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1.
PLoS Negl Trop Dis ; 14(4): e0007534, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32240160

RESUMEN

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.


Asunto(s)
Predisposición Genética a la Enfermedad , Lepra/genética , Lepra/patología , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/análisis , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Mycobacterium leprae/inmunología , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Estudios Transversales , Femenino , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
2.
PLoS Negl Trop Dis ; 14(4): e0008276, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32339201

RESUMEN

Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae) and the more recently discovered Mycobacterium lepromatosis (M. lepromatosis). The two leprosy bacilli cause similar pathologic conditions. They primarily target the skin and the peripheral nervous system. Currently it is considered a Neglected Tropical Disease, being endemic in specific locations within countries of the Americas, Asia, and Africa, while in Europe it is only rarely reported. The reason for a spatial inequality in the prevalence of leprosy in so-called endemic pockets within a country is still largely unexplained. A systematic review was conducted targeting leprosy transmission research data, using PubMed and Scopus as sources. Publications between January 1, 1945 and July 1, 2019 were included. The transmission pathways of M. leprae are not fully understood. Solid evidence exists of an increased risk for individuals living in close contact with leprosy patients, most likely through infectious aerosols, created by coughing and sneezing, but possibly also through direct contact. However, this systematic review underscores that human-to-human transmission is not the only way leprosy can be acquired. The transmission of this disease is probably much more complicated than was thought before. In the Americas, the nine-banded armadillo (Dasypus novemcinctus) has been established as another natural host and reservoir of M. leprae. Anthroponotic and zoonotic transmission have both been proposed as modes of contracting the disease, based on data showing identical M. leprae strains shared between humans and armadillos. More recently, in red squirrels (Sciurus vulgaris) with leprosy-like lesions in the British Isles M. leprae and M. lepromatosis DNA was detected. This finding was unexpected, because leprosy is considered a disease of humans (with the exception of the armadillo), and because it was thought that leprosy (and M. leprae) had disappeared from the United Kingdom. Furthermore, animals can be affected by other leprosy-like diseases, caused by pathogens phylogenetically closely related to M. leprae. These mycobacteria have been proposed to be grouped as a M. leprae-complex. We argue that insights from the transmission and reservoirs of members of the M. leprae-complex might be relevant for leprosy research. A better understanding of possible animal or environmental reservoirs is needed, because transmission from such reservoirs may partly explain the steady global incidence of leprosy despite effective and widespread multidrug therapy. A reduction in transmission cannot be expected to be accomplished by actions or interventions from the human healthcare domain alone, as the mechanisms involved are complex. Therefore, to increase our understanding of the intricate picture of leprosy transmission, we propose a One Health transdisciplinary research approach.


Asunto(s)
Reservorios de Enfermedades , Transmisión de Enfermedad Infecciosa , Lepra/transmisión , Lepra/veterinaria , Animales , Armadillos/microbiología , Salud Global , Humanos , Incidencia , Lepra/epidemiología , Mycobacterium/aislamiento & purificación , Mycobacterium leprae/aislamiento & purificación , Prevalencia , Sciuridae/microbiología
3.
Mem Inst Oswaldo Cruz ; 115: e190324, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32130367

RESUMEN

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.


Asunto(s)
Evasión Inmune/inmunología , Inflamasomas/metabolismo , Lepra/inmunología , Lepra/metabolismo , Mycobacterium leprae/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estudios Transversales , Humanos , Inmunohistoquímica , Lepra/patología
4.
PLoS Negl Trop Dis ; 14(3): e0008127, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32203502

RESUMEN

Understanding the prevalence of M. leprae infection in armadillos is important because of evidence from Brazil and other countries of an association between contact with armadillos and the development of Hansen's Disease (leprosy). Our aim was to characterize studies which have investigated natural M. leprae infection in wild armadillos in Brazil, and to quantify and explore variability in the reported prevalence of infection. We conducted a systematic review (PROSPERO CRD42019155277) of publications in MEDLINE, EMBASE, Global Health, Scopus, LILACS, Biblioteca Digital Brasileira de Teses e Dissertações, Catálogo de Teses e Dissertações de CAPES, and Biblioteca Virtual em Saúde up to 10/2019 using Mesh and text search terms (in English, Portuguese, Spanish, and French). The 10 included studies represented a total sample of 302 armadillos comprising 207 (69%) Dasypus novemcinctus, 67 (22%) Euphractus sexcinctus, 16 (5%) Priodontes maximus, 10 (3%) Cabassous unicinctus, and 2 (1%) Cabassous tatouay from 7 different states. Methods used included histopathology (4 studies), PGL-1 and LID-1 antigen detection (4 studies) and examination for clinical signs of disease (4 studies). Eight studies used PCR of which 7 targeted the RLEP repetitive element and 3 tested for inhibitory substances. M. leprae prevalence by PCR ranged from 0% (in 3 studies) to 100% in one study, with a summary estimate of 9.4% (95% CI 0.4% to 73.1%) and a predictive interval of 0-100%. The average prevalence is equivalent to 1 in 10 armadillos in Brazil being infected with M. leprae, but wide variation in sample estimates means that the prevalence in any similar study would be entirely unpredictable. We propose instead that future studies aim to investigate transmission and persistence of M. leprae within and between armadillo populations, meanwhile adopting the precautionary principle to protect human health and an endangered species in Brazil.


Asunto(s)
Armadillos/microbiología , Lepra/epidemiología , Lepra/veterinaria , Mycobacterium leprae/aislamiento & purificación , Animales , Animales Salvajes/microbiología , Brasil/epidemiología , ADN Bacteriano/análisis , Bases de Datos Factuales , Mapeo Geográfico , Mycobacterium leprae/genética , Reacción en Cadena de la Polimerasa , Prevalencia , Secuencias Repetitivas de Ácidos Nucleicos , Zoonosis/epidemiología , Zoonosis/microbiología
5.
Am J Trop Med Hyg ; 102(4): 724-727, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32043454

RESUMEN

The ongoing transmission of leprosy in India is worrisome, and emerging drug resistance may be one of the factors responsible for the continued transmission of leprosy in India. Emerging cases of multidrug-resistant Mycobacterium leprae pose a great threat to eradication of leprosy and must be addressed with utmost priority. We report a case of multidrug-resistant M. leprae in a case of relapse where slit skin smear (SSS) was negative and histopathology was inconclusive. Drug resistance studies in leprosy are undertaken only in smear-positive relapse cases, and detection of this type of multidrug resistance in a case with negative SSS and innocuous histopathology is rather unusual and highlights the importance of undertaking drug resistance tests even in smear-negative cases of leprosy relapse. Resistance to ofloxacin (OFL) is also a cause for concern as OFL is one of the reserve drugs recommended for treatment of rifampicin-resistant strains.


Asunto(s)
Leprostáticos/farmacología , Leprostáticos/uso terapéutico , Lepra/tratamiento farmacológico , Lepra/microbiología , Mycobacterium leprae/efectos de los fármacos , Adulto , Farmacorresistencia Bacteriana Múltiple , Humanos , India/epidemiología , Lepra/epidemiología , Masculino , Recurrencia
6.
Infect Dis Poverty ; 9(1): 19, 2020 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-32051036

RESUMEN

BACKGROUND: Mycobacterium leprae and Toxoplasma gondii infections are both neglected tropical diseases highly prevalent in Brazil. Infection with certain parasite species can significantly alter susceptibility to other important pathogens, and/or influence the development of pathology. Here we investigated the possible influence of M. leprae/T. gondii co-parasitism on the manifestation of leprosy and its clinical forms. METHODS: Participants (n = 291) were recruited in Campos dos Goytacazes city, Rio de Janeiro state, southeast Brazil, from August 2015 to December 2019 and clinically diagnosed for leprosy. Participants were selected based on the presence (patients) or absence (healthy controls) of the leprosy disease. Contacts of patients were also recruited for this study. Serum samples from patients (n = 199) with leprosy, contacts (n = 40) and healthy controls (n = 52) were investigated for levels of IgM and IgG anti-phenolic glycolipid-1 (PGL-1) by ELISA. Additionally, IgG antibody against soluble Toxoplasma antigen (STAg) was measured in sera samples from leprosy patients, contacts and healthy controls for Toxoplasma gondii serology by ELISA. Anti-PGL-1 IgG and IgM levels were compared using one-way ANOVA Kruskal-Wallis or Mann-Whitney, while Spearman test was used to correlate levels of IgG anti-STAg and IgM/IgG anti-PGL-1 from seropositive and seronegative individuals for T. gondii infection. The risk of T. gondii infection for leprosy disease was assessed using Fisher's test. RESULTS: Levels of IgM anti-PGL-1 antibodies were significantly higher in multibacillary (MB) patients compared to paucibacillary (PB) patients (P = 0.0068). Higher IgM and IgG levels anti-PGL-1 were detected in patients with the lepromatous forms. The serologic prevalence for T. gondii infection was 74.9%. We detected increased anti-STAg antibody levels in leprosy patients (79.4%), reaching 88.8% within those with lepromatous form of this disease. The leprosy risk increase in T. gondii seropositive individuals was two-fold (odds ratio [OR] = 2.055; 95% confidence intervals [95% CI]: 1.18-3.51) higher than those seronegative, and considering the lepromatous leprosy risk this increase was even dramatic (OR = 4.33; 95% CI: 1.76-9.69) in T. gondii seropositive individuals. Moreover the leprosy risk in T. gondii seropositive individuals was weakly correlated to the levels of IgG anti-STAg and IgM/IgG anti-PGL-1. CONCLUSIONS: Altogether, our results suggest that T. gondii infection may exert immunomodulatory properties that influence to the susceptibility of leprosy, mainly on its more severe clinical form. A better understanding of parasite immunomodulation can ultimately contribute to the development of medical applications.


Asunto(s)
Anticuerpos Antibacterianos/sangre , Lepra Lepromatosa/epidemiología , Mycobacterium leprae/inmunología , Toxoplasma/inmunología , Toxoplasmosis/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Brasil/epidemiología , Estudios de Casos y Controles , Niño , Comorbilidad , Ensayo de Inmunoadsorción Enzimática , Femenino , Glucolípidos/inmunología , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Masculino , Persona de Mediana Edad , Estudios Seroepidemiológicos , Adulto Joven
7.
Am J Trop Med Hyg ; 102(3): 547-552, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31933458

RESUMEN

Resistance to anti-leprosy drugs is on the rise. Several studies have documented resistance to rifampicin, dapsone, and ofloxacin in patients with leprosy. We looked for point mutations within the folP1, rpoB, and gyrA gene regions of the Mycobacterium leprae genome predominantly in the neural form of leprosy. DNA samples from 77 nerve tissue samples were polymerase chain reaction (PCR)-amplified for M leprae DNA and sequenced for drug resistance-determining regions of genes rpoB, folP1, and gyrA. The mean age at presentation and onset was 38.2 ± 13.4 (range 14-71) years and 34.9 ± 12.6 years (range 10-63) years, respectively. The majority had borderline tuberculoid leprosy (53 [68.8%]). Mutations associated with resistance were identified in 6/77 (7.8%) specimens. Mutations seen were those associated with resistance to rifampicin, ofloxacin, and dapsone. All the six patients were drug-naive. The clinical and pathological manifestations in this group did not differ from the drug-sensitive group. This study highlights the occurrence of resistance to the standard multidrug therapy and ofloxacin in leprosy. Among the entire cohort, 1/77 (1.3%) showed resistance to rifampicin, 2/77 (2.6%) to dapsone, and 5/77 (6.4%) to ofloxacin. Six new patients showing infection by mutant strains indicated the emergence of primary resistance. Resistance to ofloxacin could be due to frequent use of quinolones for many bacterial infections. The results of the study indicate the need for development of a robust and strict surveillance system for detecting drug resistance in leprosy in India.


Asunto(s)
Leprostáticos/uso terapéutico , Lepra/tratamiento farmacológico , Lepra/microbiología , Mycobacterium leprae/efectos de los fármacos , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Cohortes , Estudios Transversales , Farmacorresistencia Bacteriana , Quimioterapia Combinada , Femenino , Humanos , India/epidemiología , Lactante , Leprostáticos/farmacología , Lepra/epidemiología , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Mutación , Mycobacterium leprae/genética , Adulto Joven
8.
Sci Rep ; 10(1): 1284, 2020 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-31992776

RESUMEN

Host genetic susceptibility to leprosy has been intensively investigated over the last decades; however, there are no studies on the role of genetic variants in disease recurrence. A previous initiative identified three recurrent cases of leprosy for which none of the M. leprae strains, as obtained in the first and the second diagnosis, had any known genomic variants associated to resistance to Multidrug therapy; in addition, whole genome sequencing indicated that the same M. leprae was causing two out of the three recurrences. Thus, these individuals were suspected of being particularly susceptible to M. leprae infection, either as relapse or reinfection. To verify this hypothesis, 19 genetic markers distributed across 11 loci (14 genes) classically associated with leprosy were genotyped in the recurrent and in three matching non-recurrent leprosy cases. An enrichment of risk alleles was observed in the recurrent cases, suggesting the existence of a particularly high susceptibility genetic profile among leprosy patients predisposing to disease recurrence.


Asunto(s)
Sitios Genéticos , Predisposición Genética a la Enfermedad , Lepra/genética , Mycobacterium leprae , Polimorfismo de Nucleótido Simple , Secuenciación Completa del Genoma , Femenino , Humanos , Masculino , Recurrencia
9.
BMC Infect Dis ; 20(1): 62, 2020 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-31959113

RESUMEN

BACKGROUND: To evaluate the effectiveness and safety of the World Health Organization antibiotic regimen for the treatment of paucibacillary (PB) and multibacillary (MB) leprosy compared to other available regimens. METHODS: We performed a search from 1982 to July 2018 without language restriction. We included randomized controlled trials, quasi-randomized trials, and comparative observational studies (cohorts and case-control studies) that enrolled patients of any age with PB or MB leprosy that were treated with any of the leprosy antibiotic regimens established by the WHO in 1982 and used any other antimicrobial regimen as a controller. Primary efficacy outcomes included: complete clinical cure, clinical improvement of the lesions, relapse rate, treatment failure. Data were pooled using a random effects model to estimate the treatment effects reported as relative risk (RR) with 95% confidence intervals (CI). RESULTS: We found 25 eligible studies, 11 evaluated patients with paucibacillary leprosy, while 13 evaluated patients with MB leprosy and 1 evaluated patients of both groups. Diverse regimen treatments and outcomes were studied. Complete cure at 6 months of multidrug therapy (MDT) in comparison to rifampin-ofloxacin-minocycline (ROM) found RR of 1.06 (95% CI 0.88-1.27) in five studies. Whereas six studies compare the same outcome at different follow up periods between 6 months and 5 years, according to the analysis ROM was not better than MDT (RR of 1.01 (95% CI 0.78-1.31)) in PB leprosy. CONCLUSION: Not better treatment than the implemented by the WHO was found. Diverse outcome and treatment regimens were studied, more statements to standardized the measurements of outcomes are needed.


Asunto(s)
Leprostáticos/uso terapéutico , Lepra Multibacilar/tratamiento farmacológico , Lepra Paucibacilar/tratamiento farmacológico , Minociclina/uso terapéutico , Ofloxacino/uso terapéutico , Rifampin/uso terapéutico , Organización Mundial de la Salud , Adolescente , Adulto , Anciano , Niño , Protocolos Clínicos , Quimioterapia Combinada/efectos adversos , Femenino , Humanos , Leprostáticos/efectos adversos , Masculino , Persona de Mediana Edad , Minociclina/efectos adversos , Mycobacterium leprae/efectos de los fármacos , Mycobacterium leprae/aislamiento & purificación , Enfermedades Desatendidas/tratamiento farmacológico , Ofloxacino/efectos adversos , Recurrencia , Rifampin/efectos adversos , Insuficiencia del Tratamiento , Adulto Joven
10.
BMC Infect Dis ; 19(1): 1013, 2019 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-31783808

RESUMEN

BACKGROUND: Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae. It is a polymorphic disease with a wide range of cutaneous and neural manifestations. Ulcer is not a common feature in leprosy patients, except during reactional states, Lucio's phenomenon (LP), or secondary to neuropathies. CASES PRESENTATION: We report eight patients with multibacillary leprosy who presented specific skin ulcers as part of their main leprosy manifestation. Ulcers were mostly present on lower limbs (eight patients), followed by the upper limbs (three patients), and the abdomen (one patient). Mean time from onset of skin ulcers to diagnosis of leprosy was 17.4 months: all patients were either misdiagnosed or had delayed diagnosis, with seven of them presenting grade 2 disability by the time of the diagnosis. Reactional states, LP or neuropathy as potential causes of ulcers were ruled out. Biopsy of the ulcer was available in seven patients: histopathology showed mild to moderate lympho-histiocytic infiltrate with vacuolized histiocytes and intact isolated and grouped acid-fast bacilli. Eosinophils, vasculitis, vasculopathy or signs of chronic venous insufficiency were not observed. Skin lesions improved rapidly after multidrug therapy, without any concomitant specific treatment for ulcers. CONCLUSIONS: This series of cases highlights the importance of recognizing ulcers as a specific cutaneous manifestation of leprosy, allowing diagnosis and treatment of the disease, and therefore avoiding development of disabilities and persistence of the transmission chain of M. leprae.


Asunto(s)
Lepra Multibacilar/diagnóstico , Úlcera Cutánea/diagnóstico , Adolescente , Adulto , Anciano , Errores Diagnósticos , Humanos , Leprostáticos , Lepra Multibacilar/complicaciones , Masculino , Persona de Mediana Edad , Mycobacterium leprae/aislamiento & purificación , Piel/patología , Úlcera Cutánea/complicaciones
11.
MSMR ; 26(12): 2-6, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31860322

RESUMEN

Leprosy, or Hansen's disease (HD), is caused by the bacterium Mycobacterium leprae and is a significant cause of morbidity worldwide. Clinical manifestations range from isolated skin rash to severe peripheral neuropathy. Treatment involves a prolonged course of multiple antimicrobials. Although rare in the U.S., with only 168 new cases reported in 2016, HD remains a prevalent disease throughout the world, with 214,783 new cases worldwide that same year.1 It remains clinically relevant for service members born in and deployed to endemic regions. This report describes a case of HD diagnosed in an active duty soldier born and raised in Micronesia, a highly endemic region.


Asunto(s)
Lepra/patología , Personal Militar/estadística & datos numéricos , Mycobacterium leprae , Enfermedades Profesionales/patología , Úlcera Cutánea/patología , Humanos , Lepra/epidemiología , Lepra/microbiología , Masculino , Micronesia/epidemiología , Enfermedades Profesionales/epidemiología , Enfermedades Profesionales/microbiología , Úlcera Cutánea/microbiología , Estados Unidos/epidemiología , Adulto Joven
12.
mBio ; 10(6)2019 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-31848273

RESUMEN

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.


Asunto(s)
Carbono/metabolismo , Glucosa/metabolismo , Mycobacterium leprae/fisiología , Células de Schwann/metabolismo , Células de Schwann/microbiología , Metabolismo de los Hidratos de Carbono , Línea Celular , Interacciones Huésped-Patógeno , Humanos , Lepra/metabolismo , Lepra/microbiología , Macrófagos/metabolismo , Macrófagos/microbiología , Redes y Vías Metabólicas
13.
PLoS Negl Trop Dis ; 13(12): e0007946, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31881061

RESUMEN

BACKGROUND: Although leprosy is efficiently treated by multidrug therapy, resistance to first-line (dapsone, rifampin) and second-line (fluoroquinolones) drugs has been described worldwide. However, the characteristics of drug resistance in Southwest China remain unknown. Furthermore, the sensitivity of polymerase chain reaction (PCR)/sequencing for resistance detection is limited, especially for paucibacillary (PB) leprosy patients. The current study aimed to develop a nested PCR/sequencing and TaqMan SNP Genotyping Assay to increase the sensitivity of the method used to detect drug resistance in Mycobacterium leprae and to reveal the nature of M. leprae drug resistance in Southwest China. METHODOLOGY/PRINCIPAL FINDINGS: Seventy-six specimens, including skin biopsy (n = 64), formalin-fixed paraffin-embedded (FFPE) (n = 11) and skin-slit smear (SSS) (n = 1) samples from multibacillary (MB, n = 70) and PB (n = 6) leprosy patients from Southwest China, were included in this study. The presence of mutations in drug resistance-determining regions (DRDRs) of the rpoB, folP1, and gyrA genes, which are associated with rifampicin, dapsone, and quinolone resistance, respectively, was detected by PCR/sequencing, as recommended by the WHO, and the nested PCR and TaqMan SNP Genotyping Assay developed in this study. Mutations in the folP gene were detected in 19 (25.00%) samples, indicating dapsone-resistant M. leprae, with one (1.31%) sample showing mutations in two genes, folP and gyrA, reflecting multidrug-resistant strains to dapsone and ofloxacin. However, no rpoB mutation was detected. Compared with PCR/sequencing, nested PCR increased the sensitivity of detecting rpoB (from 51.39% to 78.94% for leprosy patients and from 0.00% to 50.00% for PB), gyrA (from 75.00% to 80.26% for leprosy patients and from 50.00% to 66.67% for PB), and folP1 (from 5.26% to 84.21% for leprosy patients and from 0.00% to 66.67% for PB). Moreover, the TaqMan SNP Genotyping Assay showed greater sensitivity for folP1 detection (from 5.26% to 78.94-86.84% for leprosy patients and from 0.00% to 33.33%-83.33% for PB patients) than the PCR/sequencing method. In addition, the latter method was able to more easily distinguish heterozygous genotypes and mutant homozygous genotypes from homozygous genotypes. CONCLUSIONS/SIGNIFICANCE: Nested PCR/sequencing and the TaqMan SNP Genotyping Assay are rapid and highly sensitive methods for detecting drug resistance in leprosy cases. The current study revealed that diamino-diphenylsulfone (DDS; also known as dapsone) resistance in M. leprae, as indicated by folP1 gene detection, is still the most concerning form of drug resistance in leprosy patients from Southwest China.


Asunto(s)
Farmacorresistencia Bacteriana , Técnicas de Genotipaje/métodos , Lepra/microbiología , Pruebas de Sensibilidad Microbiana/métodos , Mycobacterium leprae/efectos de los fármacos , Mycobacterium leprae/genética , Reacción en Cadena de la Polimerasa/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , China , Femenino , Genes Bacterianos , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mycobacterium leprae/aislamiento & purificación , Sensibilidad y Especificidad , Análisis de Secuencia de ADN/métodos , Adulto Joven
14.
Emerg Microbes Infect ; 8(1): 1479-1489, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31621517

RESUMEN

Reports on antimicrobial resistance (AMR) of Mycobacterium leprae, relationship with bacteriological index (BI), and transmission in China are limited. We investigated the emergence of AMR mutations, the relationship between BI and AMR in complete, moderate and lack of BI decline cases, and molecular epidemiological features of AMR cases by enrolling 290 leprosy cases from four endemic provinces. Seven (2.41%), one (0.34%), five (1.72%), one (0.34%), and one (0.34%) strains had single mutations in folP1, rpoC, gyrA, gyrB, and 23S rRNA, respectively. Double mutations in folP1 and gyrA, rpoB and gyrA, and gyrA and 23S rRNA were observed in one (0.34%) strain each. Mutated strains occurred in three out of 81 (95% CI-0.005-0.079, p = 0.083) cases with complete BI decline, in seven out of 103 (95% CI 0.018-0.117, p = 0.008) cases with moderate BI decline, and in four out of 34 (95% CI 0.003-0.231, p = 0.044) cases with lack of BI decline. Most of these mutated strains were geographically separated and diverged genotypically. AMR mutations may not be the main cause of the lack of BI decline. The low transmission of AMR strains at the county level indicates an ongoing transmission at close contact levels.


Asunto(s)
Farmacorresistencia Bacteriana , Leprostáticos/farmacología , Lepra/microbiología , Mycobacterium leprae/efectos de los fármacos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , China/epidemiología , Femenino , Humanos , Lepra/epidemiología , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Mutación , Mycobacterium leprae/clasificación , Mycobacterium leprae/genética , Mycobacterium leprae/aislamiento & purificación , Filogenia , Adulto Joven
15.
PLoS Negl Trop Dis ; 13(10): e0007731, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31577795

RESUMEN

BACKGROUND: Detection and pathology analysis of Mycobacterium leprae using skin biopsy tissues are essential for leprosy diagnosis and monitoring response to treatment. Although formalin fixation of patient tissues may not be ideal for molecular studies, biopsy samples are the most accessible material from suspected cases. Therefore, clinical molecular laboratories must be able to utilize formalin-fixed, paraffin-embedded (FFPE) material. OBJECTIVE: To determine the best molecular method for diagnosing and monitoring leprosy in FFPE specimens, we developed a single-tube nested PCR (STNPCR) (131 bp) and SYBRGreen PCR (101 bp) assay using primers for the M. leprae-specific repetitive element (RLEP) gene and evaluated the results compared to those using previously established RLEP primers (372 bp). METHODS: FFPE biopsy samples obtained from 145 leprosy patients (during or after multidrug therapy (MDT)) and patients with 29 other confounding dermatoses were examined by the bacteria index (BI) and by simple PCR, STNPCR, and SYBRGreen PCR using primers amplifying a 372-bp, 131-bp or 101-bp fragment of RLEP, respectively. RESULTS: In leprosy patients receiving MDT, STNPCR showed a highest specificity of 100% and a positive predictive value (PPV) of 100%. For multibacillary (MB), paucibacillary (PB) and all leprosy patients, the highest sensitivities were 91.42%, 39.13%, and 67.92%, negative predictive values (NPVs) were 8.57%, 60.36%, and 32.07%, and the highest accuracies were 93.93%, 62.67%, and 74.81%, respectively, higher than the results of SYBRGreen PCR and simple PCR. For post-MDT leprosy patients, SYBRGreen PCR showed the highest sensitivity of 50.0%, highest specificity of 100%, a PPV of 100%, an NPV of 100% and the highest accuracy of 83.72% for MB patients, which were higher than those of STNPCR and simple PCR. STNPCR showed the highest sensitivity of 26.66% and 34.48%, highest specificity of 100% and 100%, a PPV of 100% and 100%, NPV of 72.50% and 60.21%, and highest accuracy of 75.00% and 67.24% for PB and leprosy patients, respectively, higher than those of SYBRGreen PCR and simple PCR. CONCLUSIONS: These findings suggest that STNPCR or SYBRGreen PCR (131-bp and 101-bp fragment amplification, respectively) for RLEP using FFPE specimens performs better as a diagnostic test and for monitoring response to MDT than does simple PCR based on 372-bp fragment amplification. Additionally, STNPCR showed increased sensitivity for PB diagnosis using FFPE specimens, which can be transferred remotely or retrieved from previous leprosy patients.


Asunto(s)
Formaldehído , Lepra/diagnóstico , Mycobacterium leprae/aislamiento & purificación , Adhesión en Parafina/métodos , Reacción en Cadena de la Polimerasa/métodos , Biopsia/métodos , China , Cartilla de ADN , ADN Bacteriano/genética , Quimioterapia Combinada , Humanos , Leprostáticos/uso terapéutico , Lepra/tratamiento farmacológico , Mycobacterium leprae/genética , Secuencias Repetitivas de Ácidos Nucleicos/genética , Sensibilidad y Especificidad , Piel/microbiología
16.
PLoS Negl Trop Dis ; 13(10): e0007764, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31600201

RESUMEN

Reversal reactions (RRs) in leprosy are characterized by a reduction in the number of bacilli in lesions associated with an increase in cell-mediated immunity against the intracellular bacterium Mycobacterium leprae, the causative pathogen of leprosy. To identify the mechanisms that contribute to cell-mediated immunity in leprosy, we measured changes in the whole blood-derived transcriptome of patients with leprosy before, during and after RR. We identified an 'RR signature' of 1017 genes that were upregulated at the time of the clinical diagnosis of RR. Using weighted gene correlated network analysis (WGCNA), we detected a module of 794 genes, bisque4, that was significantly correlated with RR, of which 434 genes were part of the RR signature. An enrichment for both IFN-γ and IFN-ß downstream gene pathways was present in the RR signature as well as the RR upregulated genes in the bisque4 module, including those encoding proteins of the guanylate binding protein (GBP) family that contributes to antimicrobial responses against mycobacteria. Specifically, GBP1, GBP2, GBP3 and GBP5 mRNAs were upregulated in the RR peripheral blood transcriptome, with GBP1, GBP2 and GBP5 mRNAs also upregulated in the RR disease lesion transcriptome. These data indicate that RRs involve a systemic upregulation of IFN-γ downstream genes including GBP family members as part of the host antimicrobial response against mycobacteria.


Asunto(s)
Proteínas de Unión al GTP/genética , Interferón gamma/inmunología , Lepra/inmunología , Lepra/metabolismo , Mapeo Cromosómico , Expresión Génica/efectos de los fármacos , Perfilación de la Expresión Génica , Humanos , Inmunidad Celular , Interferón beta , Mycobacterium leprae/inmunología , ARN Mensajero , Transcriptoma , Regulación hacia Arriba
17.
Int J Infect Dis ; 88: 65-72, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31499206

RESUMEN

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.


Asunto(s)
Vacuna BCG/administración & dosificación , Leprostáticos/administración & dosificación , Lepra/prevención & control , Rifampin/administración & dosificación , Adolescente , Adulto , Bangladesh , Niño , Preescolar , Femenino , Humanos , Incidencia , Lepra/diagnóstico , Lepra/tratamiento farmacológico , Lepra/microbiología , Masculino , Persona de Mediana Edad , Mycobacterium leprae/efectos de los fármacos , Mycobacterium leprae/fisiología , Vacunación , Adulto Joven
18.
Rev Inst Med Trop Sao Paulo ; 61: e44, 2019 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-31531622

RESUMEN

Mycobacterium leprae is the primary causative agent of Hansen's disease or leprosy. Besides human beings, natural infection has been described in animals such as mangabey monkeys and armadillos. Leprosy is considered a global health problem and its complete pathogenesis is still unknown. As M. leprae does not grow in artificial media, armadillos have become the primary experimental model for leprosy, mimicking human disease including involvement of the peripheral nervous system. Leprosy transmission occurs through continuous and close contact of susceptible people with untreated infected people. However, unknown leprosy contact has been reported in leprosy-affected people, and contact with armadillos is a risk factor for leprosy. In the USA, leprosy is considered a zoonosis and this classification has recently been accepted in Brazil. This review presents information regarding the role of wild armadillos as a source of M. leprae for human infections, as well as the pathogenesis of leprosy.


Asunto(s)
Armadillos/microbiología , Reservorios de Enfermedades/microbiología , Lepra/veterinaria , Mycobacterium leprae , Animales , Modelos Animales de Enfermedad , Humanos , Lepra/microbiología , Lepra/transmisión
19.
Biosens Bioelectron ; 145: 111698, 2019 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-31539652

RESUMEN

Mycobacterium leprae causes endemic disease leprosy which becomes chronic if not treated timely. To expedite this 'timely diagnosis', and that also at an early stage, here an attempt is made to fabricate an epitope-imprinted sensor. A molecularly imprinted polymer nanoparticles modified electrochemical quartz crystal microbalance sensor was developed for sensing of Mycobacterium leprae bacteria through its epitope sequence. Multiple monomers, 3-sulphopropyl methacrylate potassium salt, benzyl methacrylate and 4-aminothiophenol were utilized to imprint this bacterial epitope. Imprinted nanoparticles were electropolymerized on gold coated quartz electrode. The sensor was able to show specific binding towards the blood samples of infected patients, even in the presence of 'matrix' and other plasma proteins such as albumin and globulin. Even other peptide sequences, similar to epitope sequences only with two amino acid mismatches were also unable to show any binding. Sensor withstood analytical tests viz. selectivity, specificity, matrix effect, detection limit (0.161 nM), quantification limit (and 0.536 nM), reproducibility (RSD 2.01%). Hence a diagnostic tool for bacterium causing leprosy is successfully fabricated in a facile manner which will broaden the clinical access and efficient population screening can be made feasible.


Asunto(s)
Técnicas Biosensibles , Lepra/diagnóstico , Mycobacterium leprae/aislamiento & purificación , Tecnicas de Microbalanza del Cristal de Cuarzo , Epítopos/química , Epítopos/inmunología , Oro/química , Humanos , Lepra/microbiología , Impresión Molecular , Mycobacterium leprae/inmunología , Mycobacterium leprae/patogenicidad , Nanopartículas/química , Polímeros/química
20.
Biomedica ; 39(Supl. 2): 26-31, 2019 08 01.
Artículo en Inglés, Español | MEDLINE | ID: mdl-31529831

RESUMEN

Patients with lepromatous leprosy that have received treatment for many years usually get follow up biopsies for persistent skin lesions or positive bacilloscopy even if the values are lower than in the initial bacilloscopy. We report the case of a 48-year old woman with long-standing lepromatous leprosy of 15 years of evolution, with a bacterial index of 4 in the direct smear and the initial skin biopsy. The patient was treated with multidrug therapy for 32 months although the treatment recommended by the World Health Organization (WHO) is only for 12 months. A skin biopsy was taken to determine if there was an active disease. We observed a diffuse dermal inflammation with numerous foreign body giant cells and vacuolated macrophages (Virchow´s cells). These cells contained granular acid-fast material that was also positive with immunohistochemistry for BCG. There were fragmented bacilli and the BI was 2. These cells were also strongly positive for CD68. The biopsy was interpreted as a residual form of lepromatous leprosy that did not require further multidrug therapy. We have observed similar histological profiles in several cases. The lack of clinical data makes it a histological challenge. The accumulation of lipids in these giant cells is due to bacillary destruction and fusion of vacuolated macrophages. We discuss here the role of bacillary and host lipids in the pathogenesis of lepromatous leprosy. We concluded that there was no need to extend the 12-month multidrug therapy recommended by WHO.


Asunto(s)
Células Espumosas/patología , Células Gigantes de Cuerpo Extraño/patología , Lepra Lepromatosa/patología , Piel/patología , Antígenos CD/análisis , Antígenos de Diferenciación Mielomonocítica/análisis , Biopsia , Pared Celular/química , Quimioterapia Combinada , Femenino , Células Espumosas/química , Células Espumosas/microbiología , Células Gigantes de Cuerpo Extraño/química , Células Gigantes de Cuerpo Extraño/microbiología , Interacciones Huésped-Patógeno , Humanos , Leprostáticos/uso terapéutico , Lepra Lepromatosa/tratamiento farmacológico , Lípidos/análisis , Persona de Mediana Edad , Mycobacterium leprae/química , Mycobacterium leprae/aislamiento & purificación , Piel/microbiología , Vacuolas
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