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1.
PLoS Negl Trop Dis ; 15(8): e0009716, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34415916

RESUMO

BACKGROUND: Regarding the leprosy transmission through the upper airways, overcrowded locations such as prisons can become a risk to get sick. Like the leprosy hidden endemic demonstrated in male prison population, being interesting to assess the leprosy scene also among confined women. METHODS: A prospective descriptive study conducted at Female Penitentiary, Brazil. Leprosy Suspicion Questionnaire (LSQ) were applied to the participants, and submitted to specialized dermatoneurological exam, peripheral nerve ultrasonography, and anti-PGL-I serology. FINDINGS: 404 female inmates were evaluated, 14 new cases were diagnosed (LG-leprosy group), a new case detection rate (NCDR) of 3.4%, 13 multibacillary, while another 390 constituted the Non-Leprosy group (NLG). Leprosy cases were followed up during multidrug therapy with clinical improvement. The confinement time median was 31 months in LG, similar to NLG, less than the time of leprosy incubation. Regarding LSQ, the neurological symptoms reached the highest x2 values as Q1-numbness (5.6), Q3-anesthetizes areas in the skin (7.5), Q5-Stinging sensation (5.8), and Q7-pain in the nerves (34.7), while Q4-spots on the skin was 4.94. When more than one question were marked in the LSQ means a 12.8-fold higher to have the disease than a subject who marked only one or none. The high 34% rate of anti-PGL-I seropositivity in the penitentiary, higher levels in LG than NLG. Three additional leprosy cases each were diagnosed on the second (n = 66) and third (n = 14) reevaluations 18 and 36 months after the initial one. Semmes-Weinstein monofilaments demonstrated lower limbs (32.2%) more affected than the upper limbs (25%) with improvement during the follow-up. INTERPRETATION: The NCDR in this population showed an hidden endemic of leprosy as well as the efficacy of a search action on the part of a specialized team with the aid of the LSQ and anti-PGL-I serology as an auxiliary tracking tools.


Assuntos
Hanseníase/diagnóstico , Prisões/estatística & dados numéricos , Adulto , Brasil/epidemiologia , Feminino , Seguimentos , Humanos , Hansenostáticos/efeitos adversos , Hansenostáticos/uso terapêutico , Hanseníase/tratamento farmacológico , Hanseníase/epidemiologia , Hanseníase/microbiologia , Pessoa de Meia-Idade , Mycobacterium leprae/efeitos dos fármacos , Mycobacterium leprae/fisiologia , Estudos Prospectivos , Adulto Jovem
2.
PLoS Negl Trop Dis ; 15(5): e0009436, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34038422

RESUMO

BACKGROUND: Leprosy is an infectious disease caused by Mycobacterium leprae. As incidence begins to decline, the characteristics of new cases shifts away from those observed in highly endemic areas, revealing potentially important insights into possible ongoing sources of transmission. We aimed to investigate whether transmission is driven mainly by undiagnosed and untreated new leprosy cases in the community, or by incompletely treated or relapsing cases. METHODOLOGY/PRINCIPAL FINDINGS: A literature search of major electronic databases was conducted in January, 2020 with 134 articles retained out of a total 4318 records identified (PROSPERO ID: CRD42020178923). We presented quantitative data from leprosy case records with supporting evidence describing the decline in incidence across several contexts. BCG vaccination, active case finding, adherence to multidrug therapy and continued surveillance following treatment were the main strategies shared by countries who achieved a substantial reduction in incidence. From 3950 leprosy case records collected across 22 low endemic countries, 48.3% were suspected to be imported, originating from transmission outside of the country. Most cases were multibacillary (64.4%) and regularly confirmed through skin biopsy, with 122 cases of suspected relapse from previous leprosy treatment. Family history was reported in 18.7% of cases, while other suspected sources included travel to high endemic areas and direct contact with armadillos. None of the countries included in the analysis reported a distinct increase in leprosy incidence in recent years. CONCLUSIONS/SIGNIFICANCE: Together with socioeconomic improvement over time, several successful leprosy control programmes have been implemented in recent decades that led to a substantial decline in incidence. Most cases described in these contexts were multibacillary and numerous cases of suspected relapse were reported. Despite these observations, there was no indication that these cases led to a rise in new secondary cases, suggesting that they do not represent a large ongoing source of human-to-human transmission.


Assuntos
Hanseníase/epidemiologia , Hanseníase/transmissão , Mycobacterium leprae/fisiologia , Animais , Tatus/microbiologia , Vacina BCG/administração & dosagem , Quimioterapia Combinada , Humanos , Hansenostáticos/uso terapêutico , Hanseníase/tratamento farmacológico , Recidiva , Viagem
3.
Int J Infect Dis ; 107: 145-152, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33864913

RESUMO

OBJECTIVE: Leprosy is a chronic infectious disease caused by Mycobacterium leprae and it remains a significant health problem in several parts of the world. Early and accurate diagnosis of this disease is therefore essential. Previously published loop-mediated isothermal amplification (LAMP) protocols for detecting mycobacterial species used conventional primers targeting the 16S rRNA, gyrB and insertion sequence genes. METHODS: In this study, we conducted a LAMP assay for leprosy and compared it with quantitative polymerase chain reaction (q-PCR) and conventional PCR assays to determine the efficiency, sensitivity and specificity of each technique. We chose conserved sequence RLEP as a suitable molecular target for assays. RESULTS: The LAMP assay provided rapid and accurate results, confirming leprosy in 91/110 clinical skin tissue samples from leprosy patients and amplifying the target pathogen in <60 min at 65 °C. The assay was more sensitive than conventional PCR and more straightforward and faster than the q-PCR assay. CONCLUSIONS: The LAMP assay has the potential for developing quicker, more accessible visual methods for the detection of M. leprae, which will enable early diagnosis and treatment and prevent further infection in endemic areas.


Assuntos
Hanseníase/microbiologia , Técnicas de Diagnóstico Molecular/métodos , Mycobacterium leprae/genética , Mycobacterium leprae/isolamento & purificação , Técnicas de Amplificação de Ácido Nucleico/métodos , Primers do DNA/genética , Humanos , Limite de Detecção , Mycobacterium leprae/fisiologia , RNA Ribossômico 16S/genética
4.
Int J Infect Dis ; 105: 261-266, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33592342

RESUMO

BACKGROUND: Evidence suggests that biological mechanisms involved in helminth infections and vitamin deficiencies increase susceptibility to other infections. The aim of this study was to investigate the associations of helminth co-infection and select micronutrient deficiencies with leprosy using a case-control design. METHODS: From 2016 to 2018, individuals aged ≥3 years were recruited at clinics in and around Governador Valadares, Minas Gerais, Brazil in three groups: cases of leprosy, household contacts and community-matched (non-contact) controls. Helminths were diagnosed through stool Kato Katz examination and serum reactivity to anti-soluble adult worm antigen preparation IgG4. Serum ferritin, 25-OH vitamin D and retinol concentrations were measured. Multi-variate logistic regression was conducted to identify associations with active leprosy. RESULTS: Seventy-nine cases of leprosy, 96 household contacts and 81 non-contact controls were recruited; 48.1% of participants were male with a median age of 40 years. Helminths were found in 7.1% of participants on Kato Katz test, all but one of which were Schistosoma mansoni, and 32.3% of participants were positive for S. mansoni serology. On multi-variate analysis, cases were more likely to be infected with helminths (diagnosed by stool) than household contacts [adjusted odds ratio (aOR) 8.69, 95% confidence interval (CI) 1.50-50.51]. Vitamin D deficiency was common, and was more likely in cases compared with non-contact controls (aOR 4.66, 95% CI 1.42,-15.33). Iron deficiency was not associated with leprosy, and vitamin A deficiency was not detected. CONCLUSION: These associations suggest that the immune consequences of schistosomiasis and vitamin D deficiency may increase the risk of active leprosy. Comorbid conditions of poverty deserve further study as addressing co-infections and nutritional deficiencies could be incorporated into programmes to improve leprosy control.


Assuntos
Coinfecção/complicações , Helmintos/fisiologia , Hanseníase/complicações , Mycobacterium leprae/fisiologia , Deficiência de Vitamina D/complicações , Adolescente , Adulto , Idoso , Animais , Brasil/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Fezes/parasitologia , Feminino , Humanos , Hanseníase/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco
5.
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
6.
Front Immunol ; 11: 1493, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849508

RESUMO

In HIV-infected individuals, a paradoxical clinical deterioration may occur in preexisting leprosy when highly active antiretroviral therapy (HAART)-associated reversal reaction (RR) develops. Leprosy-HIV co-infected patients during HAART may present a more severe form of the disease (RR/HIV), but the immune mechanisms related to the pathogenesis of leprosy-HIV co-infection remain unknown. Although the adaptive immune responses have been extensively studied in leprosy-HIV co-infected individuals, recent studies have described that innate immune cells may drive the overall immune responses to mycobacterial antigens. Monocytes are critical to the innate immune system and play an important role in several inflammatory conditions associated with chronic infections. In leprosy, different tissue macrophage phenotypes have been associated with the different clinical forms of the disease, but it is not clear how HIV infection modulates the phenotype of innate immune cells (monocytes or macrophages) during leprosy. In the present study, we investigated the phenotype of monocytes and macrophages in leprosy-HIV co-infected individuals, with or without RR. We did not observe differences between the monocyte profiles in the studied groups; however, analysis of gene expression within the skin lesion cells revealed that the RR/HIV group presents a higher expression of macrophage scavenger receptor 1 (MRS1), CD209 molecule (CD209), vascular endothelial growth factor (VEGF), arginase 2 (ARG2), and peroxisome proliferator-activated receptor gamma (PPARG) when compared with the RR group. Our data suggest that different phenotypes of tissue macrophages found in the skin from RR and RR/HIV patients could differentially contribute to the progression of leprosy.


Assuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Infecções por HIV/imunologia , HIV-1/fisiologia , Hanseníase/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Mycobacterium leprae/fisiologia , Adulto , Idoso , Diferenciação Celular , Coinfecção , Progressão da Doença , Feminino , Infecções por HIV/complicações , Infecções por HIV/terapia , Humanos , Hanseníase/complicações , Hanseníase/terapia , Masculino , Pessoa de Meia-Idade , Receptores Depuradores Classe A/metabolismo
7.
Cell Microbiol ; 22(1): e13128, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31652371

RESUMO

Leprosy neuropathy is a chronic degenerative infectious disorder of the peripheral nerve caused by the intracellular obligate pathogen Mycobacterium leprae (M. leprae). Among all nonneuronal cells that constitute the nerve, Schwann cells are remarkable in supporting M. leprae persistence intracellularly. Notably, the success of leprosy infection has been attributed to its ability in inducing the demyelination phenotype after contacting myelinated fibres. However, the exact role M. leprae plays during the ongoing process of myelin breakdown is entirely unknown. Here, we provided evidence showing an unexpected predilection of leprosy pathogen for degenerating myelin ovoids inside Schwann cells. In addition, M. leprae infection accelerated the rate of myelin breakdown and clearance leading to increased formation of lipid droplets, by modulating a set of regulatory genes involved in myelin maintenance, autophagy, and lipid storage. Remarkably, the blockage of myelin breakdown significantly reduced M. leprae content, demonstrating a new unpredictable role of myelin dismantling favouring M. leprae physiology. Collectively, our study provides novel evidence that may explain the demyelination phenotype as an evolutionarily conserved mechanism used by leprosy pathogen to persist longer in the peripheral nerve.


Assuntos
Mycobacterium leprae/fisiologia , Bainha de Mielina/metabolismo , Células de Schwann/microbiologia , Animais , Células Cultivadas , Humanos , Hanseníase/complicações , Hanseníase/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium leprae/patogenicidade , Bainha de Mielina/microbiologia
8.
Immunobiology ; 225(1): 151866, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31757558

RESUMO

Serological tests for subclinical Mycobacterium leprae infection based on antibodies to phenolic glycolipid-1 (PGL-1) and leprosy IDRI diagnostic-1 (LID-1) have not been compared in HIV-infected and uninfected individuals. PGL-1 seropositivity by ELISA was 6.0 % (21/350) in HIV-infected compared with 29.1 % (102/350) in HIV-uninfected individuals (p < 0.001); LID-1 seropositivity was 45.4 % (159/350) in HIV-infected compared with 50.3 % (153/304) in HIV-uninfected individuals (p = 0.21). In HIV-infected individuals, LID-1 but not PGL-1 antibody levels were inversely associated with CD4+ cell count (p = 0.02). These differential associations of HIV infection and CD4 count with PGL-1 and LID-1 have implications for M leprae immunodiagnostic tools and require replication.


Assuntos
Anticorpos Antibacterianos/sangue , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Hanseníase/imunologia , Mycobacterium leprae/fisiologia , Adulto , Formação de Anticorpos , Antígenos de Bactérias/imunologia , Brasil/epidemiologia , Contagem de Células , Doenças Endêmicas , Feminino , Glicolipídeos/imunologia , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Humanos , Testes Imunológicos , Hanseníase/diagnóstico , Hanseníase/epidemiologia , Proteínas Associadas a Gotículas Lipídicas/imunologia , Masculino , Adulto Jovem
9.
mBio ; 10(6)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848273

RESUMO

New approaches are needed to control leprosy, but understanding of the biology of the causative agent Mycobacterium leprae remains rudimentary, principally because the pathogen cannot be grown in axenic culture. Here, we applied 13C isotopomer analysis to measure carbon metabolism of M. leprae in its primary host cell, the Schwann cell. We compared the results of this analysis with those of a related pathogen, Mycobacterium tuberculosis, growing in its primary host cell, the macrophage. Using 13C isotopomer analysis with glucose as the tracer, we show that whereas M. tuberculosis imports most of its amino acids directly from the host macrophage, M. leprae utilizes host glucose pools as the carbon source to biosynthesize the majority of its amino acids. Our analysis highlights the anaplerotic enzyme phosphoenolpyruvate carboxylase required for this intracellular diet of M. leprae, identifying this enzyme as a potential antileprosy drug target.IMPORTANCE Leprosy remains a major problem in the world today, particularly affecting the poorest and most disadvantaged sections of society in the least developed countries of the world. The long-term aim of research is to develop new treatments and vaccines, and these aims are currently hampered by our inability to grow the pathogen in axenic culture. In this study, we probed the metabolism of M. leprae while it is surviving and replicating inside its primary host cell, the Schwann cell, and compared it to a related pathogen, M. tuberculosis, replicating in macrophages. Our analysis revealed that unlike M. tuberculosis, M. leprae utilized host glucose as a carbon source and that it biosynthesized its own amino acids, rather than importing them from its host cell. We demonstrated that the enzyme phosphoenolpyruvate carboxylase plays a crucial role in glucose catabolism in M. leprae Our findings provide the first metabolic signature of M. leprae in the host Schwann cell and identify novel avenues for the development of antileprosy drugs.


Assuntos
Carbono/metabolismo , Glucose/metabolismo , Mycobacterium leprae/fisiologia , Células de Schwann/metabolismo , Células de Schwann/microbiologia , Metabolismo dos Carboidratos , Linhagem Celular , Interações Hospedeiro-Patógeno , Humanos , Hanseníase/metabolismo , Hanseníase/microbiologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Redes e Vias Metabólicas
10.
Int J Infect Dis ; 88: 65-72, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499206

RESUMO

OBJECTIVE: To assess the effectiveness of single-dose rifampicin (SDR) after bacillus Calmette-Guérin (BCG) vaccination in preventing leprosy in contacts. METHODS: This was a single-centre, cluster-randomized controlled trial at a leprosy control programme in northwest Bangladesh. Participants were the 14988 contacts of 1552 new leprosy patients who were randomized into the SDR-arm (n=7379) and the SDR+arm (n=7609). In the intervention group, BCG vaccination was followed by SDR 8-12 weeks later. In the control group, BCG vaccination only was given. Follow-up was performed at 1year and 2 years after intake. The main outcome measure was the occurrence of leprosy. RESULTS: The incidence rate per 10000 person-years at risk was 44 in the SDR-arm and 31 in the SDR+arm at 1year; the incidence rate was 34 in the SDR-arm and 41 in the SDR+arm at 2 years. There was a statistically non-significant (p=0.148; 42%) reduction for paucibacillary (PB) leprosy in the SDR+ arm at 1 year. Of all new cases, 33.6% appeared within 8-12 weeks after BCG vaccination. CONCLUSIONS: In the first year, SDR after BCG vaccination reduced the incidence of PB leprosy among contacts by 42%. This was a statistically non-significant reduction due to the limited number of cases after SDR was administered. To what extent SDR suppresses excess leprosy cases after BCG vaccination is difficult to establish because many cases appeared before the SDR intervention. TRIAL REGISTRATION: Netherlands Trial Register: NTR3087.


Assuntos
Vacina BCG/administração & dosagem , Hansenostáticos/administração & dosagem , Hanseníase/prevenção & controle , Rifampina/administração & dosagem , Adolescente , Adulto , Bangladesh , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Hanseníase/diagnóstico , Hanseníase/tratamento farmacológico , Hanseníase/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/efeitos dos fármacos , Mycobacterium leprae/fisiologia , Vacinação , Adulto Jovem
11.
Microbiol Spectr ; 7(4)2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31322104

RESUMO

The mammalian nervous system is invaded by a number of intracellular bacterial pathogens which can establish and progress infection in susceptible individuals. Subsequent clinical manifestation is apparent with the impairment of the functional units of the nervous system, i.e., the neurons and the supporting glial cells that produce myelin sheaths around axons and provide trophic support to axons and neurons. Most of these neurotrophic bacteria display unique features, have coevolved with the functional sophistication of the nervous system cells, and have adapted remarkably to manipulate neural cell functions for their own advantage. Understanding how these bacterial pathogens establish intracellular adaptation by hijacking endogenous pathways in the nervous system, initiating myelin damage and axonal degeneration, and interfering with myelin maintenance provides new knowledge not only for developing strategies to combat neurodegenerative conditions induced by these pathogens but also for gaining novel insights into cellular and molecular pathways that regulate nervous system functions. Since the pathways hijacked by bacterial pathogens may also be associated with other neurodegenerative diseases, it is anticipated that detailing the mechanisms of bacterial manipulation of neural systems may shed light on common mechanisms, particularly of early disease events. This chapter details a classic example of neurodegeneration, that caused by Mycobacterium leprae, which primarily infects glial cells of the peripheral nervous system (Schwann cells), and how it targets and adapts intracellularly by reprogramming Schwann cells to stem cells/progenitor cells. We also discuss implications of this host cell reprogramming by leprosy bacilli as a model in a wider context.


Assuntos
Hanseníase/microbiologia , Mycobacterium leprae/fisiologia , Sistema Nervoso Periférico/microbiologia , Adaptação Fisiológica , Animais , Humanos , Mycobacterium leprae/genética , Mycobacterium leprae/isolamento & purificação , Células de Schwann/microbiologia
12.
Acta Trop ; 197: 105041, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31152726

RESUMO

Leprosy is an ancient disease caused by the acid-fast bacillus Mycobacterium leprae, also known as Hansen's bacillus. M. leprae is an obligate intracellular microorganism with a marked Schwann cell tropism and is the only human pathogen capable of invading the superficial peripheral nerves. The transmission mechanism of M. leprae is not fully understood; however, the nasal mucosa is accepted as main route of M. leprae entry to the human host. The complete sequencing and the comparative genome analysis show that M. leprae underwent a genome reductive evolution process, as result of lifestyle change and adaptation to different environments; some of lost genes are homologous to those of host cells. Thus, M. leprae reduced its genome size to 3.3 Mbp, contributing to obtain the lowest GC content (approximately 58%) among mycobacteria. The M. leprae genome contains 1614 open reading frames coding for functional proteins, and 1310 pseudogenes corresponding to 41% of the genome, approximately. Comparative analyses to different microorganisms showed that M. leprae possesses the highest content of pseudogenes among pathogenic and non-pathogenic bacteria and archaea. The pathogen adaptation into host cells, as the Schwann cells, brought about the reduction of the genome and induced multiple gene inactivation. The present review highlights the characteristics of genome's reductive evolution that M. leprae experiences in the genetic aspects compared with other pathogens. The possible mechanisms of pseudogenes formation are discussed.


Assuntos
Aclimatação/genética , Evolução Molecular , Hanseníase/microbiologia , Mycobacterium leprae/genética , Mycobacterium leprae/fisiologia , DNA Bacteriano , Regulação Bacteriana da Expressão Gênica , Genoma Bacteriano , Humanos
13.
PLoS Negl Trop Dis ; 13(6): e0007339, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31233498

RESUMO

Although Mycobacterium leprae (M.leprae) is usually found in macrophages and nerves of the dermis of patients with multibacillary leprosy, it is also present in all layers of the epidermis, basal, suprabasal, prickle cells, and keratin layers. However, the mechanism by which M.leprae invades the dermis remains unknown, whereas the underlying mechanism by which M.leprae invades peripheral nerves, especially Schwann cells, is well defined. M. leprae binds to the α-dystroglycan (DG) of Schwann cells via the interaction of α-DG and laminin (LN) -α2 in the basal lamina, thus permitting it to become attached to and invade peripheral nerves. In the current study, we investigated the issue of how M.leprae is phagocytosed by human epidermal keratinocytes, neonatal (HEKn). LN-5 is the predominant form of laminin in the epidermis and allows the epidermis to be stably attached to the dermis via its interaction with α/ß-DG as well as integrins that are produced by keratinocytes. We therefore focused on the role of LN-5 when M. leprae is internalized by HEKn cells. Our results show that M.leprae preferentially binds to LN-5-coated slides and this binding to LN-5 enhances its binding to HEKn cells. The findings also show that pre-treatment with an antibody against α-DG, integrin-ß1, or -ß4 inhibited the binding of LN-5-coated M.leprae to HEKn cells. These results suggest that M. leprae binds to keratinocytes by taking advantage of the interaction of LN-5 in the basal lamina of the epidermis and a surface receptor of keratinocytes, such as α-DG, integrin-ß1, or -ß4.


Assuntos
Aderência Bacteriana , Moléculas de Adesão Celular/metabolismo , Distroglicanas/metabolismo , Integrina beta1/metabolismo , Integrina beta4/metabolismo , Queratinócitos/microbiologia , Mycobacterium leprae/fisiologia , Células Cultivadas , Humanos , Fagocitose , Ligação Proteica
14.
Front Biosci (Landmark Ed) ; 24: 712-722, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844707

RESUMO

Although not without controversy, as a general trend, the human sperm count is declining world-wide. One major reason for such a decline is an increase in the human life-span.  According to the life history tradeoff theory, fecundity is inversely related to the lifespan; the longer the lifespan, the lower the fecundity. This is essential to the maintainance of diversity and balance of different species. Such a corrleation validated by experimental data that show that the extension of life in Caenorhabditis elegans, Drosophila and Rodents is  associated with reduction in fecundity. The demographic data from a public data source, shows that the total fertility rate is positively correlated with the infant death rate, it is inversely correlated with the life expectancy. We postulate that the fall in spermatogenesis might be regulated by the neuroendocrine system that underlie human longevity.


Assuntos
Expectativa de Vida , Oligospermia/epidemiologia , Contagem de Espermatozoides , Animais , Coeficiente de Natalidade , Caenorhabditis elegans , Dinamarca , Drosophila melanogaster , Poluentes Ambientais , Escherichia coli/fisiologia , Fertilidade , Saúde Global , Humanos , Estilo de Vida , Longevidade , Masculino , Modelos Teóricos , Mycobacterium leprae/fisiologia , Mycobacterium tuberculosis/fisiologia , Ratos , Leveduras/fisiologia
15.
PLoS Negl Trop Dis ; 12(12): e0007001, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30566440

RESUMO

Leprosy is an infectious disease caused by Mycobacterium leprae and frequently resulting in irreversible deformities and disabilities. Ticks play an important role in infectious disease transmission due to their low host specificity, worldwide distribution, and the biological ability to support transovarial transmission of a wide spectrum of pathogens, including viruses, bacteria and protozoa. To investigate a possible role for ticks as vectors of leprosy, we assessed transovarial transmission of M. leprae in artificially-fed adult female Amblyomma sculptum ticks, and infection and growth of M. leprae in tick cell lines. Our results revealed M. leprae RNA and antigens persisting in the midgut and present in the ovaries of adult female A. sculptum at least 2 days after oral infection, and present in their progeny (eggs and larvae), which demonstrates the occurrence of transovarial transmission of this pathogen. Infected tick larvae were able to inoculate viable bacilli during blood-feeding on a rabbit. Moreover, following inoculation with M. leprae, the Ixodes scapularis embryo-derived tick cell line IDE8 supported a detectable increase in the number of bacilli for at least 20 days, presenting a doubling time of approximately 12 days. As far as we know, this is the first in vitro cellular system able to promote growth of M. leprae. Finally, we successfully transformed a clinical M. leprae isolate by inserting the reporter plasmid pCHERRY3; transformed bacteria infected and grew in IDE8 cells over a 2-month period. Taken together, our data not only support the hypothesis that ticks may have the potential to act as a reservoir and/or vector of leprosy, but also suggest the feasibility of technological development of tick cell lines as a tool for large-scale production of M. leprae bacteria, as well as describing for the first time a method for their transformation.


Assuntos
Vetores Aracnídeos/fisiologia , Ixodes/microbiologia , Ixodidae/microbiologia , Hanseníase/transmissão , Mycobacterium leprae/fisiologia , Animais , Vetores Aracnídeos/microbiologia , Linhagem Celular , Feminino , Humanos , Ixodes/fisiologia , Ixodidae/fisiologia , Hanseníase/microbiologia , Masculino , Mycobacterium leprae/genética , Coelhos
16.
PLoS Negl Trop Dis ; 12(12): e0007035, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30592714

RESUMO

BACKGROUND: Erythema nodosum leprosum (ENL) is a systemic inflammatory complication occurring mainly in patients with lepromatous leprosy (LL) and borderline lepromatous leprosy (BL). Prednisolone is widely used for treatment of ENL reactions. However, it has been reported that prolonged treatment with prednisolone increases the risk for prednisolone-induced complications such as osteoporosis, diabetes, cataract and arteriosclerosis. It has been speculated that perhaps these complications result from lipid profile alterations by prednisolone. The effects of extended prednisolone treatment on lipid profiles in ENL patients have not been studied in leprosy patients with ENL reactions. Therefore, in this study we conducted a case-control study to investigate the changes in lipid profiles and serological responses in Ethiopian patients with ENL reaction after prednisolone treatment. METHODS: A prospective matched case-control study was employed to recruit 30 patients with ENL and 30 non-reactional LL patient controls at ALERT Hospital, Ethiopia. Blood samples were obtained from each patient with ENL reaction before and after prednisolone treatment as well as from LL controls. The serological host responses to PGL-1, LAM and Ag85 M. leprae antigens were measured by ELISA. Total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL) and low density lipoprotein (LDL) were measured by spectrophotometric method. RESULTS: The host antibody response to M. leprae PGL-1, LAM and Ag85 antigens were significantly reduced in patients with ENL reactions compared to LL controls after treatment. Comparison between patients with acute and chronic ENL showed that host-response to PGL-1 was significantly reduced in chronic ENL after prednisolone treatment. Untreated patients with ENL reactions had low lipid concentration compared to LL controls. However, after treatment, both groups had comparable lipid profiles except for LDL, which was significantly higher in patients with ENL reaction. Comparison within the ENL group before and after treatment showed that prednisolone significantly increased LDL and HDL levels in ENL patients and this was more prominent in chronic ENL than in acute patients with ENL. CONCLUSION: The significantly increased prednisolone-induced LDL and TG levels, particularly in patients with chronic ENL reactions, is a concern in the use of prednisolone for extended periods in ENL patients. The findings highlight the importance of monitoring lipid profiles during treatment of patients to minimize the long-term risk of prednisolone-induced complications.


Assuntos
Eritema Nodoso/sangue , Eritema Nodoso/tratamento farmacológico , Hanseníase Virchowiana/complicações , Prednisolona/administração & dosagem , Adolescente , Adulto , Estudos de Casos e Controles , Colesterol/sangue , Eritema Nodoso/etiologia , Eritema Nodoso/imunologia , Feminino , Humanos , Hanseníase Virchowiana/microbiologia , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/fisiologia , Prednisolona/efeitos adversos , Estudos Prospectivos , Triglicerídeos/sangue , Adulto Jovem
17.
PLoS Negl Trop Dis ; 12(10): e0006815, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30300363

RESUMO

Following infection, virulent mycobacteria persist and grow within the macrophage, suggesting that the intrinsic activation of an innate antimicrobial response is subverted by the intracellular pathogen. For Mycobacterium leprae, the intracellular bacterium that causes leprosy, the addition of exogenous innate or adaptive immune ligands to the infected monocytes/macrophages was required to detect a vitamin D-dependent antimicrobial activity. We investigated whether there is an intrinsic immune response to M. leprae in macrophages that is inhibited by the pathogen. Upon infection of monocytes with M. leprae, there was no upregulation of CYP27B1 nor its enzymatic activity converting the inactive prohormone form of vitamin D (25-hydroxyvitamin D) to the bioactive form (1,25α-dihydroxyvitamin D). Given that M. leprae-induced type I interferon (IFN) inhibited monocyte activation, we blocked the type I IFN receptor (IFNAR), revealing the intrinsic capacity of monocytes to recognize M. leprae and upregulate CYP27B1. Consistent with these in vitro studies, an inverse relationship between expression of CYP27B1 vs. type I IFN downstream gene OAS1 was detected in leprosy patient lesions, leading us to study cytokine-derived macrophages (MΦ) to model cellular responses at the site of disease. Infection of IL-15-derived MΦ, similar to MΦ in lesions from the self-limited form of leprosy, with M. leprae did not inhibit induction of the vitamin D antimicrobial pathway. In contrast, infection of IL-10-derived MΦ, similar to MΦ in lesions from patients with the progressive form of leprosy, resulted in induction of type I IFN and suppression of the vitamin D directed pathway. Importantly, blockade of the type I IFN response in infected IL-10 MΦ decreased M. leprae viability. These results indicate that M. leprae evades the intrinsic capacity of human monocytes/MΦ to activate the vitamin D-mediated antimicrobial pathway via the induction of type I IFN.


Assuntos
Evasão da Resposta Imune , Fatores Imunológicos/farmacologia , Interferon Tipo I/metabolismo , Macrófagos/imunologia , Macrófagos/microbiologia , Mycobacterium leprae/fisiologia , Vitamina D/farmacologia , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/biossíntese , Humanos , Imunidade Inata , Mycobacterium leprae/imunologia , Regulação para Cima
18.
Int J Biol Macromol ; 119: 604-616, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30055280

RESUMO

Ultraviolet radiation, an effective sterilizing source, rapidly kills the causative organism (Mycobacterium leprae) of leprosy. But, the reasons behind this quick death are not clearly understood. Also, the impact of UV radiation on the antigen(s) which is/are responsible for the survival of this pathogen is still unknown. Many reports have revealed that M. leprae secrets a major immunodominant antigen, namely HSP18, whose chaperone function plays an important role in the growth and survival of this pathogen under various environmental insults. However, the effect of UV radiation on its structure and chaperone function is still unclear. Therefore, we have taken a thorough attempt to understand these two aspects of HSP18 under different UV radiations (UVA/UVB/UVC; doses: 1-50 J/cm2). Our study revealed that its chaperone function is decreased significantly with increasing doses of various UV radiations. These different UV irradiations perturb only its tertiary structure and induce tryptophan and tyrosine photo-oxidation to N-formyl kynurenine, kynurenine and dityrosine. Such photo-oxidation promotes the subunit cross-linking within a HSP18 oligomer, lowers the surface hydrophobicity and thermostability of the protein. All these factors together damage/reduce the chaperone function of HSP18 which may be an important factor behind the rapid death of M. leprae under UV exposure.


Assuntos
Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Mycobacterium leprae/metabolismo , Mycobacterium leprae/efeitos da radiação , Raios Ultravioleta , Sequência de Aminoácidos , Relação Dose-Resposta à Radiação , Viabilidade Microbiana/efeitos da radiação , Mycobacterium leprae/fisiologia , Relação Estrutura-Atividade
19.
PLoS Negl Trop Dis ; 12(7): e0006608, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29965969

RESUMO

BACKGROUND: The immune system depends on effector pathways to eliminate invading pathogens from the host in vivo. Macrophages (MΦ) of the innate immune system are armed with vitamin D-dependent antimicrobial responses to kill intracellular microbes. However, how the physiological levels of vitamin D during MΦ differentiation affect phenotype and function is unknown. METHODOLOGY/PRINCIPAL: The human innate immune system consists of divergent MΦ subsets that serve distinct functions in vivo. Both IL-15 and IL-10 induce MΦ differentiation, but IL-15 induces primary human monocytes to differentiate into antimicrobial MΦ (IL-15 MΦ) that robustly express the vitamin D pathway. However, how vitamin D status alters IL-15 MΦ phenotype and function is unknown. In this study, we found that adding 25-hydroxyvitamin D3 (25D3) during the IL-15 induced differentiation of monocytes into MΦ increased the expression of the antimicrobial peptide cathelicidin, including both CAMP mRNA and the encoded protein cathelicidin in a dose-dependent manner. The presence of physiological levels of 25D during differentiation of IL-15 MΦ led to a significant vitamin D-dependent antimicrobial response against intracellular Mycobacterium leprae but did not change the phenotype or phagocytic function of these MΦ. These data suggest that activation of the vitamin D pathway during IL-15 MΦ differentiation augments the antimicrobial response against M. leprae infection. CONCLUSIONS/SIGNIFICANCE: Our data demonstrates that the presence of vitamin D during MΦ differentiation bestows the capacity to mount an antimicrobial response against M. leprae.


Assuntos
Hanseníase/imunologia , Macrófagos/imunologia , Mycobacterium leprae/fisiologia , Vitamina D/imunologia , Diferenciação Celular , Humanos , Interleucina-10/imunologia , Interleucina-15/imunologia , Hanseníase/microbiologia , Macrófagos/citologia , Macrófagos/microbiologia
20.
Front Immunol ; 9: 1223, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29915584

RESUMO

Leprosy reactions are responsible for incapacities in leprosy and represent the major cause of permanent neuropathy. The identification of biomarkers able to identify patients more prone to develop reaction could contribute to adequate clinical management and the prevention of disability. Reversal reaction may occur in unstable borderline patients and also in lepromatous patients. To identify biomarker signature profiles related with the reversal reaction onset, multibacillary patients were recruited and classified accordingly the occurrence or not of reversal reaction during or after multidrugtherapy. Analysis of skin lesion cells at diagnosis of multibacillary leprosy demonstrated that in the group that developed reaction (T1R) in the future there was a downregulation of autophagy associated with the overexpression of TLR2 and MLST8. The autophagy impairment in T1R group was associated with increased expression of NLRP3, caspase-1 (p10) and IL-1ß production. In addition, analysis of IL-1ß production in serum from multibacillary patients demonstrated that patients who developed reversal reaction have significantly increased concentrations of IL-1ß at diagnosis, suggesting that the pattern of innate immune responses could predict the reactional episode outcome. In vitro analysis demonstrated that the blockade of autophagy with 3-methyladenine (3-MA) in Mycobacterium leprae-stimulated human primary monocytes increased the assembly of NLRP3 specks assembly, and it was associated with an increase of IL-1ß and IL-6 production. Together, our data suggest an important role for autophagy in multibacillary leprosy patients to avoid exacerbated inflammasome activation and the onset of reversal reaction.


Assuntos
Autofagia , Inflamassomos/metabolismo , Hanseníase Multibacilar/etiologia , Hanseníase Multibacilar/metabolismo , Adulto , Idoso , Biomarcadores , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Interleucina-1beta/metabolismo , Hanseníase Multibacilar/patologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/microbiologia , Mycobacterium leprae/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais , Transcriptoma
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