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1.
Cells ; 10(9)2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34571865

RESUMO

Leprosy reactional episodes are acute inflammatory events that may occur during the clinical course of the disease. Type 1 reaction (T1R) is associated with an increase in neural damage, and the understanding of the molecular pathways related to T1R onset is pivotal for the development of strategies that may effectively control the reaction. Interferon-gamma (IFN-γ) is a key cytokine associated with T1R onset and is also associated with autophagy induction. Here, we evaluated the modulation of the autophagy pathway in Mycobacterium leprae-stimulated cells in the presence or absence of IFN-γ. We observed that IFN-γ treatment promoted autophagy activation and increased the expression of genes related to the formation of phagosomes, autophagy regulation and function, or lysosomal pathways in M. leprae-stimulated cells. IFN-γ increased interleukin (IL)-15 secretion in M. leprae-stimulated THP-1 cells in a process associated with autophagy activation. We also observed higher IL15 gene expression in multibacillary (MB) patients who later developed T1R during clinical follow-up when compared to MB patients who did not develop the episode. By overlapping gene expression patterns, we observed 13 common elements shared between T1R skin lesion cells and THP-1 cells stimulated with both M. leprae and IFN-γ. Among these genes, the autophagy regulator Translocated Promoter Region, Nuclear Basket Protein (TPR) was significantly increased in T1R cells when compared with non-reactional MB cells. Overall, our results indicate that IFN-γ may induce a TPR-mediated autophagy transcriptional program in M. leprae-stimulated cells similar to that observed in skin cells during T1R by a pathway that involves IL-15 production, suggesting the involvement of this cytokine in the pathogenesis of T1R.


Assuntos
Autofagia/genética , Interleucina-15/genética , Hanseníase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Criança , Citocinas/genética , Feminino , Expressão Gênica/genética , Humanos , Interferon gama/genética , Hanseníase/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/patogenicidade , Pele/metabolismo , Pele/microbiologia , Células THP-1/metabolismo , Adulto Jovem
2.
Front Immunol ; 12: 662307, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34354699

RESUMO

The treatment of multibacillary cases of leprosy with multidrug therapy (MDT) comprises 12 doses of a combination of rifampicin, dapsone and clofazimine. Previous studies have described the immunological phenotypic pattern in skin lesions in multibacillary patients. Here, we evaluated the effect of MDT on skin cell phenotype and on the Mycobacterium leprae-specific immune response. An analysis of skin cell phenotype demonstrated a significant decrease in MRS1 (SR-A), CXCL10 (IP-10) and IFNG (IFN-γ) gene and protein expression after MDT release. Patients were randomized according to whether they experienced a reduction in bacillary load after MDT. A reduction in CXCL10 (IP-10) in sera was associated with the absence of a reduction in the bacillary load at release. Although IFN-γ production in response to M. leprae was not affected by MDT, CXCL10 (IP-10) levels in response to M. leprae increased in cells from patients who experienced a reduction in bacillary load after treatment. Together, our results suggest that CXCL10 (IP-10) may be a good marker for monitoring treatment efficacy in multibacillary patients.


Assuntos
Quimiocina CXCL10/sangue , Hansenostáticos/uso terapêutico , Hanseníase/tratamento farmacológico , Pele/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carga Bacteriana/efeitos dos fármacos , Biomarcadores/sangue , Quimiocina CXCL10/imunologia , Quimioterapia Combinada , Feminino , Humanos , Hansenostáticos/administração & dosagem , Hanseníase/imunologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Pele/microbiologia , Pele/patologia , Resultado do Tratamento , Adulto Jovem
3.
Nat Immunol ; 22(7): 839-850, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34168371

RESUMO

Granulomas are complex cellular structures composed predominantly of macrophages and lymphocytes that function to contain and kill invading pathogens. Here, we investigated the single-cell phenotypes associated with antimicrobial responses in human leprosy granulomas by applying single-cell and spatial sequencing to leprosy biopsy specimens. We focused on reversal reactions (RRs), a dynamic process whereby some patients with disseminated lepromatous leprosy (L-lep) transition toward self-limiting tuberculoid leprosy (T-lep), mounting effective antimicrobial responses. We identified a set of genes encoding proteins involved in antimicrobial responses that are differentially expressed in RR versus L-lep lesions and regulated by interferon-γ and interleukin-1ß. By integrating the spatial coordinates of the key cell types and antimicrobial gene expression in RR and T-lep lesions, we constructed a map revealing the organized architecture of granulomas depicting compositional and functional layers by which macrophages, T cells, keratinocytes and fibroblasts can each contribute to the antimicrobial response.


Assuntos
Hanseníase Virchowiana/imunologia , Hanseníase Tuberculoide/imunologia , Mycobacterium leprae/imunologia , Pele/imunologia , Adolescente , Adulto , Idoso , Feminino , Fibroblastos/imunologia , Fibroblastos/microbiologia , Fibroblastos/patologia , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Queratinócitos/imunologia , Queratinócitos/microbiologia , Queratinócitos/patologia , Hanseníase Virchowiana/genética , Hanseníase Virchowiana/microbiologia , Hanseníase Virchowiana/patologia , Hanseníase Tuberculoide/genética , Hanseníase Tuberculoide/microbiologia , Hanseníase Tuberculoide/patologia , Macrófagos/imunologia , Macrófagos/microbiologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/patogenicidade , RNA-Seq , Análise de Célula Única , Pele/microbiologia , Pele/patologia , Linfócitos T/imunologia , Linfócitos T/microbiologia , Linfócitos T/patologia , Transcriptoma
4.
mSphere ; 6(3)2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952660

RESUMO

Mycobacterium tuberculosis infections claim more than a million lives each year, and better treatments or vaccines are required. A crucial pathogenicity factor is translocation from phagolysosomes to the cytosol upon phagocytosis by macrophages. Translocation from the phagolysosome to the cytosol is an ESX-1-dependent process, as previously shown in vitro Here, we show that in vivo, mycobacteria also translocate to the cytosol but mainly when host immunity is compromised. We observed only low numbers of cytosolic bacilli in mice, armadillos, zebrafish, and patient material infected with M. tuberculosis, M. marinum, or M. leprae In contrast, when innate or adaptive immunity was compromised, as in severe combined immunodeficiency (SCID) or interleukin-1 receptor 1 (IL-1R1)-deficient mice, significant numbers of cytosolic M. tuberculosis bacilli were detected in the lungs of infected mice. Taken together, in vivo, translocation to the cytosol of M. tuberculosis is controlled by adaptive immune responses as well as IL-1R1-mediated signals.IMPORTANCE For decades, Mycobacterium tuberculosis has been one of the deadliest pathogens known. Despite infecting approximately one-third of the human population, no effective treatment or vaccine is available. A crucial pathogenicity factor is subcellular localization, as M. tuberculosis can translocate from phagolysosome to the cytosol in macrophages. The situation in vivo is more complicated. In this study, we establish that high-level cytosolic escape of mycobacteria can indeed occur in vivo but mainly when host resistance is compromised. The IL-1 pathway is crucial for the control of the number of cytosolic mycobacteria. The establishment that immune signals result in the clearance of cells containing cytosolic mycobacteria connects two important fields, cell biology and immunology, which is vital for the understanding of the pathology of M. tuberculosis.


Assuntos
Citosol/microbiologia , Mycobacterium/imunologia , Mycobacterium/patogenicidade , Fagossomos/microbiologia , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/imunologia , Transdução de Sinais/imunologia , Animais , Tatus/microbiologia , Translocação Bacteriana , Citosol/imunologia , Feminino , Humanos , Hanseníase/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Mycobacterium/classificação , Fagossomos/imunologia , Pele/microbiologia , Pele/patologia , Células THP-1 , Peixe-Zebra
5.
PLoS Negl Trop Dis ; 15(5): e0009382, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33939710

RESUMO

The World Health Organization has raised concerns about the increasing number of Hansen disease (HD) relapses worldwide, especially in Brazil, India, and Indonesia that report the highest number of recurrent cases. Relapses are an indicator of MDT effectiveness and can reflect Mycobacterium leprae persistence or re-infection. Relapse is also a potential marker for the development or progression of disability. In this research, we studied a large cohort of persons affected by HD treated with full fixed-dose multibacillary (MB) multidrug therapy (MDT) followed for up to 20 years and observed that relapses are a rare event. We estimated the incidence density of relapse in a cohort of patients classified to receive MB regime (bacillary index (BI) > 0), diagnosed between September 1997 and June 2017, and treated with twelve-dose MB-MDT at a HD reference center in Rio de Janeiro, Brazil. We obtained the data from the data management system of the clinic routine service. We linked the selected cases to the dataset of relapses of the national HD data to confirm possible relapse cases diagnosed elsewhere. We diagnosed ten cases of relapse in a cohort of 713 patients followed-up for a mean of 12.1 years. This resulted in an incidence rate of 1.16 relapse cases per 1000 person-year (95% CI = 0.5915-2.076). The accumulated risk was 0.025 in 20 years. The very low risk observed in this cohort of twelve-dose-treated MB patients reinforces the success of the current MDT scheme.


Assuntos
Hansenostáticos/uso terapêutico , Hanseníase Virchowiana/tratamento farmacológico , Hanseníase Virchowiana/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Criança , Pré-Escolar , Clofazimina/uso terapêutico , Dapsona/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/efeitos dos fármacos , Recidiva , Estudos Retrospectivos , Rifampina/uso terapêutico , Pele/microbiologia , Pele/patologia , Adulto Jovem
9.
PLoS Negl Trop Dis ; 14(10): e0008850, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33075048

RESUMO

Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae). In lepromatous leprosy (LL), skin macrophages, harboring extensive bacterial multiplication, gain a distinctive foamy appearance due to increased intracellular lipid load. To determine the mechanism by which M. leprae modifies the lipid homeostasis in host cells, an in vitro M. leprae infection system, using human macrophage precursor THP-1 cells and M. leprae prepared from the footpads of nude mice, was employed. RNA extracted from skin smear samples of patients was used to investigate host gene expressions before and after multidrug therapy (MDT). We found that a cluster of peroxisome proliferator-activated receptor (PPAR) target genes associated with adipocyte differentiation were strongly induced in M. leprae-infected THP-1 cells, with increased intracellular lipid accumulation. PPAR-δ and PPAR-γ expressions were induced by M. leprae infection in a bacterial load-dependent manner, and their proteins underwent nuclear translocalization after infection, indicating activation of PPAR signaling in host cells. Either PPAR-δ or PPAR-γ antagonist abolished the effect of M. leprae to modify host gene expressions and inhibited intracellular lipid accumulation in host cells. M. leprae-specific gene expressions were detected in the skin smear samples both before and after MDT, whereas PPAR target gene expressions were dramatically diminished after MDT. These results suggest that M. leprae infection activates host PPAR signaling to induce an array of adipocyte differentiation-associated genes, leading to accumulation of intracellular lipids to accommodate M. leprae parasitization. Certain PPAR target genes in skin lesions may serve as biomarkers for monitoring treatment efficacy.


Assuntos
Células Espumosas/microbiologia , Hanseníase/metabolismo , Macrófagos/microbiologia , Mycobacterium leprae/fisiologia , PPAR delta/metabolismo , PPAR gama/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Adipócitos/microbiologia , Animais , Diferenciação Celular , Células Espumosas/metabolismo , Humanos , Hansenostáticos/uso terapêutico , Hanseníase/tratamento farmacológico , Hanseníase/genética , Hanseníase/microbiologia , Metabolismo dos Lipídeos , Macrófagos/metabolismo , Camundongos , Camundongos Nus , Mycobacterium leprae/efeitos dos fármacos , PPAR delta/genética , PPAR gama/genética , Pele/metabolismo , Pele/microbiologia
10.
Trop Doct ; 50(4): 378-380, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32600120

RESUMO

Leprosy is caused by the obligate intracellular organism Mycobacterium leprae which mainly affects the skin and nervous system. The course of the disease is determined by host immunity, it is thus believed that in lepromatous leprosy (LL), all manifestations are bilaterally symmetrical. This is because of the inability of the host to mount an adequate cell-mediated immune response, resulting in widespread haematogenous dissemination of bacilli. Varied manifestations of LL have been reported; however, a multidermatomal pattern of nodules is hitherto unreported and we suggest a hypothesis for its presentation.


Assuntos
Hanseníase Virchowiana/patologia , Pele/patologia , Humanos , Hansenostáticos/uso terapêutico , Hanseníase Virchowiana/tratamento farmacológico , Hanseníase Virchowiana/imunologia , Hanseníase Virchowiana/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/isolamento & purificação , Doenças Negligenciadas , Pele/imunologia , Pele/microbiologia
11.
J Infect Dev Ctries ; 14(6.1): 10S-15S, 2020 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-32614790

RESUMO

INTRODUCTION: Following the recommendation of the Global Leprosy Strategy, Ethiopia targeted to reduce the incidence of new leprosy cases, and the proportion with severe disability (grade 2) from 13.6% in 2016 to < 1% in 2020. This study assessed the clinical profile of new leprosy cases and the sequelae of previously treated ones 20 years after leprosy was eliminated as a public health problem in the country. METHODOLOGY: Hospital based cross sectional study was conducted  by reviewing the medical records of all leprosy patients seen at the dermatology clinic of Boru Meda Hospital from August to December 2018.The  data were captured using a standard data collection form. RESULTS: Over the study period, 57 (27.4%) new cases and 151 (72.6%) previously treated cases were seen.The median age was 44 years (interquartile range 32-57). Among the newly diagnosed cases, two were under the age of 15 years , 51 (89.5%) were multibacillary and 34 (59.6%) had grade 2 disability. This included visual impairment in 10 (17.5%) and neurological complications in 44 (77.2%). Of the 151 previously treated cases, 104 (68.9%) presented with disabilities, including 97 (64.2%) with grade 2. Amongst previously treated cases, 130 (86.1%) had neurological complications. In addition, 53 (35.1%) had vision impairment. CONCLUSIONS: This study showed evidence of ongoing leprosy transmission and delayed diagnosis in the country. This calls for operational research to determine the underlying reasons and provide ways forward. At the same time, the high burden of disabilities in previously treated cases should be addressed.


Assuntos
Diagnóstico Tardio , Hospitais/estatística & dados numéricos , Hanseníase/diagnóstico , Hanseníase/epidemiologia , Adulto , Estudos Transversais , Etiópia/epidemiologia , Feminino , Humanos , Hanseníase/complicações , Hanseníase/transmissão , Masculino , Pessoa de Meia-Idade , Pele/microbiologia , Pele/patologia
12.
Int J Mycobacteriol ; 9(1): 18-23, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474483

RESUMO

Background: Leprosy is a contagious disease and was eliminated globally in 2002. Since then, new cases were continuously detected from different parts of the world. Untreated leprosy cases shed millions of bacteria and are the main cause of dissemination of the disease. Currently, leprosy is detected by acid-fast bacilli (AFB) microscopy and has a low sensitivity ranging from 10% to 50%. The correlation between clinical findings and microscopy is unable to provide a conclusive case detection. Thus, in the present study, we compared to molecular methods, namely RLEP-polymerase chain reaction (RLEP-PCR) and inter-simple sequence repeat-PCR (ISSR-PCR) taking AFB microscopy as a gold standard for the detection of leprosy. Methods: A total of 168 clinically diagnosed leprosy patients were recruited in this study including 58 multibacillary and 110 paucibacillary patients. Slit-skin smear samples were taken for both microscopy and molecular study. Primers for RLEP-PCR were taken from the previous reports. The primers for ISSR-PCR were designed by screening the whole genome of Mycobacterium leprae TN strain (GenBank accession AL450380) for the presence of simple sequence repeats. One primer (TA)8CA3was synthesized and used for molecular amplification of ISSR-PCR. Results: We found that the efficacy of the AFB microscopy was 24.40%, whereas the efficacy of RLEP-PCR and ISSR-PCR was 63.09% and 73.21% (P = 0.000, 0.000, and 0.469), respectively. The area under the curve of receiver operating characteristic curve for the comparison of three diagnostic methods was 0.845. An enhancement of 48.81% in the case detection rate by ISSR-PCR over AFB microscopy and 10.12% over RLEP-PCR was also found. Our study clearly reveals that ISSR-PCR is a better tool for diagnosis of leprosy than AFB microscopy and RLEP-PCR. Interestingly, both the PCR techniques RLEP-PCR and ISSR-PCR are able to detect samples which were negative for AFB microscopy. Conclusion: Thus, the demonstration of ISSR-PCR in SSS samples can provide a better sensitive and confirmative tool for early diagnosis of leprosy.


Assuntos
Hanseníase/diagnóstico , Técnicas de Diagnóstico Molecular/normas , Reação em Cadeia da Polimerase em Tempo Real/normas , Estudos Transversais , Primers do DNA , DNA Bacteriano/genética , Genoma Bacteriano , Humanos , Índia , Hanseníase/microbiologia , Técnicas de Diagnóstico Molecular/métodos , Mycobacterium leprae/genética , Estudos Prospectivos , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real/métodos , Sensibilidade e Especificidade , Pele/microbiologia
13.
Int J Mycobacteriol ; 9(2): 223-225, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474550

RESUMO

Patients with leprosy rarely present ulcerated lesions that can appear during reactional states like Lucio's phenomenon (LP), as in our case. LP is a rare complication of multibacillary leprosy due to massive bacilli invasion of endothelial cells causing a thrombotic syndrome. The initial macular lesion is purpuric followed by multiple infiltrated papules and nodules, some of them ulcerated, associated to loss of sensation on lower limbs. The importance of recognizing ulcers as a specific cutaneous manifestation of leprosy allows early diagnosis and treatment, and therefore avoiding the development of disabilities and persistence of illness. Infection by Mycobacterium lepromatosis is associated with LP and it should be especially sought in patients from endemic areas.


Assuntos
Infecções por Mycobacterium/diagnóstico , Mycobacterium/patogenicidade , Úlcera/microbiologia , Úlcera/patologia , Adulto , Diagnóstico Diferencial , Células Endoteliais/patologia , Feminino , Humanos , Hansenostáticos/uso terapêutico , Hanseníase Multibacilar/diagnóstico , Infecções por Mycobacterium/complicações , Infecções por Mycobacterium/tratamento farmacológico , Pele/microbiologia , Pele/patologia , Fatores de Tempo , Úlcera/diagnóstico
15.
Indian J Pathol Microbiol ; 63(2): 289-291, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32317536

RESUMO

Various renal abnormalities in leprosy have been described largely in literature but the occurrence of IgA dominant infection related glomerulonephritis in leprosy with type 2 lepra reaction has not been reported so far. We present here a 60-year-old man with a history of leprosy in the past admitted with type 2 lepra reaction, rapidly progressive glomerulonephritis with severe renal failure requiring dialysis and diagnosed to have IgA dominant infection related glomerulonephritis.


Assuntos
Glomerulonefrite/diagnóstico , Glomerulonefrite/imunologia , Imunoglobulina A/imunologia , Hanseníase/diagnóstico , Hanseníase/imunologia , Biópsia , Glomerulonefrite/microbiologia , Histiócitos/microbiologia , Humanos , Rim/microbiologia , Rim/patologia , Hanseníase/complicações , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae , Pele/microbiologia , Pele/patologia
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