RESUMEN
BACKGROUND: The impact of nutrient availability on the survival of Mycobacterium leprae and the development of leprosy remains largely unknown. Iron is essential for the survival and replication of pathogens, while vitamin D has been involved with pathogen elimination and immunoregulation. OBJECTIVES: We evaluated the influence of dietary iron and vitamin D supplementation and restriction on the inflammatory response of mouse immune cells in vitro. METHODS: After 30 days of standard or modified diets, peritoneal cells and splenocytes were stimulated with the alive microorganisms and sonicated antigens of M. leprae, respectively. The production of inflammatory cytokines, reactive oxygen species, and cell proliferation were evaluated. FINDINGS: In peritoneal cells, vitamin D supplementation and iron restriction reduced the production of IL-6 and TNF in response to M. leprae, while splenocytes presented a reduction in TNF production under the same conditions. Lower levels of IFN-γ and TNF were observed in both iron-supplemented and iron-deficient splenocytes. Besides, iron supplementation also reduced the production of IL-6 and IL-10. No changes in the production of reactive oxygen species or in cell proliferation were observed related to different diets. MAIN CONCLUSIONS: Taken together, these data point to an interference of the status of these nutrients on the interaction between the host and M. leprae, with the potential to interfere with the progression of leprosy. Our results highlight the impact of nutritional aspects on this neglected disease, which is significantly associated with unfavourable social conditions.
Asunto(s)
Citocinas , Mycobacterium leprae , Especies Reactivas de Oxígeno , Bazo , Vitamina D , Animales , Mycobacterium leprae/inmunología , Mycobacterium leprae/efectos de los fármacos , Vitamina D/farmacología , Vitamina D/administración & dosificación , Bazo/inmunología , Ratones , Citocinas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Hierro/metabolismo , Proliferación Celular/efectos de los fármacos , Suplementos Dietéticos , Femenino , Lepra/inmunología , Masculino , Ratones Endogámicos BALB CRESUMEN
Leprosy continues to pose a significant challenge to public health, particularly in certain global regions. Accurate diagnosis and understanding of the disease's etiology are crucial for effective management and prevention. This study aimed to explore the contribution of Natural resistance-associated macrophage protein 1 (NRAMP1) and its genetic variations, as well as the levels of anti-PGL-1 antibodies, to the pathology of multibacillary leprosy in affected individuals and their household contacts. The study included 23 multibacillary leprosy patients and 28 household contacts. NRAMP1 protein expression and anti-PGL-1 IgG and IgM levels were measured using PCR and ELISA techniques, respectively. Genotypic variants of the NRAMP1 gene were also examined. Statistical analyses, including Mann-Whitney tests and univariate logistic regression, were employed to evaluate the data. Significant differences were observed in NRAMP1 protein expression and IgG and IgM levels between the patient and household contact groups. The study also highlighted the role of the NRAMP1 gene and its D543N and 3'UTR polymorphisms in leprosy susceptibility. No significant differences were observed in the genotype variants of INT4 between the two groups. These findings emphasize the potential of integrating PCR technology with serological tests to enhance diagnostic precision in leprosy. They also suggest the need for further research to clarify the role of NRAMP1 and its polymorphisms in leprosy susceptibility and resistance.
Asunto(s)
Anticuerpos Antibacterianos , Antígenos Bacterianos , Proteínas de Transporte de Catión , Glucolípidos , Inmunoglobulina M , Lepra Multibacilar , Humanos , Masculino , Lepra Multibacilar/genética , Femenino , Adulto , Inmunoglobulina M/sangre , Anticuerpos Antibacterianos/sangre , Proteínas de Transporte de Catión/genética , Persona de Mediana Edad , Antígenos Bacterianos/inmunología , Antígenos Bacterianos/genética , Inmunoglobulina G/sangre , Adulto Joven , Genotipo , Adolescente , Composición Familiar , Expresión Génica , Mycobacterium leprae/inmunología , Mycobacterium leprae/genéticaRESUMEN
The assessment of ELISA plates coated with phenolic glycolipid-I/PGL-I revealed excellent stability during eight years of storage at room temperature, promoting consistent IgM antibody detection in multibacillary leprosy patients. These stable, standardized plates can significantly contribute to efficient leprosy serology research and support its widespread distribution and use in endemic countries.
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Anticuerpos Antibacterianos , Antígenos Bacterianos , Ensayo de Inmunoadsorción Enzimática , Glucolípidos , Inmunoglobulina M , Mycobacterium leprae , Inmunoglobulina M/sangre , Ensayo de Inmunoadsorción Enzimática/métodos , Mycobacterium leprae/inmunología , Humanos , Anticuerpos Antibacterianos/inmunología , Glucolípidos/inmunología , Antígenos Bacterianos/inmunología , Lepra/diagnóstico , Lepra/microbiología , Lepra/inmunología , Factores de TiempoRESUMEN
Mycobacterium Indicus Pranii (MIP) vaccine is a killed vaccine developed in India for leprosy with immunotherapeutic as well as immunoprophylactic effects. MIP, earlier known as Mycobacterium welchii, is a rapidly growing non-pathogenic mycobacterium. The novelty of this bacterium is due to its translational application as an immunotherapeutic agent. When administered intradermally, the vaccine induces cell-mediated immunity in the host towards Mycobacterium leprae. It leads to faster clinical and histopathological improvement, rapid bacillary clearance, and also lepromin conversion in anergic leprosy patients. The beneficial role of the MIP vaccine in augmenting the therapeutic efficacy of Multidrug Therapy (MDT), particularly in highly bacillated leprosy patients, is well documented in various studies from India. The role of the vaccine in reactional states is controversial, with varied results in different studies. Overall, it is found to decrease the frequency of type 2 lepra reactions and is useful in recalcitrant erythema nodosum leprosum. Even though there may be an increased likelihood of type 1 reactions, no additional nerve function impairment is attributed to the vaccine in various studies. In household contacts of leprosy who are administered MIP, it is noted to confer protection from disease lasting up to 10 years. It may prove to be a cost-effective strategy in national leprosy programmes. Apart from local injection site reactions, the vaccine is relatively safe, but it is not recommended in pregnancy and lactation. This article provides an overview of the MIP vaccine's clinical application in the context of leprosy spanning over 40 years. It also considers the vaccine's possible future applications in the management of disease-related complications and achieving the long-term goal of zero leprosy.
Asunto(s)
Vacunas Bacterianas , Lepra , Humanos , Vacunas Bacterianas/administración & dosificación , Leprostáticos/uso terapéutico , Lepra/prevención & control , Lepra/inmunología , Mycobacterium leprae/inmunología , Vacunas de Productos InactivadosRESUMEN
Leprosy is a chronic infectious disease caused by the bacillus Mycobacterium leprae. The disease may evolve for inflammatory reactions, reversal reaction (RR) and erythema nodosum leprosum (ENL), the major cause of irreversible neuropathy in leprosy, which occur in 1 in 3 people with leprosy, even with effective treatment of M. leprae. Leprosy remains persistently endemic in our region where it predominantly affects lowest socioeconomic conditions people, as Toxoplasma gondii infection in the municipality studied. Previously, we have shown T. gondii coinfection as a risk marker for leprosy, mainly in its severe form. This present study assessed whether T. gondii infection is also a risk factor for leprosy reactions and the predictive value of immunoglobulin production prior to development of leprosy reactions. Patients with leprosy (n = 180), co-infected or not with T. gondii, had their serum investigated for levels of IgA, IgE, IgG1, IgG2, IgG3 and IgG4 anti-PGL-1 by ELISA prior to development of leprosy reactions. The serologic prevalence for T. gondii infection was 87.7% in leprosy reaction patients reaching 90.9% in those with ENL. The leprosy reaction risk increased in T. gondii seropositive individuals was two-fold ([OR] = 2.366; 95% confidence interval [CI 95%]: 1.024-5.469) higher than those seronegative, and considering the risk of ENL, this increase was even more evident (OR = 6.753; 95% CI: 1.050-72.85) in coinfected individuals. When evaluated the prediction of anti-PGL-1 immunoglobulin levels for development of leprosy reactions in patients coinfected or not with T. gondii, only the increase IgE levels were associated to occurrence of reactional episodes of leprosy, specifically ENL type, in patients coinfected with T. gondii, compared to those not coinfected or no reaction. Thus, the immunomodulation in co-parasitism T. gondii-M. leprae suggest increased levels of IgE as a biomarker for early detection of these acute inflammatory episodes and thereby help prevent permanent neuropathy and disability in leprosy patients.
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Eritema Nudoso , Inmunoglobulina E , Toxoplasma , Toxoplasmosis , Humanos , Toxoplasmosis/sangre , Toxoplasmosis/complicaciones , Toxoplasmosis/inmunología , Toxoplasmosis/epidemiología , Eritema Nudoso/inmunología , Eritema Nudoso/epidemiología , Eritema Nudoso/sangre , Femenino , Masculino , Adulto , Inmunoglobulina E/sangre , Persona de Mediana Edad , Toxoplasma/inmunología , Coinfección/inmunología , Coinfección/parasitología , Mycobacterium leprae/inmunología , Adulto Joven , Adolescente , Factores de Riesgo , Anciano , Lepra Lepromatosa/inmunología , Lepra Lepromatosa/complicaciones , Lepra Lepromatosa/sangre , Lepra Lepromatosa/epidemiologíaRESUMEN
The nine-banded armadillo (Dasypus novemcinctus) is currently considered an invasive species in parts of its range in the USA, and this range continues to expand to the north and east. Nine-banded armadillos are one of a handful of mammals known to contract leprosy (also known as Hansen's disease); range expansion thus leads to public health concerns about whether this might increase human exposure to infected animals. We collected blood samples from 61 road-killed armadillos over two summers (2021 and 2022) in Tennessee, a US state near the northern extreme of the species' current range, and screened them for exposure to Mycobacterium leprae, the causative agent of leprosy. All animals were seronegative, providing no evidence that range expansion is increasing the distribution of leprosy in the US.
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Armadillos , Lepra , Mycobacterium leprae , Animales , Armadillos/microbiología , Lepra/veterinaria , Lepra/epidemiología , Tennessee/epidemiología , Estudios Seroepidemiológicos , Mycobacterium leprae/inmunología , Femenino , MasculinoRESUMEN
The diagnosis if leprosy is difficult, as it requires clinical expertise and sensitive laboratory tests. In this study, we develop a serological test for leprosy by using bioinformatics tools to identify specific B-cell epitopes from Mycobacterium leprae hypothetical proteins, which were used to construct a recombinant chimeric protein, M1. The synthetic peptides were obtained and showed good reactivity to detect leprosy patients, although the M1 chimera have showed sensitivity (Se) and specificity (Sp) values higher than 90.0% to diagnose both paucibacillary (PB) and multibacillary (MB) leprosy patients, but not those developing tegumentary or visceral leishmaniasis, tuberculosis, Chagas disease, malaria, histoplasmosis and aspergillosis, in ELISA experiments. Using sera from household contacts, values for Se and Sp were 100% and 65.3%, respectively. In conclusion, our proof-of-concept study has generated data that suggest that a new recombinant protein could be developed into a diagnostic antigen for leprosy.
Asunto(s)
Antígenos Bacterianos , Proteínas Bacterianas , Epítopos de Linfocito B , Lepra , Mycobacterium leprae , Sensibilidad y Especificidad , Humanos , Mycobacterium leprae/inmunología , Mycobacterium leprae/genética , Epítopos de Linfocito B/inmunología , Epítopos de Linfocito B/genética , Antígenos Bacterianos/inmunología , Antígenos Bacterianos/genética , Lepra/diagnóstico , Lepra/inmunología , Proteínas Bacterianas/inmunología , Proteínas Bacterianas/genética , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/genética , Ensayo de Inmunoadsorción Enzimática/métodos , Adulto , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Masculino , Femenino , Pruebas Serológicas/métodos , Biología Computacional/métodos , Persona de Mediana Edad , Adulto Joven , AdolescenteRESUMEN
Leprosy is a chronic granulomatous infectious and disabling disease caused by two mycobacteria, Mycobacterium leprae and Mycobacterium lepromatosis. Acute inflammatory responses, known as leprosy reactions, are significant contributors to disabilities. Three types of leprosy reactions have been identified based on excessive cytokine release (e.g. type 1) or the accumulation of immune complexes in tissues inducing multiorgan damage (e.g. types 2 and 3). The type of leprosy reaction has implications on treatment and management strategies, yet are not well understood by health workers caring for leprosy patients. We attempt to describe the immunologic mechanisms behind the different leprosy reactions and the rationale for tailoring clinical treatment and management to the particular type of leprosy reaction based on the underlying immunologic situation.
Asunto(s)
Lepra , Mycobacterium leprae , Humanos , Lepra/inmunología , Lepra/microbiología , Lepra/patología , Mycobacterium leprae/inmunología , Citocinas/metabolismoRESUMEN
Leprosy diagnosis is difficult due to the clinical similarity with other infectious diseases, and laboratory tests presents problems related to sensitivity and/or specificity. In this study, we used bioinformatics to assess Mycobacterium leprae proteins and formulated a chimeric protein that was tested as a diagnostic marker for the disease. The amino acid sequences from ML0008, ML0126, ML0308, ML1057, ML2028, ML2038, ML2498 proteins were evaluated, and the B-cell epitopes QASVAYPATSYADFRAHNHWWNGP, SLQRSISPNSYNTARVDP and QLLGQTADVAGAAKSGPVQPMGDRGSVSPVGQ were considered M. leprae-specific and used to construct the gene encoding the recombinant antigen. The gene was constructed, the recombinant protein was expressed, purified and tested in ELISA using 252 sera, which contained samples from multibacillary (MB) or paucibacillary (PB) leprosy patients, from their household contacts and healthy individuals, as well as from patients with Chagas disease, visceral and tegumentary leishmaniases (VL/TL), malaria, tuberculosis, and HIV. Sensitivity (Se) and specificity (Sp) for MB and PB samples compared to sera from both healthy subjects and individuals with cross-reactive diseases were 100%. The Se value for MB and PB samples compared to sera from household contacts was 100%, but Sp was 64%. In conclusion, data suggest that this protein could be considered in future studies for leprosy diagnosis.
Asunto(s)
Antígenos Bacterianos , Proteínas Bacterianas , Ensayo de Inmunoadsorción Enzimática , Epítopos de Linfocito B , Lepra Multibacilar , Lepra Paucibacilar , Mycobacterium leprae , Pruebas Serológicas , Mycobacterium leprae/inmunología , Mycobacterium leprae/genética , Humanos , Epítopos de Linfocito B/inmunología , Pruebas Serológicas/métodos , Ensayo de Inmunoadsorción Enzimática/métodos , Antígenos Bacterianos/inmunología , Antígenos Bacterianos/genética , Lepra Paucibacilar/diagnóstico , Lepra Paucibacilar/inmunología , Proteínas Bacterianas/inmunología , Proteínas Bacterianas/genética , Lepra Multibacilar/diagnóstico , Lepra Multibacilar/inmunología , Anticuerpos Antibacterianos/sangre , Proteínas Recombinantes de Fusión/inmunología , Valor Predictivo de las Pruebas , Femenino , Masculino , Sensibilidad y Especificidad , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/genéticaRESUMEN
BACKGROUND: C-C motif chemokine ligand 2, a gene that codes for a protein involved in inflammation. Certain SNPs in the CCL2 gene have been studied for their potential associations with susceptibility to various diseases. These SNPs may affect the production and function of the CCL2 protein, which is involved in the recruitment of immune cells to the site of inflammation. Variations in CCL2 may influence the immune response to Mycobacterium leprae infection. OBJECTIVE: To investigate the association of the C-C motif chemokine ligand-2 single nucleotide polymorphisms with leprosy. METHODS: CCL2 single nucleotide polymorphisms were analyzed in a total of 975 leprosy patients and 357 healthy controls. Of those, 577 leprosy and 288 healthy controls were analyzed by PCR-RFLP for CCL2 -2518 A>G, 535 leprosy and 290 controls for CCL2 -362 G>C, 295 leprosy and 240 controls for CCL2 -2134 T>G, 325 leprosy and 288 controls for CCL2 -1549 A>T SNPs by melting curve analysis using hybridization probe chemistry and detection by fluorescence resonance energy transfer (FRET) technique in Realtime PCR. The levels of CCL2, IL-12p70, IFN-γ, TNF-α, and TGF-ß were estimated in sera samples and correlated with CCL2 genotypes. RESULTS: The frequency of the GCT (-2518 A>G, -362 G>C, -2134 T>G) haplotype is observed to be higher in leprosy patients compared to healthy controls (P = 0.04). There was no significant difference observed in genotypic frequencies between leprosy patients and healthy controls {(-2518A>G, p = 0.53), (-362 G>C, p = 0.01), (-2134 T>G, p = 0.10)}. G allele at the -2134 site is predominant in leprosy (borderline) without any reaction (8 %) compared to borderline patients with RR reactions (2.1 %) (P = 0.03). GG genotype (p = 0.008) and G allele at -2518 (p = 0.030) of the CCL 2 gene were found to be associated with patients with ENL reaction. An elevated level of serum CCL2 was observed in leprosy patients with the -2518 AA and AG genotypes (p = 0.0001). CONCLUSIONS: G allele and GG genotype at the CCL2 -2518 site are associated with a risk of ENL reactions.
Asunto(s)
Quimiocina CCL2 , Predisposición Genética a la Enfermedad , Lepra , Polimorfismo de Nucleótido Simple , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Estudios de Casos y Controles , Quimiocina CCL2/genética , Quimiocina CCL2/sangre , Citocinas/genética , Citocinas/sangre , Frecuencia de los Genes , Genotipo , Lepra/genética , Lepra/inmunología , Mycobacterium leprae/inmunología , Mycobacterium leprae/genética , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Leprosy is a chronic and infectious disease that primarily affects the skin and peripheral nervous system, presenting a wide spectrum of clinical forms with different degrees of severity. The distinct host immune response patters developed in the response to the bacillus Mycobacterium leprae, the leprosy etiologic agent, are associated with the spectral clinical forms and outcome of the disease. In this context, B cells are allegedly involved in the disease immunopathogenesis, usually as antibody-producing cells, but also as potential effector or regulatory elements. In order to determine the regulatory B cells role in experimental leprosy, this study evaluated the outcome of M. leprae infection in B cell deficient mice (BKO) and WT C57Bl/6 control, by means of microbiological/bacilloscopic, immunohistochemical and molecular analysis, performed 8 months after M. leprae inoculation. The results demonstrated that infected BKO showed a higher bacilli number when compared with WT animals, demonstrating the importance of these cells in experimental leprosy. The molecular analysis demonstrates that the expression of IL-4, IL-10 and TGF-ß was significantly higher in the BKO footpads when compared to WT group. Conversely, there was no difference in IFN-γ, TNF-α and IL-17 expression levels in BKO and WT groups. IL-17 expression was significantly higher in the lymph nodes of WT group. The immunohistochemical analysis revealed that M1 (CD80+) cells counts were significantly lower in the BKO group, while no significant difference was observed to M2 (CD206+) counts, resulting a skewed M1/M2 balance. These results demonstrated that the absence of B lymphocytes contribute to the persistence and multiplication of M. leprae, probably due to the increased expression of the IL-4, IL-10 and TGF-ß cytokines, as well as a decrease in the number of M1 macrophages in the inflammatory site.
Asunto(s)
Animales , Ratas , Lepra/inmunología , Mycobacterium leprae/inmunología , Factor de Crecimiento Transformador beta , Interleucina-4 , Interleucina-10 , Interleucina-17 , Susceptibilidad a EnfermedadesRESUMEN
Several Mycobacterial infections including leprosy and tuberculosis are known to evoke autoimmune responses by modulating homeostatic mechanism of the host. Presence of autoantibodies like, rheumatoid factor, anti-nuclear factor and antibodies to host, collagen, keratin, myelin basic protein (MBP) and myosin, have been earlier reported in leprosy patients. In the present study, we detected the role of mimicking epitopes between Mycobacterium leprae and host components in the induction of autoimmune response in leprosy. Based on our previous findings, we predicted and synthesized a total of 15 mimicking linear B cell epitopes (BCE) and 9 mimicking linear T cell epitopes (TCE) of keratin and MBP. Humoral and cell-mediated immune responses against these epitopes were investigated in Non-reaction (NR), Type 1 reaction (T1R) leprosy patients, and healthy controls. We observed significantly higher levels of antibodies against 8 BCE in T1R in comparison to NR leprosy patients. Further, we also found 5 TCE significantly associated with lymphocyte proliferation in the T1R group. Our results indicated that these epitopes play a key role in the induction of autoimmune response in leprosy and are also strongly associated with the inflammatory episodes of T1R. Conclusively, these molecules may be employed as a biomarker to predict the inflammatory episodes of T1R.
Asunto(s)
Epítopos de Linfocito B/inmunología , Epítopos de Linfocito T/inmunología , Lepra , Mycobacterium leprae/inmunología , Adulto , Antígenos Bacterianos/inmunología , Biomarcadores/metabolismo , Femenino , Humanos , Lepra/inmunología , Lepra/microbiología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The respiratory tract is considered the main port of entry of Mycobacterium leprae, the causative agent of leprosy. However, the great majority of individuals exposed to the leprosy bacillus will never manifest the disease due to their capacity to develop protective immunity. Besides acting as a physical barrier, airway epithelium cells are recognized as key players by initiating a local innate immune response that orchestrates subsequent adaptive immunity to control airborne infections. However, to date, studies exploring the interaction of M. leprae with the respiratory epithelium have been scarce. In this work, the capacity of M. leprae to immune activate human alveolar epithelial cells was investigated, demonstrating that M. leprae-infected A549 cells secrete significantly increased IL-8 that is dependent on NF-κB activation. M. leprae was also able to induce IL-8 production in human primary nasal epithelial cells. M. leprae-treated A549 cells also showed higher expression levels of human ß-defensin-2 (hßD-2), MCP-1, MHC-II and the co-stimulatory molecule CD80. Furthermore, the TLR-9 antagonist inhibited both the secretion of IL-8 and NF-κB activation in response to M. leprae, indicating that bacterial DNA sensing by this Toll-like receptor constitutes an important innate immune pathway activated by the pathogen. Finally, evidence is presented suggesting that extracellular DNA molecules anchored to Hlp, a histone-like protein present on the M. leprae surface, constitute major TLR-9 ligands triggering this pathway. The ability of M. leprae to immune activate respiratory epithelial cells herein demonstrated may represent a very early event during infection that could possibly be essential to the generation of a protective response.
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Células Epiteliales Alveolares/inmunología , Células Epiteliales Alveolares/metabolismo , Inmunidad Innata , Lepra/inmunología , Lepra/metabolismo , Mycobacterium leprae/inmunología , Receptor Toll-Like 9/metabolismo , Células A549 , Biomarcadores , Células Cultivadas , Histonas/metabolismo , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunomodulación , Lepra/microbiología , FN-kappa B/metabolismoRESUMEN
BACKGROUND: Leprosy elimination primarily targets transmission of Mycobacterium leprae which is not restricted to patients' households. As interruption of transmission is imminent in many countries, a test to detect infected asymptomatic individuals who can perpetuate transmission is required. Antibodies directed against M. leprae antigens are indicative of M. leprae infection but cannot discriminate between active and past infection. Seroprevalence in young children, however, reflects recent M. leprae infection and may thus be used to monitor transmission in an area. Therefore, this literature review aimed to evaluate what has been reported on serological tests measuring anti-M. leprae antibodies in children without leprosy below the age of 15 in leprosy-endemic areas. METHODS AND FINDINGS: A literature search was performed in the databases Pubmed, Infolep, Web of Science and The Virtual Health Library. From the 724 articles identified through the search criteria, 28 full-text articles fulfilled all inclusion criteria. Two additional papers were identified through snowballing, resulting in a total of 30 articles reporting data from ten countries. All serological tests measured antibodies against phenolic glycolipid-I or synthetic derivatives thereof, either quantitatively (ELISA or UCP-LFA) or qualitatively (ML-flow or NDO-LID rapid test). The median seroprevalence in children in endemic areas was 14.9% and was stable over time if disease incidence remained unchanged. Importantly, seroprevalence decreased with age, indicating that children are a suitable group for sensitive assessment of recent M. leprae infection. However, direct comparison between areas, solely based on the data reported in these studies, was impeded by the use of different tests and variable cut-off levels. CONCLUSIONS: Quantitative anti-PGL-I serology in young children holds promise as a screening test to assess M. leprae infection and may be applied as a proxy for transmission and thereby as a means to monitor the effect of (prophylactic) interventions on the route to leprosy elimination.
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Anticuerpos Antibacterianos/sangre , Lepra/epidemiología , Mycobacterium leprae/aislamiento & purificación , Antígenos Bacterianos/inmunología , Niño , Preescolar , Trazado de Contacto , Enfermedades Endémicas , Composición Familiar , Humanos , Lepra/sangre , Lepra/transmisión , Mycobacterium leprae/inmunologíaRESUMEN
The treatment of multibacillary cases of leprosy with multidrug therapy (MDT) comprises 12 doses of a combination of rifampicin, dapsone and clofazimine. Previous studies have described the immunological phenotypic pattern in skin lesions in multibacillary patients. Here, we evaluated the effect of MDT on skin cell phenotype and on the Mycobacterium leprae-specific immune response. An analysis of skin cell phenotype demonstrated a significant decrease in MRS1 (SR-A), CXCL10 (IP-10) and IFNG (IFN-γ) gene and protein expression after MDT release. Patients were randomized according to whether they experienced a reduction in bacillary load after MDT. A reduction in CXCL10 (IP-10) in sera was associated with the absence of a reduction in the bacillary load at release. Although IFN-γ production in response to M. leprae was not affected by MDT, CXCL10 (IP-10) levels in response to M. leprae increased in cells from patients who experienced a reduction in bacillary load after treatment. Together, our results suggest that CXCL10 (IP-10) may be a good marker for monitoring treatment efficacy in multibacillary patients.
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Quimiocina CXCL10/sangre , Leprostáticos/uso terapéutico , Lepra/tratamiento farmacológico , Piel/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carga Bacteriana/efectos de los fármacos , Biomarcadores/sangre , Quimiocina CXCL10/inmunología , Quimioterapia Combinada , Femenino , Humanos , Leprostáticos/administración & dosificación , Lepra/inmunología , Masculino , Persona de Mediana Edad , Mycobacterium leprae/inmunología , Piel/microbiología , Piel/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Trials of BCG vaccination to prevent or reduce severity of COVID-19 are taking place in adults, some of whom have been previously vaccinated, but evidence of the beneficial, non-specific effects of BCG come largely from data on mortality in infants and young children, and from in-vitro and animal studies, after a first BCG vaccination. We assess all-cause mortality following a large BCG revaccination trial in Malawi. METHODS: The Karonga Prevention trial was a population-based, double-blind, randomised controlled in Karonga District, northern Malawi, that enrolled participants between January, 1986, and November, 1989. The trial compared BCG (Glaxo-strain) revaccination versus placebo to prevent tuberculosis and leprosy. 46 889 individuals aged 3 months to 75 years were randomly assigned to receive BCG revaccination (n=23 528) or placebo (n=23 361). Here we report mortality since vaccination as recorded during active follow-up in northern areas of the district in 1991-94, and in a demographic surveillance follow-up in the southern area in 2002-18. 7389 individuals who received BCG (n=3746) or placebo (n=3643) lived in the northern follow-up areas, and 5616 individuals who received BCG (n=2798) or placebo (n=2818) lived in the southern area. Year of death or leaving the area were recorded for those not found. We used survival analysis to estimate all-cause mortality. FINDINGS: Follow-up information was available for 3709 (99·0%) BCG recipients and 3612 (99·1%) placebo recipients in the northern areas, and 2449 (87·5%) BCG recipients and 2413 (85·6%) placebo recipients in the southern area. There was no difference in mortality between the BCG and placebo groups in either area, overall or by age group or sex. In the northern area, there were 129 deaths per 19 694 person-years at risk in the BCG group (6·6 deaths per 1000 person-years at risk [95% CI 5·5-7·8]) versus 133 deaths per 19 111 person-years at risk in the placebo group (7·0 deaths per 1000 person-years at risk [95% CI 5·9-8·2]; HR 0·94 [95% CI 0·74-1·20]; p=0·62). In the southern area, there were 241 deaths per 38 399 person-years at risk in the BCG group (6·3 deaths per 1000 person-years at risk [95% CI 5·5-7·1]) versus 230 deaths per 38 676 person-years at risk in the placebo group (5·9 deaths per 1000 person-years at risk [95% CI 5·2-6·8]; HR 1·06 [95% CI 0·88-1·27]; p=0·54). INTERPRETATION: We found little evidence of any beneficial effect of BCG revaccination on all-cause mortality. The high proportion of deaths attributable to non-infectious causes beyond infancy, and the long time interval since BCG for most deaths, might obscure any benefits. FUNDING: British Leprosy Relief Association (LEPRA); Wellcome Trust.
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Vacuna BCG/administración & dosificación , Inmunización Secundaria/estadística & datos numéricos , Mortalidad , Vacunación/métodos , Adolescente , Adulto , Anciano , Vacuna BCG/inmunología , COVID-19/epidemiología , COVID-19/inmunología , COVID-19/prevención & control , Niño , Preescolar , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Inmunogenicidad Vacunal , Lepra/inmunología , Lepra/mortalidad , Lepra/prevención & control , Malaui/epidemiología , Masculino , Persona de Mediana Edad , Mycobacterium leprae/inmunología , SARS-CoV-2/inmunología , Resultado del Tratamiento , Tuberculosis/inmunología , Tuberculosis/mortalidad , Tuberculosis/prevención & control , Vacunación/estadística & datos numéricos , Adulto JovenRESUMEN
Granulomas are complex cellular structures composed predominantly of macrophages and lymphocytes that function to contain and kill invading pathogens. Here, we investigated the single-cell phenotypes associated with antimicrobial responses in human leprosy granulomas by applying single-cell and spatial sequencing to leprosy biopsy specimens. We focused on reversal reactions (RRs), a dynamic process whereby some patients with disseminated lepromatous leprosy (L-lep) transition toward self-limiting tuberculoid leprosy (T-lep), mounting effective antimicrobial responses. We identified a set of genes encoding proteins involved in antimicrobial responses that are differentially expressed in RR versus L-lep lesions and regulated by interferon-γ and interleukin-1ß. By integrating the spatial coordinates of the key cell types and antimicrobial gene expression in RR and T-lep lesions, we constructed a map revealing the organized architecture of granulomas depicting compositional and functional layers by which macrophages, T cells, keratinocytes and fibroblasts can each contribute to the antimicrobial response.
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Lepra Lepromatosa/inmunología , Lepra Tuberculoide/inmunología , Mycobacterium leprae/inmunología , Piel/inmunología , Adolescente , Adulto , Anciano , Femenino , Fibroblastos/inmunología , Fibroblastos/microbiología , Fibroblastos/patología , Perfilación de la Expresión Génica , Interacciones Huésped-Patógeno , Humanos , Queratinocitos/inmunología , Queratinocitos/microbiología , Queratinocitos/patología , Lepra Lepromatosa/genética , Lepra Lepromatosa/microbiología , Lepra Lepromatosa/patología , Lepra Tuberculoide/genética , Lepra Tuberculoide/microbiología , Lepra Tuberculoide/patología , Macrófagos/inmunología , Macrófagos/microbiología , Macrófagos/patología , Masculino , Persona de Mediana Edad , Mycobacterium leprae/patogenicidad , RNA-Seq , Análisis de la Célula Individual , Piel/microbiología , Piel/patología , Linfocitos T/inmunología , Linfocitos T/microbiología , Linfocitos T/patología , TranscriptomaRESUMEN
BACKGROUND: This study evaluates implementation strategies for leprosy diagnosis based on responses to a Leprosy Suspicion Questionnaire (LSQ), and analyzes immunoepidemiological aspects and follow-up of individuals living in a presumptively nonendemic area in Brazil. METHODOLOGY/PRINCIPAL FINDINGS: Quasi-experimental study based on LSQ throughout Jardinópolis town by community health agents, theoretical-practical trainings for primary care teams, dermatoneurological examination, anti-PGL-I serology, RLEP-PCR, and spatial epidemiology. A Leprosy Group (LG, n = 64) and Non-Leprosy Group (NLG, n = 415) were established. Overall, 3,241 LSQs were distributed; 1,054 (32.5%) LSQ were positive for signs/symptoms (LSQ+). Among LSQ+ respondents, Q2-Tingling (pricking)? (11.8%); Q4-Spots on the skin? (11.7%); Q7-Pain in the nerves? (11.6%); Q1-Numbness in your hands and/or feet? (10.7%) and Q8-Swelling of hands and feet? (8.5%) were most frequently reported symptoms. We evaluated 479 (14.8%) individuals and diagnosed 64 new cases, a general new case detection rate (NCDR) of 13.4%; 60 were among 300 LSQ+ (NCDR-20%), while 4 were among 179 LSQ negative (NCDR-2.23%). In LG, Q7(65%), Q2(60%), Q1(45%), Q4(40%) and Q8(25%) were most frequent. All 2x2 crossings of these 5 questions showed a relative risk for leprosy ranging from 3 to 5.8 compared with NLG. All patients were multibacillary and presented hypochromatic macules with loss of sensation. LG anti-PGL-I titers were higher than NLG, while 8.9% were positive for RLEP-PCR. The leprosy cases and anti-PGL-I spatial mappings demonstrated the disease spread across the town. CONCLUSIONS/SIGNIFICANCE: Implementation actions, primarily LSQ administration focused on neurological symptoms, indicate hidden endemic leprosy in a nonendemic Brazilian state.
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Agentes Comunitarios de Salud/educación , Lepra/diagnóstico , Lepra/epidemiología , Mycobacterium leprae/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Brasil/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mycobacterium leprae/genética , Mycobacterium leprae/aislamiento & purificación , Prevalencia , Encuestas y CuestionariosRESUMEN
Leprosy is a disease with a clinical spectrum of presentations that is also manifested in diverse histological features. At one pole, lepromatous lesions (L-pole) have phagocytic foamy macrophages heavily parasitized with freely multiplying intracellular Mycobacterium leprae. At the other pole, the presence of epithelioid giant cells and granulomatous formation in tuberculoid lesions (T-pole) lead to the control of M. leprae replication and the containment of its spread. The mechanism that triggers this polarization is unknown, but macrophages are central in this process. Over the past few years, leprosy has been studied using large scale techniques to shed light on the basic pathways that, upon infection, rewire the host cellular metabolism and gene expression. M. leprae is particularly peculiar as it invades Schwann cells in the nerves, reprogramming their gene expression leading to a stem-like cell phenotype. This modulatory behavior exerted by M. leprae is also observed in skin macrophages. Here, we used live M. leprae to infect (10:1 multiplicity of infection) monocyte-derived macrophages (MDMs) for 48 h and analyzed the whole gene expression profile using microarrays. In this model, we observe an intense upregulation of genes consistent with a cellular immune response, with enriched pathways including peptide and protein secretion, leukocyte activation, inflammation, and cellular divalent inorganic cation homeostasis. Among the most differentially expressed genes (DEGs) are CCL5/RANTES and CYP27B1, and several members of the metallothionein and metalloproteinase families. This is consistent with a proinflammatory state that would resemble macrophage rewiring toward granulomatous formation observed at the T-pole. Furthermore, a comparison with a dataset retrieved from the Gene Expression Omnibus of M. leprae-infected Schwann cells (MOI 100:1) showed that the patterns among the DEGs are highly distinct, as the Schwann cells under these conditions had a scavenging and phagocytic gene profile similar to M2-like macrophages, with enriched pathways rearrangements in the cytoskeleton, lipid and cholesterol metabolism and upregulated genes including MVK, MSMO1, and LACC1/FAMIN. In summary, macrophages may have a central role in defining the paradigmatic cellular (T-pole) vs. humoral (L-pole) responses and it is likely that the multiplicity of infection and genetic polymorphisms in key genes are gearing this polarization.