Exp Med ; 219(3)2022 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-35061012

RESUMO

Orchestration of an effective T lymphocyte response at infection sites is critical for protection against Mycobacterium tuberculosis (Mtb) infection. However, the local T cell immunity landscape in human tuberculosis is poorly defined. Tuberculous pleural effusion (TPE), caused by Mtb, is characterized by an influx of leukocytes to the pleural space, providing a platform suitable for delineating complex tissue responses to Mtb infection. Using single-cell transcriptomics and T cell receptor sequencing, we analyzed mononuclear cell populations in paired pleural fluid and peripheral blood of TPE patients. While all major cell clusters were present in both tissues, their relative proportions varied significantly by anatomic location. Lineage tracking analysis revealed subsets of CD8 and CD4 T cell populations with distinct effector functions specifically expanded at pleural sites. Granzyme K-expressing CD8 T cells were preferentially enriched and clonally expanded in pleural fluid from TPE, suggesting that they are involved in the pathogenesis of the disease. The findings collectively reveal the landscape of local T cell immunity in tuberculosis.


Assuntos
Mycobacterium tuberculosis/imunologia , Derrame Pleural/etiologia , Derrame Pleural/metabolismo , Derrame Pleural/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Tuberculose/complicações , Tuberculose/imunologia , Biomarcadores , Diferenciação Celular , Suscetibilidade a Doenças , Perfilação da Expressão Gênica/métodos , Interações Hospedeiro-Patógeno , Humanos , Imunofenotipagem , Ativação Linfocitária , Contagem de Linfócitos , Receptores de Antígenos de Linfócitos T/metabolismo , Análise de Célula Única/métodos , Tuberculose/microbiologia , Tuberculose/patologia
5.
PLoS One ; 17(1): e0262720, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35089953

RESUMO

BACKGROUND: Worldwide tuberculosis (TB) takes more lives than any other infectious diseases. WHO estimates around 68,000 incident TB cases in Nepal. However, in 2018 only around 27,232 new TB cases were reported in the national system, resulting around 40,768 incident TB cases missing every year in Nepal. National Tuberculosis Control Center carried out this study in anti-retroviral therapy (ART) sites to estimate the prevalence of TB and identify the associated risk factors for TB among the people living with Human Immunodeficiency Virus (PLHIVs) in Nepal. METHODS: It was a cross-sectional institution-based study conducted between March and August 2018. Six ART sites with high caseloads of PLHIVs were selected. PLHIVs who were equal or above 18 years of age and were in ART program at the selected study sites were considered eligible for the study. Diagnosis of tuberculosis among PLHIVs who agreed to participate in the study was carried out as per the National Tuberculosis Management Guideline of National Tuberculosis Program of Nepal. RESULTS: Among 403 PLHIVs, tuberculosis was diagnosed in 40 (9.9%) individuals. Median age of the participants was 36 (30-43) years. Prevalence of TB was significantly higher among male PLHIVs than female PLHIVs (13.6% Vs 5.8%; P = 0.02) and Dalit ethnic group compared to Brahmin/Chettri (22.0%Vs5.9%, P = 0.01). The risk of developing TB was found significant among those with HIV stage progressed to WHO stage 3 and 4 (OR = 4.85, P<0.001) and with the family history of TB (OR = 4.50, P = 0.002). CONCLUSIONS: Prevalence of TB among PLHIVs in Nepal was found 9.9%. Risk of developing TB was higher among PLHIVs who were male, Dalit, with HIV stage progressed to WHO stage 3 and 4 and with family history of TB. Hence, targeted interventions are needed to prevent the risk of developing TB among PLHIVs. Similarly, integrated, and comprehensive TB and HIV diagnosis and treatment services are needed for the management of TB/HIV co-infection in Nepal.


Assuntos
Coinfecção/epidemiologia , Infecções por HIV/complicações , HIV/isolamento & purificação , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose/epidemiologia , Adulto , Coinfecção/etiologia , Estudos Transversais , Feminino , Infecções por HIV/virologia , Soropositividade para HIV , Humanos , Masculino , Pessoa de Meia-Idade , Nepal/epidemiologia , Prevalência , Fatores de Risco , Tuberculose/etiologia , Tuberculose/patologia , Adulto Jovem
6.
Cell Mol Life Sci ; 79(1): 62, 2022 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-35001155

RESUMO

Availability of iron is a key factor in the survival and multiplication of Mycobacterium tuberculosis (M.tb) within host macrophage phagosomes. Despite host cell iron regulatory machineries attempts to deny supply of this essential micronutrient, intraphagosomal M.tb continues to access extracellular iron. In the current study, we report that intracellular M.tb exploits mammalian secreted Glyceraldehyde 3-phosphate dehydrogenase (sGAPDH) for the delivery of host iron carrier proteins lactoferrin (Lf) and transferrin (Tf). Studying the trafficking of iron carriers in infected cells we observed that sGAPDH along with the iron carrier proteins are preferentially internalized into infected cells and trafficked to M.tb containing phagosomes where they are internalized by resident mycobacteria resulting in iron delivery. Collectively our findings provide a new mechanism of iron acquisition by M.tb involving the hijack of host sGAPDH. This may contribute to its successful pathogenesis and provide an option for targeted therapeutic intervention.


Assuntos
Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Ferro/metabolismo , Lactoferrina/metabolismo , Mycobacterium tuberculosis/metabolismo , Transferrina/metabolismo , Animais , Transporte Biológico/fisiologia , Linhagem Celular Tumoral , Humanos , Células L , Camundongos , Camundongos Endogâmicos C57BL , Fagossomos/metabolismo , Células THP-1 , Tuberculose/patologia
7.
Clin Nucl Med ; 47(4): 344-345, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35020654

RESUMO

ABSTRACT: A 57-year-old woman was admitted to the hospital with persisting cough and sputum for 2 months. Chest CT revealed multiple nodules in the left lung. 18F-FDG PET/CT scan was carried out to further evaluate these pulmonary lesions. In addition to multiple hypermetabolic nodules in the upper lobe of left lung, diffuse thickening of the trachea and left bronchial wall with increased FDG uptake was also found. Inflammatory granulation tissue with Mycobacterium tuberculosis was confirmed through the pathological examination of bronchoscopy.


Assuntos
Tuberculose Pulmonar , Tuberculose , Brônquios/diagnóstico por imagem , Brônquios/patologia , Feminino , Fluordesoxiglucose F18 , Humanos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tuberculose/patologia , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/diagnóstico por imagem
8.
J Small Anim Pract ; 63(3): 174-187, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34101189

RESUMO

OBJECTIVES: To identify and describe histological and immunohistochemical criteria that may differentiate between skin and lymph node lesions associated with Mycobacterium (M.) bovis and M. microti in a diagnostic pathology setting. MATERIALS AND METHODS: Archived skin and lymph node biopsies of tuberculous lesions were stained with haematoxylin and eosin, Ziehl-Neelsen and Masson's Trichrome. Immunohistochemistry was performed to detect the expression of calprotectin, CD3 and Pax5. Samples were scored for histological parameters (i.e. granulomas with central necrosis versus small granulomas without central necrosis, percentage necrosis and/or multinucleated giant cells), number of acid-fast bacilli (bacterial index) and lesion percentage of fibrosis and positive immunohistochemical staining. RESULTS: Twenty-two samples were examined (M. bovis n=11, M. microti n=11). When controlling for age, gender and tissue, feline M. bovis-associated lesions more often featured large multi-layered granulomas with central necrosis. Conversely, this presentation was infrequent in feline M. microti-associated lesions, where small granulomas without central necrosis predominated. The presence of an outer fibrous capsule was variable in both groups, as was the bacterial index. There were no differences in intralesional expression of immunohistochemical markers. CLINICAL SIGNIFICANCE: Differences in the histological appearance of skin and lymph node lesions may help to infer feline infection with either M. bovis or M. microti at an earlier stage when investigating these cases, informing clinicians of the potential zoonotic risk. Importantly, cases of tuberculosis can present with numerous acid-fast bacilli. This implies that a high bacterial index does not infer infection with non-zoonotic non-tuberculous mycobacteria.


Assuntos
Doenças do Gato , Tuberculose , Animais , Doenças do Gato/patologia , Gatos , Granuloma/veterinária , Imuno-Histoquímica , Linfonodos/patologia , Necrose/patologia , Necrose/veterinária , Tuberculose/microbiologia , Tuberculose/patologia , Tuberculose/veterinária
9.
Biochim Biophys Acta Mol Basis Dis ; 1868(1): 166292, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34710568

RESUMO

Tuberculosis (TB) remains a major cause of mortality and morbidity worldwide, and it is instant to discover novel anti-TB drugs due to the rapidly growing drug-resistance TB. Mycobacterium tuberculosis (Mtb) secreted effector ESAT6 plays a critical role in modulation miRNAs to regulate host defense mechanisms during Mtb infection, it can be a possible target for new tuberculosis drugs. The non-tuberculous mycobacteria Mycobacterium smegmatis (M. smegmatis) and Mtb have high gene homology but no pathogenicity. We used ESAT6 to interfere with macrophages or mice infected by M. smegmatis and determined that it enhanced the survival rate of bacteria and regulated miR-222-3p target PTEN. Expression of miR-222-3p reduced and PTEN enhanced with the progression of macrophages infected by M. smegmatis with ESAT6 co-incubation. MiR-222-3p overexpression diminished M. smegmatis survival and upregulated proinflammatory cytokines. VO-Ohpic trihydrate (PTEN inhibitor) reduced M. smegmatis survival and upregulated proinflammatory cytokines in vivo and in vitro, and VO-Ohpic trihydrate reversed the tissue damage of mouse organs caused by ESAT6. These results uncover an ESAT6 dependent role for miR-222-3p and its target PTEN in regulating host immune responses to bacterial infection and may provide a potential site for the development of anti-tuberculosis drugs that specifically antagonize the virulence of ESAT6.


Assuntos
Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Tuberculose/genética , Animais , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata/genética , Camundongos , Mycobacterium smegmatis/genética , Mycobacterium smegmatis/patogenicidade , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidade , Tuberculose/imunologia , Tuberculose/patologia
10.
PLoS One ; 16(12): e0261246, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34890419

RESUMO

INTRODUCTION: Meta-analyses conducted so far on the association between diabetes mellitus (DM) and the tuberculosis (TB) development risk did not sufficiently take confounders into account in their estimates. The objective of this systematic review was to determine whether DM is associated with an increased risk of developing TB with a sensitivity analyses incorporating a wider range of confounders including age, gender, alcohol consumption, smoke exposure, and other comorbidities. METHODS: Pubmed, Embase, Web of Science and Global Index Medicus were queried from inception until October 2020. Without any restriction to time of study, geographical location, and DM and TB diagnosis approaches, all observational studies that presented data for associations between DM and TB were included. Studies with no abstract or complete text, duplicates, and studies with wrong designs (review, case report, case series, comment on an article, and editorial) or populations were excluded. The odds ratios (OR) and their 95% confidence intervals were estimated by a random-effect model. RESULTS: The electronic and manual searches yielded 12,796 articles of which 47 were used in our study (23 case control, 14 cross-sectional and 10 cohort studies) involving 503,760 cases (DM or TB patients) and 3,596,845 controls. The size of the combined effect of TB risk in the presence of DM was OR = 2.3, 95% CI = [2.0-2.7], I2 = 94.2%. This statistically significant association was maintained in cohort (OR = 2.0, CI 95% = [1.5-2.4], I2 = 94.3%), case control (OR = 2.4, CI 95% = [2.0-2.9], I2 = 93.0%) and cross-sectional studies (OR = 2.5, CI 95% = [1.8-3.5], I2 = 95.2%). The association between DM and TB was also maintained in the sensitivity analysis including only studies with similar proportions of confounders between cases and controls. The substantial heterogeneity observed was mainly explained by the differences between geographic regions. CONCLUSIONS: DM is associated with an increased risk of developing latent and active TB. To further explore the role of DM in the development of TB, more investigations of the biological mechanisms by which DM increases the risk of TB are needed. REVIEW REGISTRATION: PROSPERO, CRD42021216815.


Assuntos
Complicações do Diabetes/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Tuberculose/epidemiologia , Fatores de Confusão Epidemiológicos , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Diabetes Mellitus Tipo 2/microbiologia , Diabetes Mellitus Tipo 2/patologia , Humanos , Fatores de Risco , Tuberculose/metabolismo , Tuberculose/patologia
11.
Cells ; 10(12)2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34943984

RESUMO

Mycobacterium tuberculosis (Mtb) is an intracellular pathogenic bacterium and the causative agent of tuberculosis. This disease is one of the most ancient and deadliest bacterial infections, as it poses major health, social and economic challenges at a global level, primarily in low- and middle-income countries. The lack of an effective vaccine, the long and expensive drug therapy, and the rapid spread of drug-resistant strains of Mtb have led to the re-emergence of tuberculosis as a global pandemic. Here, we assessed the in vitro activity of new imidazole-thiosemicarbazide derivatives (ITDs) against Mtb infection and their effects on mycobacterial biofilm formation. Cytotoxicity studies of the new compounds in cell lines and human monocyte-derived macrophages (MDMs) were performed. The anti-Mtb activity of ITDs was evaluated by determining minimal inhibitory concentrations of resazurin, time-kill curves, bacterial intracellular growth and the effect on biofilm formation. Mutation frequency and whole-genome sequencing of mutants that were resistant to ITDs were performed. The antimycobacterial potential of ITDs with the ability to penetrate Mtb-infected human macrophages and significantly inhibit the intracellular growth of tubercle bacilli and suppress Mtb biofilm formation was observed.


Assuntos
Imidazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Semicarbazidas/farmacologia , Tuberculose/tratamento farmacológico , Antituberculosos , Biofilmes/efeitos dos fármacos , Linhagem Celular , Humanos , Imidazóis/química , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/patogenicidade , Tuberculose/microbiologia , Tuberculose/patologia
12.
PLoS Pathog ; 17(11): e1010020, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34724002

RESUMO

Mycobacterium tuberculosis, the main causative agent of human tuberculosis, is transmitted from person to person via small droplets containing very few bacteria. Optimizing the chance to seed in the lungs is therefore a major adaptation to favor survival and dissemination in the human population. Here we used TnSeq to identify genes important for the early events leading to bacterial seeding in the lungs. Beside several genes encoding known virulence factors, we found three new candidates not previously described: rv0180c, rv1779c and rv1592c. We focused on the gene, rv0180c, of unknown function. First, we found that deletion of rv0180c in M. tuberculosis substantially reduced the initiation of infection in the lungs of mice. Next, we established that Rv0180c enhances entry into macrophages through the use of complement-receptor 3 (CR3), a major phagocytic receptor for M. tuberculosis. Silencing CR3 or blocking the CR3 lectin site abolished the difference in entry between the wild-type parental strain and the Δrv0180c::km mutant. However, we detected no difference in the production of both CR3-known carbohydrate ligands (glucan, arabinomannan, mannan), CR3-modulating lipids (phthiocerol dimycocerosate), or proteins in the capsule of the Δrv0180c::km mutant in comparison to the wild-type or complemented strains. By contrast, we established that Rv0180c contributes to the functionality of the bacterial cell envelope regarding resistance to toxic molecule attack and cell shape. This alteration of bacterial shape could impair the engagement of membrane receptors that M. tuberculosis uses to invade host cells, and open a new perspective on the modulation of bacterial infectivity.


Assuntos
Proteínas de Bactérias/metabolismo , Forma Celular , Parede Celular/química , Macrófagos/microbiologia , Metaloproteinases da Matriz/metabolismo , Mycobacterium tuberculosis/fisiologia , Tuberculose/microbiologia , Animais , Proteínas de Bactérias/genética , Parede Celular/metabolismo , Feminino , Humanos , Pulmão/metabolismo , Pulmão/microbiologia , Macrófagos/metabolismo , Macrófagos/patologia , Metaloproteinases da Matriz/genética , Camundongos , Camundongos Endogâmicos BALB C , Polissacarídeos/metabolismo , Tuberculose/metabolismo , Tuberculose/patologia , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
13.
Am J Trop Med Hyg ; 106(1): 75-79, 2021 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-34814111

RESUMO

Tuberculosis (TB) remains a global problem and a diagnostic challenge, especially in pediatrics. The aim of this study was to describe the clinical, microbiological, radiological, and histopathological data of TB in children. A 7-year retrospective and descriptive cohort study that included 127 patients under 18 years of age with diagnosis of active TB was conducted from 2011 to 2018 in a pediatric hospital. Tuberculosis was microbiologically confirmed using Ziehl-Neelsen (ZN) staining, culture or polymerase chain reaction (PCR) in a total of 94 (74%) cases. Thirty-three cases were defined as probable TB based on tuberculin skin test result and epidemiological evaluation. The TB forms found were lymph node (39.3%), bone (15.7%), lung (13.6%), and meningeal TB (8.6%). The most common symptoms were fever (48.8%) and adenopathy (45.6%). History of contact was established in 34.6%. Positive ZN staining (sensitivity 30%) and culture (sensitivity 37%) were found in 29% and 37.7% of subjects, respectively. About 64.5% depicted abnormal chest X-ray. Xpert MTB/RIF® (PCR) was positive in 9.4% and biopsy was compatible in 52.7% of these samples. It is fundamental to have laboratory and epidemiological evaluation that support the diagnosis of the disease in children and thus, define its management; since, in most cases, early microbiologic confirmation is lacking.


Assuntos
Hospitais Pediátricos , Tuberculose , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Corantes , Feminino , Humanos , Masculino , México/epidemiologia , Mycobacterium tuberculosis/isolamento & purificação , Patologia Molecular , Estudos Retrospectivos , Sensibilidade e Especificidade , Tuberculose/diagnóstico , Tuberculose/epidemiologia , Tuberculose/patologia , Tuberculose dos Linfonodos/diagnóstico , Tuberculose dos Linfonodos/epidemiologia , Tuberculose dos Linfonodos/patologia , Tuberculose Meníngea/diagnóstico , Tuberculose Meníngea/epidemiologia , Tuberculose Meníngea/patologia , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/patologia
14.
Elife ; 102021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34751132

RESUMO

Encapsulin nanocompartments are an emerging class of prokaryotic protein-based organelle consisting of an encapsulin protein shell that encloses a protein cargo. Genes encoding nanocompartments are widespread in bacteria and archaea, and recent works have characterized the biochemical function of several cargo enzymes. However, the importance of these organelles to host physiology is poorly understood. Here, we report that the human pathogen Mycobacterium tuberculosis (Mtb) produces a nanocompartment that contains the dye-decolorizing peroxidase DyP. We show that this nanocompartment is important for the ability of Mtb to resist oxidative stress in low pH environments, including during infection of host cells and upon treatment with a clinically relevant antibiotic. Our findings are the first to implicate a nanocompartment in bacterial pathogenesis and reveal a new mechanism that Mtb uses to combat oxidative stress.


Assuntos
Mycobacterium tuberculosis/fisiologia , Organelas/metabolismo , Estresse Oxidativo , Peroxidase/metabolismo , Animais , Antituberculosos/farmacologia , Macrófagos/microbiologia , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Organelas/genética , Peroxidase/genética , Pirazinamida/farmacologia , Tuberculose/patologia
15.
Bull Exp Biol Med ; 172(1): 42-45, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34796425

RESUMO

In cultures of peritoneal macrophages (MP) of male BALB/c mice infected with Mycobacterium tuberculosis from the BCG vaccine, the expression of CD1, CD14, CD25, CD30, CD35, and CD95 receptors was studied in vitro 3 months after infection. In MP cultures from intact and infected mice, mononuclear MP predominated (96 and 92%, respectively). Bi- and trinuclear MP in MP cultures from control and infected mice constituted 4 and 8.3% of all MP, respectively. In the cultures of both groups, no obvious correlations between the number of MP expressing CD-receptors and number of nuclei in these cells were found, but the expression of CD14 receptor was more often noted. In cultures from infected animals, hypertrophied MP and enhanced (by several times) expression of all CD-receptors were observed. The increase in the expression of CD-receptor can be determined by activation of plastic processes in hypertrophied MP (in epithelioid and in numerically insignificant polynuclear MP), which is due to the phenomenon of prolonged M. tuberculosis persistence in the vacuolar apparatus of these cells.


Assuntos
Antígenos CD1/biossíntese , Macrófagos Peritoneais/imunologia , Mycobacterium tuberculosis/imunologia , Receptores de Citocinas/biossíntese , Tuberculose/imunologia , Animais , Vacina BCG/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Tuberculose/patologia
16.
Cells ; 10(10)2021 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-34685683

RESUMO

External validation in different cohorts is a key step in the translational development of new biomarkers. We previously described three host mRNA whose expression in peripheral blood is significantly higher (NPC2) or lower (DOCK9 and EPHA4) in individuals with TB compared to latent TB infection (LTBI) and controls. We have now conducted an independent validation of these genes by re-analyzing publicly available transcriptomic datasets from Brazil, China, Haiti, India, South Africa, and the United Kingdom. Comparisons between TB and control/LTBI showed significant differential expression of all three genes (NPC2high p < 0.01, DOCK9low p < 0.01, and EPHA4low p < 0.05). NPC2high had the highest mean area under the ROC curve (AUROC) for the differentiation of TB vs. controls (0.95) and LTBI (0.94). In addition, NPC2 accurately distinguished TB from the clinically similar conditions pneumonia (AUROC, 0.88), non-active sarcoidosis (0.87), and lung cancer (0.86), but not from active sarcoidosis (0.66). Interestingly, individuals progressing from LTBI to TB showed a constant increase in NPC2 expression with time when compared to non-progressors (p < 0.05), with a significant change closer to manifestation of active disease (≤3 months, p = 0.003). Moreover, NPC2 expression normalized with completion of anti-TB treatment. Taken together, these results validate NPC2 mRNA as a diagnostic host biomarker for active TB independent of host genetic background. Moreover, they reveal its potential to predict progression from latent to active infection and to indicate a response to anti-TB treatment.


Assuntos
Progressão da Doença , Transcriptoma/genética , Tuberculose/diagnóstico , Tuberculose/genética , Proteínas de Transporte Vesicular/genética , Biomarcadores/metabolismo , Estudos de Coortes , Diagnóstico Diferencial , Regulação da Expressão Gênica , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Curva ROC , Transcrição Genética , Resultado do Tratamento , Tuberculose/sangue , Tuberculose/patologia , Proteínas de Transporte Vesicular/metabolismo
17.
Bull Exp Biol Med ; 171(5): 656-660, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34617184

RESUMO

We studied the effects of M. tuberculosis secretory proteins ESAT-6 and CFP-10 on the properties of vaccinal mycobacteria BCG not producing these proteins. Phagocytosis of M. bovis by macrophages, proliferation of mycobacteria in macrophages, apoptosis and necrosis of macrophages, and the production of reactive oxygen and nitrogen species were studied. It was shown that both ESAT-6 and CFP-10 significantly increased the number of phagocytized mycobacteria by increasing the number of phagocytic-active macrophages and augment the intracellular proliferation of the pathogen. At the same time, macrophages preincubated with ESAT-6 and CFP-10 reduce the production of reactive oxygen and nitrogen species and are more susceptible to apoptosis and necrosis in the presence of mycobacteria. In summary, these proteins suppress macrophage-mediated mechanisms of anti-tuberculosis resistance and impart pronounced pathogenic properties to non-pathogenic mycobacteria that do not secrete ESAT-6 and CFP-10.


Assuntos
Antígenos de Bactérias/farmacologia , Proteínas de Bactérias/farmacologia , Granuloma/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Animais , Células Cultivadas , Granuloma/microbiologia , Macrófagos Peritoneais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Biológicos , Mycobacterium tuberculosis/patogenicidade , Tuberculose/patologia
18.
Lancet Infect Dis ; 21(11): e356-e362, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34599872

RESUMO

Spinal epidural abscess caused by Aspergillus spp is a debilitating form of invasive aspergillosis that can easily be misdiagnosed as spinal tuberculosis due to shared risk factors and clinical features. In this Grand Round, we describe a case of thoracic aspergillus spinal epidural abscess in a patient with underlying HIV infection. The initial diagnostic consideration was that of spinal tuberculosis. Consequently, despite positive microbiological cultures of Aspergillus fumigatus, antifungal therapy was delayed until histopathological evaluation of the affected tissue confirmed the presence of fungal hyphae. The patient showed an initial favourable response after surgical removal of the infected focus, but unfortunately never returned to premorbid functioning. This case highlights the importance of early diagnosis, urgent surgery, and prompt antifungal therapy for the management of aspergillus spinal epidural abscesses. Associated morbidity and mortality can be substantially increased if physicians fail to recognise this condition and do not institute appropriate and timely surgical and medical treatment.


Assuntos
Aspergilose/diagnóstico , Aspergilose/patologia , Abscesso Epidural/microbiologia , Infecções por HIV/complicações , HIV-1 , Tuberculose/diagnóstico , Adulto , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergillus , Abscesso Epidural/tratamento farmacológico , Feminino , Humanos , Itraconazol/administração & dosagem , Itraconazol/uso terapêutico , Tuberculose/patologia , Voriconazol/administração & dosagem , Voriconazol/uso terapêutico
19.
Microbiol Spectr ; 9(2): e0109521, 2021 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-34549992

RESUMO

Almost 140 years after the identification of Mycobacterium tuberculosis as the etiological agent of tuberculosis, important aspects of its biology remain poorly described. Little is known about the role of posttranscriptional control of gene expression and RNA biology, including the role of most of the small RNAs (sRNAs) identified to date. We have carried out a detailed investigation of the M. tuberculosis sRNA F6 and shown it to be dependent on SigF for expression and significantly induced in starvation conditions in vitro and in a mouse model of infection. Further exploration of F6 using an in vitro starvation model of infection indicates that F6 affects the expression of the essential chaperonins GroEL2 and GroES. Our results point toward a role for F6 during periods of low metabolic activity typically associated with long-term survival of M. tuberculosis in human granulomas. IMPORTANCE Control of gene expression via small regulatory RNAs (sRNAs) is poorly understood in one of the most successful pathogens, Mycobacterium tuberculosis. Here, we present an in-depth characterization of the sRNA F6, including its expression in different infection models and the differential gene expression observed upon deletion of the sRNA. Our results demonstrate that deletion of F6 leads to dysregulation of the two essential chaperonins GroEL2 and GroES and, moreover, indicate a role for F6 in the long-term survival and persistence of M. tuberculosis in the human host.


Assuntos
Antígenos de Bactérias/biossíntese , Proteínas de Bactérias/biossíntese , Chaperonina 60/biossíntese , Regulação Bacteriana da Expressão Gênica/genética , Proteínas de Choque Térmico/biossíntese , Mycobacterium tuberculosis/metabolismo , Pequeno RNA não Traduzido/genética , Animais , Proteínas de Bactérias/genética , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/genética , RNA Bacteriano/genética , Fator sigma/genética , Inanição/patologia , Tuberculose/patologia
20.
Microbiol Spectr ; 9(2): e0092821, 2021 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-34550010

RESUMO

Phosphopantetheinyl hydrolase, PptH (Rv2795c), is a recently discovered enzyme from Mycobacterium tuberculosis that removes 4'-phosphopantetheine (Ppt) from holo-carrier proteins (CPs) and thereby opposes the action of phosphopantetheinyl transferases (PPTases). PptH is the first structurally characterized enzyme of the phosphopantetheinyl hydrolase family. However, conditions for optimal activity of PptH have not been defined, and only one substrate has been identified. Here, we provide biochemical characterization of PptH and demonstrate that the enzyme hydrolyzes Ppt in vitro from more than one M. tuberculosis holo-CP as well as holo-CPs from other organisms. PptH provided the only detectable activity in mycobacterial lysates that dephosphopantetheinylated acyl carrier protein M (AcpM), suggesting that PptH is the main Ppt hydrolase in M. tuberculosis. We could not detect a role for PptH in coenzyme A (CoA) salvage, and PptH was not required for virulence of M. tuberculosis during infection of mice. It remains to be determined why mycobacteria conserve a broadly acting phosphohydrolase that removes the Ppt prosthetic group from essential CPs. We speculate that the enzyme is critical for aspects of the life cycle of M. tuberculosis that are not routinely modeled. IMPORTANCE Tuberculosis (TB), caused by Mycobacterium tuberculosis, was the leading cause of death from an infectious disease before COVID, yet the in vivo essentiality and function of many of the protein-encoding genes expressed by M. tuberculosis are not known. We biochemically characterize M. tuberculosis's phosphopantetheinyl hydrolase, PptH, a protein unique to mycobacteria that removes an essential posttranslational modification on proteins involved in synthesis of lipids important for the bacterium's cell wall and virulence. We demonstrate that the enzyme has broad substrate specificity, but it does not appear to have a role in coenzyme A (CoA) salvage or virulence in a mouse model of TB.


Assuntos
Mycobacterium tuberculosis/enzimologia , Panteteína/análogos & derivados , Diester Fosfórico Hidrolases/metabolismo , Animais , Parede Celular/metabolismo , Feminino , Humanos , Lipídeos/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/metabolismo , Panteteína/metabolismo , Processamento de Proteína Pós-Traducional , Tuberculose/patologia , Virulência/fisiologia
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