Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.461
Filtrar
Mais filtros


Intervalo de ano de publicação
1.
Front Immunol ; 12: 657449, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34456901

RESUMO

The respiratory tract is considered the main port of entry of Mycobacterium leprae, the causative agent of leprosy. However, the great majority of individuals exposed to the leprosy bacillus will never manifest the disease due to their capacity to develop protective immunity. Besides acting as a physical barrier, airway epithelium cells are recognized as key players by initiating a local innate immune response that orchestrates subsequent adaptive immunity to control airborne infections. However, to date, studies exploring the interaction of M. leprae with the respiratory epithelium have been scarce. In this work, the capacity of M. leprae to immune activate human alveolar epithelial cells was investigated, demonstrating that M. leprae-infected A549 cells secrete significantly increased IL-8 that is dependent on NF-κB activation. M. leprae was also able to induce IL-8 production in human primary nasal epithelial cells. M. leprae-treated A549 cells also showed higher expression levels of human ß-defensin-2 (hßD-2), MCP-1, MHC-II and the co-stimulatory molecule CD80. Furthermore, the TLR-9 antagonist inhibited both the secretion of IL-8 and NF-κB activation in response to M. leprae, indicating that bacterial DNA sensing by this Toll-like receptor constitutes an important innate immune pathway activated by the pathogen. Finally, evidence is presented suggesting that extracellular DNA molecules anchored to Hlp, a histone-like protein present on the M. leprae surface, constitute major TLR-9 ligands triggering this pathway. The ability of M. leprae to immune activate respiratory epithelial cells herein demonstrated may represent a very early event during infection that could possibly be essential to the generation of a protective response.


Assuntos
Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/metabolismo , Imunidade Inata , Hanseníase/imunologia , Hanseníase/metabolismo , Mycobacterium leprae/imunologia , Receptor Toll-Like 9/metabolismo , Células A549 , Biomarcadores , Células Cultivadas , Histonas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunomodulação , Hanseníase/microbiologia , NF-kappa B/metabolismo
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.
PLoS Negl Trop Dis ; 15(8): e0009667, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34449763

RESUMO

BACKGROUND: Leprosy elimination primarily targets transmission of Mycobacterium leprae which is not restricted to patients' households. As interruption of transmission is imminent in many countries, a test to detect infected asymptomatic individuals who can perpetuate transmission is required. Antibodies directed against M. leprae antigens are indicative of M. leprae infection but cannot discriminate between active and past infection. Seroprevalence in young children, however, reflects recent M. leprae infection and may thus be used to monitor transmission in an area. Therefore, this literature review aimed to evaluate what has been reported on serological tests measuring anti-M. leprae antibodies in children without leprosy below the age of 15 in leprosy-endemic areas. METHODS AND FINDINGS: A literature search was performed in the databases Pubmed, Infolep, Web of Science and The Virtual Health Library. From the 724 articles identified through the search criteria, 28 full-text articles fulfilled all inclusion criteria. Two additional papers were identified through snowballing, resulting in a total of 30 articles reporting data from ten countries. All serological tests measured antibodies against phenolic glycolipid-I or synthetic derivatives thereof, either quantitatively (ELISA or UCP-LFA) or qualitatively (ML-flow or NDO-LID rapid test). The median seroprevalence in children in endemic areas was 14.9% and was stable over time if disease incidence remained unchanged. Importantly, seroprevalence decreased with age, indicating that children are a suitable group for sensitive assessment of recent M. leprae infection. However, direct comparison between areas, solely based on the data reported in these studies, was impeded by the use of different tests and variable cut-off levels. CONCLUSIONS: Quantitative anti-PGL-I serology in young children holds promise as a screening test to assess M. leprae infection and may be applied as a proxy for transmission and thereby as a means to monitor the effect of (prophylactic) interventions on the route to leprosy elimination.


Assuntos
Anticorpos Antibacterianos/sangue , Hanseníase/epidemiologia , Mycobacterium leprae/isolamento & purificação , Antígenos de Bactérias/imunologia , Criança , Pré-Escolar , Busca de Comunicante , Doenças Endêmicas , Características da Família , Humanos , Hanseníase/sangue , Hanseníase/transmissão , Mycobacterium leprae/imunologia
4.
Lancet Infect Dis ; 21(11): 1590-1597, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34237262

RESUMO

BACKGROUND: Trials of BCG vaccination to prevent or reduce severity of COVID-19 are taking place in adults, some of whom have been previously vaccinated, but evidence of the beneficial, non-specific effects of BCG come largely from data on mortality in infants and young children, and from in-vitro and animal studies, after a first BCG vaccination. We assess all-cause mortality following a large BCG revaccination trial in Malawi. METHODS: The Karonga Prevention trial was a population-based, double-blind, randomised controlled in Karonga District, northern Malawi, that enrolled participants between January, 1986, and November, 1989. The trial compared BCG (Glaxo-strain) revaccination versus placebo to prevent tuberculosis and leprosy. 46 889 individuals aged 3 months to 75 years were randomly assigned to receive BCG revaccination (n=23 528) or placebo (n=23 361). Here we report mortality since vaccination as recorded during active follow-up in northern areas of the district in 1991-94, and in a demographic surveillance follow-up in the southern area in 2002-18. 7389 individuals who received BCG (n=3746) or placebo (n=3643) lived in the northern follow-up areas, and 5616 individuals who received BCG (n=2798) or placebo (n=2818) lived in the southern area. Year of death or leaving the area were recorded for those not found. We used survival analysis to estimate all-cause mortality. FINDINGS: Follow-up information was available for 3709 (99·0%) BCG recipients and 3612 (99·1%) placebo recipients in the northern areas, and 2449 (87·5%) BCG recipients and 2413 (85·6%) placebo recipients in the southern area. There was no difference in mortality between the BCG and placebo groups in either area, overall or by age group or sex. In the northern area, there were 129 deaths per 19 694 person-years at risk in the BCG group (6·6 deaths per 1000 person-years at risk [95% CI 5·5-7·8]) versus 133 deaths per 19 111 person-years at risk in the placebo group (7·0 deaths per 1000 person-years at risk [95% CI 5·9-8·2]; HR 0·94 [95% CI 0·74-1·20]; p=0·62). In the southern area, there were 241 deaths per 38 399 person-years at risk in the BCG group (6·3 deaths per 1000 person-years at risk [95% CI 5·5-7·1]) versus 230 deaths per 38 676 person-years at risk in the placebo group (5·9 deaths per 1000 person-years at risk [95% CI 5·2-6·8]; HR 1·06 [95% CI 0·88-1·27]; p=0·54). INTERPRETATION: We found little evidence of any beneficial effect of BCG revaccination on all-cause mortality. The high proportion of deaths attributable to non-infectious causes beyond infancy, and the long time interval since BCG for most deaths, might obscure any benefits. FUNDING: British Leprosy Relief Association (LEPRA); Wellcome Trust.


Assuntos
Vacina BCG/administração & dosagem , Imunização Secundária/estatística & dados numéricos , Mortalidade , Vacinação/métodos , Adolescente , Adulto , Idoso , Vacina BCG/imunologia , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/prevenção & controle , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Imunogenicidade da Vacina , Hanseníase/imunologia , Hanseníase/mortalidade , Hanseníase/prevenção & controle , Malaui/epidemiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , SARS-CoV-2/imunologia , Resultado do Tratamento , Tuberculose/imunologia , Tuberculose/mortalidade , Tuberculose/prevenção & controle , Vacinação/estatística & dados numéricos , Adulto Jovem
5.
PLoS Negl Trop Dis ; 15(6): e0009495, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34125854

RESUMO

BACKGROUND: This study evaluates implementation strategies for leprosy diagnosis based on responses to a Leprosy Suspicion Questionnaire (LSQ), and analyzes immunoepidemiological aspects and follow-up of individuals living in a presumptively nonendemic area in Brazil. METHODOLOGY/PRINCIPAL FINDINGS: Quasi-experimental study based on LSQ throughout Jardinópolis town by community health agents, theoretical-practical trainings for primary care teams, dermatoneurological examination, anti-PGL-I serology, RLEP-PCR, and spatial epidemiology. A Leprosy Group (LG, n = 64) and Non-Leprosy Group (NLG, n = 415) were established. Overall, 3,241 LSQs were distributed; 1,054 (32.5%) LSQ were positive for signs/symptoms (LSQ+). Among LSQ+ respondents, Q2-Tingling (pricking)? (11.8%); Q4-Spots on the skin? (11.7%); Q7-Pain in the nerves? (11.6%); Q1-Numbness in your hands and/or feet? (10.7%) and Q8-Swelling of hands and feet? (8.5%) were most frequently reported symptoms. We evaluated 479 (14.8%) individuals and diagnosed 64 new cases, a general new case detection rate (NCDR) of 13.4%; 60 were among 300 LSQ+ (NCDR-20%), while 4 were among 179 LSQ negative (NCDR-2.23%). In LG, Q7(65%), Q2(60%), Q1(45%), Q4(40%) and Q8(25%) were most frequent. All 2x2 crossings of these 5 questions showed a relative risk for leprosy ranging from 3 to 5.8 compared with NLG. All patients were multibacillary and presented hypochromatic macules with loss of sensation. LG anti-PGL-I titers were higher than NLG, while 8.9% were positive for RLEP-PCR. The leprosy cases and anti-PGL-I spatial mappings demonstrated the disease spread across the town. CONCLUSIONS/SIGNIFICANCE: Implementation actions, primarily LSQ administration focused on neurological symptoms, indicate hidden endemic leprosy in a nonendemic Brazilian state.


Assuntos
Agentes Comunitários de Saúde/educação , Hanseníase/diagnóstico , Hanseníase/epidemiologia , Mycobacterium leprae/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/genética , Mycobacterium leprae/isolamento & purificação , Prevalência , Inquéritos e Questionários
6.
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
7.
Front Immunol ; 12: 647832, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936067

RESUMO

Leprosy is a disease with a clinical spectrum of presentations that is also manifested in diverse histological features. At one pole, lepromatous lesions (L-pole) have phagocytic foamy macrophages heavily parasitized with freely multiplying intracellular Mycobacterium leprae. At the other pole, the presence of epithelioid giant cells and granulomatous formation in tuberculoid lesions (T-pole) lead to the control of M. leprae replication and the containment of its spread. The mechanism that triggers this polarization is unknown, but macrophages are central in this process. Over the past few years, leprosy has been studied using large scale techniques to shed light on the basic pathways that, upon infection, rewire the host cellular metabolism and gene expression. M. leprae is particularly peculiar as it invades Schwann cells in the nerves, reprogramming their gene expression leading to a stem-like cell phenotype. This modulatory behavior exerted by M. leprae is also observed in skin macrophages. Here, we used live M. leprae to infect (10:1 multiplicity of infection) monocyte-derived macrophages (MDMs) for 48 h and analyzed the whole gene expression profile using microarrays. In this model, we observe an intense upregulation of genes consistent with a cellular immune response, with enriched pathways including peptide and protein secretion, leukocyte activation, inflammation, and cellular divalent inorganic cation homeostasis. Among the most differentially expressed genes (DEGs) are CCL5/RANTES and CYP27B1, and several members of the metallothionein and metalloproteinase families. This is consistent with a proinflammatory state that would resemble macrophage rewiring toward granulomatous formation observed at the T-pole. Furthermore, a comparison with a dataset retrieved from the Gene Expression Omnibus of M. leprae-infected Schwann cells (MOI 100:1) showed that the patterns among the DEGs are highly distinct, as the Schwann cells under these conditions had a scavenging and phagocytic gene profile similar to M2-like macrophages, with enriched pathways rearrangements in the cytoskeleton, lipid and cholesterol metabolism and upregulated genes including MVK, MSMO1, and LACC1/FAMIN. In summary, macrophages may have a central role in defining the paradigmatic cellular (T-pole) vs. humoral (L-pole) responses and it is likely that the multiplicity of infection and genetic polymorphisms in key genes are gearing this polarization.


Assuntos
Imunidade Celular/genética , Hanseníase Virchowiana/genética , Hanseníase Virchowiana/imunologia , Macrófagos/imunologia , Macrófagos/virologia , Mycobacterium leprae/imunologia , Transcriptoma , Adulto , Doadores de Sangue , Polaridade Celular/genética , Células Cultivadas , Feminino , Voluntários Saudáveis , Humanos , Hanseníase Virchowiana/microbiologia , Masculino , Polimorfismo de Nucleotídeo Único , Células de Schwann/imunologia , Células de Schwann/virologia , Adulto Jovem
8.
PLoS One ; 16(5): e0251631, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33984058

RESUMO

The number of new cases of leprosy reported worldwide has remained essentially unchanged for the last decade despite continued global use of free multidrug therapy (MDT) provided to any diagnosed leprosy patient. In order to more effectively interrupt the chain of transmission, new strategies will be required to detect those with latent disease who contribute to furthering transmission. To improve the ability to diagnose leprosy earlier in asymptomatic infected individuals, we examined the combined use of two well-known biomarkers of M. leprae infection, namely the presence of M. leprae DNA by PCR from earlobe slit skin smears (SSS) and positive antibody titers to the M. leprae-specific antigen, Phenolic Glycolipid I (anti-PGL-I) from leprosy patients and household contacts living in seven hyperendemic cities in the northern state of Pará, Brazilian Amazon. Combining both tests increased sensitivity, specificity and accuracy over either test alone. A total of 466 individuals were evaluated, including 87 newly diagnosed leprosy patients, 52 post-treated patients, 296 household contacts and 31 healthy endemic controls. The highest frequency of double positives (PGL-I+/RLEP+) were detected in the new case group (40/87, 46%) with lower numbers for treated (12/52, 23.1%), household contacts (46/296, 15.5%) and healthy endemic controls (0/31, 0%). The frequencies in these groups were reversed for double negatives (PGL-I-/RLEP-) for new cases (6/87, 6.9%), treated leprosy cases (15/52, 28.8%) and the highest in household contacts (108/296, 36.5%) and healthy endemic controls (24/31, 77.4%). The data strongly suggest that household contacts that are double positive have latent disease, are likely contributing to shedding and transmission of disease to their close contacts and are at the highest risk of progressing to clinical disease. Proposed strategies to reduce leprosy transmission in highly endemic areas may include chemoprophylactic treatment of this group of individuals to stop the spread of bacilli to eventually lower new case detection rates in these areas.


Assuntos
Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Glicolipídeos/imunologia , Infecção Latente/diagnóstico , Hanseníase/diagnóstico , Mycobacterium leprae/isolamento & purificação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , DNA Bacteriano/análise , Feminino , Humanos , Infecção Latente/imunologia , Hanseníase/imunologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Adulto Jovem
9.
J Leukoc Biol ; 110(1): 167-176, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33040382

RESUMO

The enzyme IDO-1 is involved in the first stage of tryptophan catabolism and has been described in both microbicidal and tolerogenic microenvironments. Previous data from our group have shown that IDO-1 is differentially regulated in the distinctive clinical forms of leprosy. The present study aims to investigate the mechanisms associated with IDO-1 expression and activity in human monocyte-derived dendritic cells (mDCs) after stimulation with irradiated Mycobacterium leprae and its fractions. M. leprae and its fractions induced the expression and activity of IDO-1 in human mDCs. Among the stimuli studied, irradiated M. leprae and its membrane fraction (MLMA) induced the production of proinflammatory cytokines TNF and IL-6 whereas irradiated M. leprae and its cytosol fraction (MLSA) induced an increase in IL-10. We investigated if TLR2 activation was necessary for IDO-1 induction in mDCs. We observed that in cultures treated with a neutralizing anti-TLR2 antibody, there was a decrease in IDO-1 activity and expression induced by M. leprae and MLMA. The same effect was observed when we used a MyD88 inhibitor. Our data demonstrate that coculture of mDCs with autologous lymphocytes induced an increase in regulatory T (Treg) cell frequency in MLSA-stimulated cultures, showing that M. leprae constituents may play opposite roles that may possibly be related to the dubious effect of IDO-1 in the different clinical forms of disease. Our data show that M. leprae and its fractions are able to differentially modulate the activity and functionality of IDO-1 in mDCs by a pathway that involves TLR2, suggesting that this enzyme may play an important role in leprosy immunopathogenesis.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Tolerância Imunológica , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Hanseníase/etiologia , Hanseníase/metabolismo , Mycobacterium leprae/imunologia , Receptor 2 Toll-Like/metabolismo , Biomarcadores , Citometria de Fluxo , Humanos , Hanseníase/patologia , Linfócitos/imunologia , Linfócitos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
10.
Diagn Microbiol Infect Dis ; 99(2): 115232, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33130505

RESUMO

Leprosy is an infectious disease caused by Mycobacterium leprae that affects the skin and nerves. The nerve damage in leprosy may be related to alterations in transcriptional factors, such as Krox-20, Oct-6, Sox-10. Thirty skin biopsies in leprosy patients and 15 non-leprosy skin biopsies were evaluated using RT-qPCR to assess Krox-20, Oct-6, and Sox-10 and these data was related with S-100 immunohistochemistry. Changes in gene expression were observed in the skin and dermal nerves of leprosy patients in Oct-6 and Sox-10. When comparing Oct-6 with S-100 IHC as diagnostic tests for leprosy, Oct-6 showed a sensitivity of 73.3%, and specificity of 100%, while S-100 IHC showed a sensitivity of 96.6% and specificity of 100%. Our data suggest Oct-6 could be an auxiliary biomarker specific to detecting changes in dermal nerves in leprosy and thus useful to health workers and pathologists with no expertise to observe nerve injuries in leprosy.


Assuntos
Hanseníase/diagnóstico , Fator 6 de Transcrição de Octâmero/genética , Adulto , Idoso , Anticorpos Antibacterianos/sangue , Carga Bacteriana , Biomarcadores/metabolismo , Biópsia , Estudos Transversais , Proteína 2 de Resposta de Crescimento Precoce/genética , Feminino , Humanos , Imunoglobulina G/sangue , Imuno-Histoquímica , Hanseníase/genética , Hanseníase/metabolismo , Hanseníase/patologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Proteínas S100/metabolismo , Fatores de Transcrição SOXE/genética , Sensibilidade e Especificidade , Pele/inervação , Pele/metabolismo , Pele/patologia , Transcrição Genética
11.
Hum Immunol ; 82(1): 11-18, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33189423

RESUMO

Despite intense efforts, the number of new cases of leprosy has remained significantly high over the past 20 years. Host genetic background is strongly linked to the pathogenesis of this disease, which is caused by Mycobacterium leprae (M. leprae), and there is a consensus that the most significant genetic association with leprosy is attributed to the major histocompatibility complex (MHC). Here, we investigated the association of human leukocyte antigen (HLA) class I and II genes with leprosy in a Brazilian population encompassing 826 individuals from a hyperendemic area of Brazil; HLA typing of class I (-A, -B, -C) and class II (-DRB1, -DQA1, -DQB1, -DPA1, and -DPB1) loci was conducted. Initially, the associations were tested using the chi-square test, with p-values adjusted using the false discovery rate (FDR) method. Next, statistically significant signals of the associations were submitted to logistic regression analyses to adjust for sex and molecular ancestry data. The results showed that HLA-C*08, -DPB1*04, and -DPB1*18 were associated with protective effects, while HLA-C*12 and -DPB1*105 were associated with susceptibility to leprosy. Thus, our findings reveal new associations between leprosy and the HLA-DPB1 locus and confirm previous associations between the HLA-C locus and leprosy.


Assuntos
Predisposição Genética para Doença , Antígenos HLA-C/genética , Cadeias beta de HLA-DP/genética , Hanseníase/genética , Adolescente , Adulto , Idoso , Alelos , Brasil/epidemiologia , Estudos de Casos e Controles , Doenças Endêmicas , Feminino , Loci Gênicos , Antígenos HLA-C/imunologia , Cadeias beta de HLA-DP/imunologia , Humanos , Hanseníase/epidemiologia , Hanseníase/imunologia , Hanseníase/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Adulto Jovem
12.
s.l; s.n; 2021. 12 p. ilus, tab, graf.
Não convencional em Inglês | SES-SP, CONASS, HANSEN, SESSP-ILSLPROD, SES-SP, SESSP-ILSLACERVO, SES-SP | ID: biblio-1284237

RESUMO

Leprosy is a disease with a clinical spectrum of presentations that is also manifested in diverse histological features. At one pole, lepromatous lesions (L-pole) have phagocytic foamy macrophages heavily parasitized with freely multiplying intracellular Mycobacterium leprae. At the other pole, the presence of epithelioid giant cells and granulomatous formation in tuberculoid lesions (T-pole) lead to the control of M. leprae replication and the containment of its spread. The mechanism that triggers this polarization is unknown, but macrophages are central in this process. Over the past few years, leprosy has been studied using large scale techniques to shed light on the basic pathways that, upon infection, rewire the host cellular metabolism and gene expression. M. leprae is particularly peculiar as it invades Schwann cells in the nerves, reprogramming their gene expression leading to a stem-like cell phenotype. This modulatory behavior exerted by M. leprae is also observed in skin macrophages. Here, we used live M. leprae to infect (10:1 multiplicity of infection) monocyte-derived macrophages (MDMs) for 48 h and analyzed the whole gene expression profile using microarrays. In this model, we observe an intense upregulation of genes consistent with a cellular immune response, with enriched pathways including peptide and protein secretion, leukocyte activation, inflammation, and cellular divalent inorganic cation homeostasis. Among the most differentially expressed genes (DEGs) are CCL5/RANTES and CYP27B1, and several members of the metallothionein and metalloproteinase families. This is consistent with a proinflammatory state that would resemble macrophage rewiring toward granulomatous formation observed at the T-pole. Furthermore, a comparison with a dataset retrieved from the Gene Expression Omnibus of M. leprae-infected Schwann cells (MOI 100:1) showed that the patterns among the DEGs are highly distinct, as the Schwann cells under these conditions had a scavenging and phagocytic gene profile similar to M2-like macrophages, with enriched pathways rearrangements in the cytoskeleton, lipid and cholesterol metabolism and upregulated genes including MVK, MSMO1, and LACC1/FAMIN. In summary, macrophages may have a central role in defining the paradigmatic cellular (T-pole) vs. humoral (L-pole) responses and it is likely that the multiplicity of infection and genetic polymorphisms in key genes are gearing this polarization.


Assuntos
Humanos , Masculino , Feminino , Adulto , Adulto Jovem , Hanseníase Virchowiana/genética , Hanseníase Virchowiana/imunologia , Imunidade Celular/genética , Macrófagos/imunologia , Macrófagos/virologia , Mycobacterium leprae/imunologia , Células de Schwann/imunologia , Polaridade Celular/genética , Polimorfismo de Nucleotídeo Único , Transcriptoma
13.
Infect Dis Poverty ; 9(1): 156, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33183339

RESUMO

BACKGROUND: Leprosy control achieved dramatic success in the 1980s-1990s with the implementation of short course multidrug therapy, which reduced the global prevalence of leprosy to less than 1 in 10 000 population. However, a period of relative stagnation in leprosy control followed this achievement, and only limited further declines in the global number of new cases reported have been achieved over the past decade. MAIN TEXT: In 2016, major stakeholders called for the development of an innovative and comprehensive leprosy strategy aimed at reducing the incidence of leprosy, lowering the burden of disability and discrimination, and interrupting transmission. This led to the establishment of the Global Partnership for Zero Leprosy (GPZL) in 2018, with partners aligned around a shared Action Framework committed to achieving the WHO targets by 2030 through national leprosy program capacity-building, resource mobilisation and an enabling research agenda. GPZL convened over 140 experts from more than 20 countries to develop a research agenda to achieve zero leprosy. The result is a detailed research agenda focusing on diagnostics, mapping, digital technology and innovation, disability, epidemiological modelling and investment case, implementation research, stigma, post exposure prophylaxis and transmission, and vaccines. This research agenda is aligned with the research priorities identified by other stakeholders. CONCLUSIONS: Developing and achieving consensus on the research agenda for zero leprosy is a significant step forward for the leprosy community. In a next step, research programmes must be developed, with individual components of the research agenda requiring distinct expertise, varying in resource needs, and operating over different timescales. Moving toward zero leprosy now requires partner alignment and new investments at all stages of the research process, from discovery to implementation.


Assuntos
Pesquisa Biomédica , Hanseníase/prevenção & controle , Vacinas Bacterianas/uso terapêutico , Quimioterapia Combinada , Humanos , Incidência , Hansenostáticos/uso terapêutico , Hanseníase/epidemiologia , Hanseníase/terapia , Mycobacterium leprae/imunologia , Profilaxia Pós-Exposição , Projetos de Pesquisa
14.
Vaccine ; 38(48): 7629-7637, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33071000

RESUMO

This work demonstrates the presence of immune regulatory cells in the cervical lymph nodes draining Bacillus Calmette-Guérin (BCG) vaccinated site on the dorsum of the ear in guinea pigs. It is shown that whole cervical lymph node cells did not proliferate in vitro in the presence of soluble mycobacterial antigens (PPD or leprosin) despite being responsive to whole mycobacteria. Besides, T cells from these lymph nodes separated as a non-adherent fraction on a nylon wool column, proliferated to PPD in the presence of autologous antigen presenting cells. Interestingly, addition of as low as 20% nylon wool adherent cells to these, sharply decreased the proliferation by 83%. Looking into what cells in the adherent fraction suppressed the proliferation, it was found that neither the T cell nor the macrophage enriched cell fractions of this population individually showed suppressive effect, indicating that their co-presence was necessary for the suppression. Since BCG induced granulomas resolve much faster than granulomas induced by other mycobacteria such as Mycobacterium leprae the present experimental findings add to the existing evidence that intradermal BCG vaccination influences subsequent immune responses in the host and may further stress upon its beneficial role seen in Covid-19 patients.


Assuntos
Antígenos de Bactérias/farmacologia , Vacina BCG/farmacologia , Granuloma/imunologia , Linfonodos/imunologia , Linfócitos T/imunologia , Tuberculina/farmacologia , Animais , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/microbiologia , COVID-19 , Adesão Celular , Proliferação de Células , Infecções por Coronavirus/prevenção & controle , Orelha , Feminino , Granuloma/microbiologia , Cobaias , Humanos , Injeções Intradérmicas , Linfonodos/microbiologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Mycobacterium bovis/imunologia , Mycobacterium leprae/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Remissão Espontânea , Linfócitos T/classificação , Linfócitos T/efeitos dos fármacos , Linfócitos T/microbiologia
15.
Bull Exp Biol Med ; 169(6): 836-839, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33098510

RESUMO

Leprosy was modeled in an experiment on BALB/c, BALB/cNude, CBA, and C57BL/6ТNF-/- mice using three Mycobacterium leprae strains obtained from patients with a diagnosis of A30 according to ICD-10 from different regions of the Russian Federation. Proliferation of M. leprae of the used strains showed a temporal-quantitative dependence on the used mouse line. CBA and BALB/cNude mice were optimal for strain R and BALB/c and BALB/cNude lines were optimal for strain I. BALB/cNude mice infected with strain I had low lifespan. M. leprae strain M showed low proliferation activity in BALB/cNude and C57BL/6ТNF-/- mice.


Assuntos
Imunidade Adaptativa , Imunidade Inata , Hanseníase/imunologia , Longevidade/imunologia , Mycobacterium leprae/patogenicidade , Fator de Necrose Tumoral alfa/imunologia , Animais , DNA Bacteriano/genética , Modelos Animais de Doenças , Especificidade de Hospedeiro , Humanos , Hanseníase/genética , Hanseníase/microbiologia , Hanseníase/patologia , Longevidade/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Camundongos Nus , Mycobacterium leprae/genética , Mycobacterium leprae/crescimento & desenvolvimento , Mycobacterium leprae/imunologia , Fator de Necrose Tumoral alfa/deficiência , Fator de Necrose Tumoral alfa/genética
16.
Sci Rep ; 10(1): 15143, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934336

RESUMO

Th17 cells play vital role during pathogenesis of leprosy reactions. Previously, we have reported that IL-23 is involved in Th17 cells differentiation. Subsequently, our group also showed that IL-6 induces Th17 cell differentiation along with TGF-ß in leprosy reactions. Here, we next asked the question that whether IL-6 or IL-23 induced Th17 cells are different in nature? In this study, Type 1 Reactions (T1R) showed significantly (p < 0.001) higher percentage of IL-17A producing CD4+IL6R+ T cells as compared to non-reaction (NR) patients. Furthermore, recombinant IL-6, IL-23 and TGF-ß promoted IL-17A secretion by CD4+IL6R+ T cells. Subsequently, IL-6R and IL-23R blocking experiments showed significantly (p < 0.002) down regulated IL-17A in T1R reaction as compared to NR leprosy patients. The present study for the first time establishes that pathogenic Th17 cells produce IL-17 in an IL-6 dependent manner in leprosy T1R reactions. Thus, present approaches that specifically target Th17 cells and/or the cytokines that promote their development, such as IL-6, TGF-ß and IL-23A may provide more focused treatment strategies for the management of Mycobacterium leprae and its reactions.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucina-6/metabolismo , Hanseníase/imunologia , Mycobacterium leprae/imunologia , Receptores de Interleucina-6/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adolescente , Adulto , Feminino , Humanos , Interleucina-17/imunologia , Interleucina-17/metabolismo , Hanseníase/metabolismo , Hanseníase/microbiologia , Hanseníase/patologia , Masculino , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem
17.
Eur J Clin Microbiol Infect Dis ; 39(12): 2345-2360, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32666479

RESUMO

This surveillance study evaluated leprosy-serologic tests and the IFNγ whole-blood-assay/WBA as adjunct diagnostic tools. Previously diagnosed leprosy index cases, intradomiciliary, peridomiciliary contacts from a Brazilian endemic area were enrolled during domiciliary visits. Physical evaluation was performed by trained nurses and leprosy diagnosis confirmed by expert dermatologist. ELISA detected IgM anti-PGL-I, IgG anti-LID-1, and IgM/IgG anti-ND-O-LID antibodies. Heparinized WBA plasma stimulated with LID-1, 46f + LID-1, ML0276 + LID-1 (24 h, 37 °C, 5% CO2) was tested for human IFNγ (QuantiFERON®-TB Gold/QFT-G; Qiagen). The survey included 1731 participants: 44 leprosy index cases, 64 intradomiciliary, 1623 peridomiciliary contacts. Women represented 57.7%, median age was 32 years, 72.2% had BCG scar. Leprosy prevalence was higher in intradomiciliary (8.57%) versus peridomiciliary contacts (0.67%), p < 0.001. Among 23 suspects, five leprosy cases were confirmed: 4 multibacillary/MB and 1 paucibacillary/PB. Leprosy incidence was 0.30%: 1.56% in intradomiciliary versus 0.25% in peridomiciliary (p = 0.028). Seropositivity rates were 1.9% to PGL-I, 4.9% to LID-1, and 1.0% to ND-O-LID. LID-1 positivity was higher in all groups; incident cases were LID-1 seropositive. ND-O-LID positivity was higher in intra- versus peridomiciliary contacts (p = 0.022). IFNγ WBA (40 index cases, 19 suspects, 35 intradomiciliary, 74 peridomiciliary contacts) showed higher LID-1/WBA positivity in peridomiciliary contacts (p > 0.05); significant differences among groups were seen with 46f + LID-1 but 0276 + LID-1 induced higher IFNγ levels. Incident cases were LID-1 seropositive, while IFNγ-WBA had marginal diagnostic application. As seropositivity indicates exposed individuals at higher risk of disease development, the utility of serologic screening for surveillance and prophylactic measures remains to be demonstrated.


Assuntos
Anticorpos Antibacterianos/sangue , Interferon gama/metabolismo , Hanseníase/diagnóstico , Mycobacterium leprae/imunologia , Adolescente , Adulto , Antígenos de Bactérias/sangue , Antígenos de Bactérias/imunologia , Brasil , Feminino , Humanos , Testes de Liberação de Interferon-gama , Hanseníase/sangue , Hanseníase/imunologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Testes Sorológicos , Adulto Jovem
18.
J Infect Public Health ; 13(8): 1078-1088, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32299687

RESUMO

The aim of this systematic review was to investigate the studies that evaluated the sensitivity and specificity of serologic tests using recombinant protein antigens from Mycobacterium leprae for leprosy diagnosis. We included 13 studies that were available in PubMed, Brazilian Virtual Library of Health, Web of Science, ScienceDirect and Scopus. From these studies, we found that the recombinant serine-rich 45-kDa protein of M. leprae (ML0411) demonstrated high performance for multibacillary (MB) also to paucibacillary (PB) patients, although this study was tested only for Indian population. Despite that, studies using the ND-O-LID antigen have been able to more accurately identify new cases of leprosy among people living in endemic or non-endemic areas and household contacts in Brazil, Colombia, and the Philippines, especially when combined with other biomarkers. Finally, low sensitivity values for PB patients' antibodies response remain challenging for tests intended to diagnose clinical forms that comprise this classification in leprosy.


Assuntos
Hanseníase , Mycobacterium leprae , Proteínas Recombinantes , Testes Sorológicos , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/metabolismo , Brasil , Colômbia , Humanos , Hanseníase/diagnóstico , Mycobacterium leprae/imunologia , Filipinas , Proteínas Recombinantes/metabolismo , Reprodutibilidade dos Testes , Testes Sorológicos/normas
19.
PLoS Negl Trop Dis ; 14(4): e0007534, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32240160

RESUMO

BACKGROUND: Deposition of complement factors on Mycobacterium leprae may enhance phagocytosis. Such deposition may occur through the lectin pathway of complement. Three proteins of the lectin pathway are produced from the gene MASP1: Mannan-binding lectin-associated serine protease 1 (MASP-1) and MASP-3 and mannan-binding lectin-associated protein of 44 kDa (MAp44). Despite their obvious importance, the roles played by these proteins have never been investigated in leprosy disease. METHODOLOGY: We haplotyped five MASP1 polymorphisms by multiplex sequence-specific PCR (intronic rs7609662*G>A and rs13064994*C>T, exon 12 3'-untranslated rs72549262*C>G, rs1109452*C>T and rs850314*G>A) and measured MASP-1, MASP-3 and MAp44 serum levels in 196 leprosy patients (60%, lepromatous) and 193 controls. PRINCIPAL FINDINGS: Lower MASP-3 and MAp44 levels were observed in patients, compared with controls (P = 0.0002 and P<0.0001, respectively) and in lepromatous, compared with non-lepromatous patients (P = 0.008 and P = 0.002, respectively). Higher MASP-3 levels were present in controls carrying variants/haplotypes associated with leprosy resistance (rs13064994*T, rs1109452_rs850314*CG within GT_CCG and rs850314*A: OR = 0.5-0.6, Pcorr = 0.01-0.04). Controls with rs1109452*T, included in susceptibility haplotypes (GT_GTG/GT_CTG: OR = 2.0, Pcorr = 0.03), had higher MASP-1 and lower MASP-3 levels (P≤0.009). Those with GC_CCG, presented increasing susceptibility (OR = 1.7, Pcorr = 0.006) and higher MAp44 levels (P = 0.015). MASP-3 expression decreased in patients, compared with controls carrying rs1109452_rs850314*CA or CG (P≤0.02), which may rely on exon 12 CpG methylation and/or miR-2861/miR-3181 mRNA binding. CONCLUSION: Polymorphisms regulating MASP-3/MAp44 availability in serum modulate leprosy susceptibility, underlining the importance of lectin pathway regulation against pathogens that exploit phagocytosis to parasitize host macrophages.


Assuntos
Predisposição Genética para Doença , Hanseníase/genética , Hanseníase/patologia , Serina Proteases Associadas a Proteína de Ligação a Manose/análise , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Mycobacterium leprae/imunologia , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos Transversais , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Mem Inst Oswaldo Cruz ; 115: e190324, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130367

RESUMO

BACKGROUND: Leprosy is an infectious-contagious disease caused by Mycobacterium leprae that remain endemic in 105 countries. This neglected disease has a wide range of clinical and histopathological manifestations that are related to the host inflammatory and immune responses. More recently, the inflammasome has assumed a relevant role in the inflammatory response against microbiological agents. However, the involvement of inflammasome in leprosy remains poorly understood. OBJECTIVES: The aim is to associate biomarkers of inflammasome with the different immunopathological forms of leprosy. METHODS: We performed an observational, cross-sectional, and comparative study of the immunophenotypic expression of inflammasome-associated proteins in immunopathological forms of leprosy of 99 skin lesion samples by immunohistochemistry. The intensity and percentage of NLRP3, Caspase-1, Caspases-4/5, interleukin-1ß and interleukin-18 immunoreactivities in the inflammatory infiltrate of skin biopsies were evaluated. FINDINGS: Strong expression of NLRP3 and inflammatory Caspases-4/5 were observed in lepromatous leprosy (lepromatous pole). In addition, were observed low expression of caspase-1, interleukin-1ß, and interleukin-18 in tuberculoid and lepromatous leprosy. The interpolar or borderline form showed immunophenotype predominantly similar to the lepromatous pole. MAIN CONCLUSIONS: Our results demonstrate that the NLRP3 inflammasome is inactive in leprosy, suggesting immune evasion of M. leprae.


Assuntos
Evasão da Resposta Imune/imunologia , Inflamassomos/metabolismo , Hanseníase/imunologia , Hanseníase/metabolismo , Mycobacterium leprae/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estudos Transversais , Humanos , Imuno-Histoquímica , Hanseníase/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA