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We synthesized a series of novel dapsone–thalidomide hybrids (3a–i) by molecular hybridization and evaluated their potential for the treatment of type 2 leprosy reactions. All of the ...compounds had analgesic properties. Compounds 3c and 3h were the most active antinociceptive compounds and reduced acetic acid-induced abdominal constrictions by 49.8% and 39.1%, respectively. The hybrid compounds also reduced tumor necrosis factor-α levels in lipopolysaccharide-stimulated L929 cells. Compound 3i was the most active compound; at concentrations of 15.62 and 125μM, compound 3i decreased tumor necrosis factor-α levels by 86.33% and 87.80%, respectively. In nude mice infected with Mycobacterium leprae in vivo, compound 3i did not reduce the number of bacilli compared with controls. Compound 3i did not have mutagenic effects in Salmonella typhimurium strains TA100 and TA102, with or without metabolic activation (S9 mixture). Our results indicate that compound 3i is a novel lead compound for the treatment of type 2 leprosy reactions.
Jorge Lobo's disease is a cutaneous and subcutaneous mycosis that affects patients in the Amazon region. The number of patients is relatively small, but the real situation of the disease as public ...health problem is not known, because Jorge Lobo's disease is not a notifiable disease. This study aims to report the clinical evolution in patients affected and to determine the prevalence and areas of occurrence of the disease. A retrospective study was carried out based on the analysis of the clinical records, which included a collection of photographs of patients in the Department of Sanitary Dermatology, in Rio Branco, and patients seen in the interior of the state. In a decade, in Rio Branco, 249 cases of the disease were reported, 30 were females and 219 males. Of these patients, 153 had localized lesions, 94 of them were on one ear, 55 had multifocal lesions and 41 had disseminated lesions. The average time between the onset of symptoms and diagnosis was 19 years. The average age at the time of diagnosis was 53 years, and ages ranged from 14 to 96 years.
Introduction: Early diagnosis of leprosy, including the diagnosis of sub-clinical disease in contacts of known cases, would be a major advance. The signs of early leprosy are often difficult to ...assess and a reliable diagnostic test could play an important role in identifying cases and thus reducing transmission. Methods: Subjects were recruited at Centro de Saude Jardim Guanabara, Rondonopolis, Mato Grosso State, Brazil. Sera were obtained from 174 recently diagnosed leprosy patients, 409 household contacts, 53 endemic controls and 12 patients with active TB. 186 of the household contacts were re-tested on subsequent visits. Both the NDO-LIDR rapid test (Orange LifeR, Rio de Janeiro, Brazil) and an anti-PGL-1 ELISA test were used on all samples for comparison. Results: LID-1 was positive in 25 of 125 PB cases (20%), but in 41 of 49 MB cases (83.7%), while the anti-PGL-1 ELISA was positive in 8 (6.4%) and 35 (71.4%) cases, respectively. Specificity for LID-1 was 85% and for the anti-PGL-1 ELISA, 97%. Amongst household contacts, 9 of 409 (2.2%) were positive on the LID-1 test, and a further 51 (12.5%) were weakly positive; although 9 cases of leprosy were subsequently identified amongst these contacts, 6 had tested negative, 2 were weakly positive and only 1 had been positive. Conclusion: The ND-O-LID-1 assay can be easily performed by the addition of serum to the assay device, and thus can be applied in resource-poor settings. The test was found to be useful for the detection of multibacillary cases, which in the long term will help to reduce transmission of the disease. This is a specific test, but it is not very sensitive for early detection of leprosy in household contacts and paucibacillary forms.
Background Leprosy is a chronic infectious disease caused by Mycobacterium leprae , which can lead to a disabling neurodegenerative condition. M. leprae preferentially infects skin macrophages and ...Schwann cells–glial cells of the peripheral nervous system. The infection modifies the host cell lipid metabolism, subverting it in favor of the formation of cholesterol-rich lipid droplets (LD) that are essential for bacterial survival. Although researchers have made progress in understanding leprosy pathogenesis, many aspects of the molecular and cellular mechanisms of host–pathogen interaction still require clarification. The purinergic system utilizes extracellular ATP and adenosine as critical signaling molecules and plays several roles in pathophysiological processes. Furthermore, nucleoside surface receptors such as the adenosine receptor A 2A R involved in neuroimmune response, lipid metabolism, and neuron–glia interaction are targets for the treatment of different diseases. Despite the importance of this system, nothing has been described about its role in leprosy, particularly adenosinergic signaling (AdoS) during M. leprae –Schwann cell interaction. Methods M. leprae was purified from the hind footpad of athymic nu/nu mice. ST88-14 human cells were infected with M. leprae in the presence or absence of specific agonists or antagonists of AdoS. Enzymatic activity assays, fluorescence microscopy, Western blotting, and RT-qPCR analysis were performed. M. leprae viability was investigated by RT-qPCR, and cytokines were evaluated by enzyme-linked immunosorbent assay. Results We demonstrated that M. leprae -infected Schwann cells upregulated CD73 and ADA and downregulated A 2A R expression and the phosphorylation of the transcription factor CREB (p-CREB). On the other hand, activation of A 2A R with its selective agonist, CGS21680, resulted in: 1) reduced lipid droplets accumulation and pro-lipogenic gene expression; 2) reduced production of IL-6 and IL-8; 3) reduced intracellular M. leprae viability; 4) increased levels of p-CREB. Conclusion These findings suggest the involvement of the AdoS in leprosy neuropathogenesis and support the idea that M. leprae , by downmodulating the expression and activity of A 2A R in Schwann cells, decreases A 2A R downstream signaling, contributing to the maintenance of LD accumulation and intracellular viability of the bacillus.
Summary Background Procedures involving the use of Mycobacterium leprae and Lacazia loboi , uncultivated organisms, depend on the collection of material from the lesions of patients or experimental ...animals. This study compared fine-needle aspiration (FNA) and skin biopsy methods for obtaining bacilli and fungal cells to experimentally infect animals. Methods Lepromas from one armadillo and one enlarged footpad of a mouse previously inoculated with L. loboi were submitted to FNA and biopsy. Materials collected were processed for inoculation in mice. Results Acid-fast bacilli (AFB) collected by two FNA procedures yielded 7.2 × 107 and 5.3 × 106 AFB/ml and biopsies yielded 1.58 × 108 and 3.5 × 108 AFB/ml from each leproma. Yeast-like cells of L. loboi collected by FNA yielded 1.0 × 106 fungal cells/ml and biopsy 1.0 × 107 fungal cells/ml. After 8 months, inoculated animals were sacrificed and the inoculated footpads submitted to histopathological examination and counting of AFB and fungal cells. The results obtained by the two methods were comparable for both microorganisms. Conclusions Biopsy may be replaced by FNA during harvesting of material for different purposes, especially for experimental inoculation of mice in leprosy and Jorge Lobo's disease, with the advantage of FNA being a simpler, less invasive, and less costly method.
Jorge Lobo's disease (Lacaziosis) is a subcutaneous infection of humans living in the Amazon region of Latin America, and in dolphins inhabiting the east coastal areas of the United States. The ...disease mainly affects people from rural areas living or working in close contact with vegetation and aquatic environments. Most patients refer having developed lesions after accidental trauma with plant thorns or insect bites. Inter-human transmission has never been confirmed suggesting that Lacazia loboi is acquired from environmental propagules.
We report the case of a 41-year-old woman from São Paulo, Brazil, a non-endemic area of Jorge Lobo's disease, with L. loboi skin infection most likely accidentally acquired while manipulating experimentally infected mice in the laboratory.
Because many patients with Jorge Lobo's disease do not recall accidental skin trauma before their infections, the possibility of accidentally acquired Jorge Lobo's disease through unnoticed broken skin should be considered during the clinical investigation of nodular skin diseases in people who have contact with the fungus or who live in endemic areas. This is the second report of animal to human transmission of this disease.
Introdução: a hanseníase é uma doença in fecciosa crônica causada pelo Mycobacterium leprae (M. leprae), um parasita intracelular obrigatório. Assim, a resistência do hospedeiro a esse patógeno ...depende da imunidade celular. O uso de modelos experimentais tem permitido o estudo da hanseníase do ponto de vista imunológico, microbiológico e terapêutico, entretanto, as diferenças na progressão da infecção entre os modelos mais empregados (camundongos imunocompetentes, BALB/c, e camundongos congenitamente atímicos, nude) são pouco estudadas. Objetivo: comparar a evolução da infecção pelo M. leprae em camundongos BALB/c e nude quanto à multiplicação bacilar e avaliação do perfil inflamatório sistêmico pela quantificação sérica de citocinas e óxido nítrico (NO). Métodos: os camundongos foram inoculados com M. leprae nos coxins plantares e avaliados aos 3, 5 e 8 meses após a infecção. Resultados: camundongos nude apresentaram multiplicação bacilar progressiva nos coxins plantares. Em camundongos BALB/c, o número de bacilos foi maior aos 5 meses. Em relação à quantificação de citocinas, nos camundongos BALB/c houve aumento de IL-2 e IL-17A e diminuição de IL-6 e NO aos 8 meses de inoculação. Nos camundongos nude, verificou-se o aumento do TNF aos 8 meses de inoculação e manutenção dos níveis de NO. Conclusão: os resultados encontrados sugerem que em camundongos BALB/c ocorre a ativação de uma resposta imune capaz de controlar a multiplicação do M. leprae, em contrapartida em camundongos nude a infecção é progressiva a despeito de altos níveis de TNF.
Although multidrug therapy is considered an effective treatment for leprosy, antimicrobial resistance is a serious concern. We performed a systematic review of studies on the diagnostic accuracy and ...screening of tests for antimicrobial resistance in leprosy. This review was registered in PROSPERO (CRD42020177958). In April 2020, we searched for studies in the PubMed, EMBASE, Web of Science, Scopus, Scielo, and LILACS databases. A random effects regression model was used for the meta-analysis. We included 129 studies. Molecular tests for dapsone resistance had a sensitivity of 78.8% (95% confidence interval CI = 65.6–87.9) and a specificity of 97.0% (95% CI = 94.0–98.6). Molecular tests for rifampicin resistance had a sensitivity and specificity of 88.7% (95% CI = 80.0–93.9) and 97.3% (95% CI = 94.3–98.8), respectively. Molecular tests for ofloxacin resistance had a sensitivity and specificity of 80.9% (95% CI = 60.1–92.3) and 96.1% (95% CI = 90.2–98.5), respectively. In recent decades, no increase in the resistance proportion was detected. However, the growing number of resistant cases is still a clinical concern.
Leprosy is a chronic infectious disease caused by the intracellular bacillus Mycobacterium leprae (M. leprae), which is known to infect skin macrophages and Schwann cells. Although adipose tissue is ...a recognized site of Mycobacterium tuberculosis infection, its role in the histopathology of leprosy was, until now, unknown. We analyzed the M. leprae capacity to infect and persist inside adipocytes, characterizing the induction of a lipolytic phenotype in adipocytes, as well as the effect of these infected cells on macrophage recruitment. We evaluated 3T3-L1-derived adipocytes, inguinal adipose tissue of SWR/J mice, and subcutaneous adipose tissue biopsies of leprosy patients. M. leprae was able to infect 3T3-L1-derived adipocytes in vitro, presenting a strong lipolytic profile after infection, followed by significant cholesterol efflux. This lipolytic phenotype was replicated in vivo by M. leprae injection into mice inguinal adipose tissue. Furthermore, M. leprae was detected inside crown-like structures in the subcutaneous adipose tissue of multibacillary patients. These data indicate that subcutaneous adipose tissue could be an important site of infection, and probably persistence, for M. leprae, being involved in the modulation of the innate immune control in leprosy via the release of cholesterol, MCP-1, and adiponectin.
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