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1.
F1000Res ; 92020.
Artículo en Inglés | MEDLINE | ID: mdl-32051758

RESUMEN

Chronic infection by the obligate intracellular pathogen Mycobacterium leprae may lead to the development of leprosy. Of note, in the lepromatous clinical form of the disease, failure of the immune system to constrain infection allows the pathogen to reproduce to very high numbers with minimal clinical signs, favoring transmission. The bacillus can modulate cellular metabolism to support its survival, and these changes directly influence immune responses, leading to host tolerance, permanent disease, and dissemination. Among the metabolic changes, upregulation of cholesterol, phospholipids, and fatty acid biosynthesis is particularly important, as it leads to lipid accumulation in the host cells (macrophages and Schwann cells) in the form of lipid droplets, which are sites of polyunsaturated fatty acid-derived lipid mediator biosynthesis that modulate the inflammatory and immune responses. In Schwann cells, energy metabolism is also subverted to support a lipogenic environment. Furthermore, effects on tryptophan and iron metabolisms favor pathogen survival with moderate tissue damage. This review discusses the implications of metabolic changes on the course of M. leprae infection and host immune response and emphasizes the induction of regulatory T cells, which may play a pivotal role in immune modulation in leprosy.

2.
Cell Microbiol ; 22(1): e13128, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31652371

RESUMEN

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

3.
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
4.
PLoS Negl Trop Dis ; 13(9): e0007368, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31504035

RESUMEN

Up to 50% of patients with the multibacillary form of leprosy are expected to develop acute systemic inflammatory episodes known as type 2 reactions (T2R), thus aggravating their clinical status. Thalidomide rapidly improves T2R symptoms. But, due to its restricted use worldwide, novel alternative therapies are urgently needed. The T2R triggering mechanisms and immune-inflammatory pathways involved in its pathology remain ill defined. In a recent report, we defined the recognition of nucleic acids by TLR9 as a major innate immunity pathway that is activated during T2R. DNA recognition has been described as a major inflammatory pathway in several autoimmune diseases, and neutrophil DNA extracellular traps (NETs) have been shown to be a prime source of endogenous DNA. Considering that neutrophil abundance is a marked characteristic of T2R lesions, the objective of this study was to investigate NETs production in T2R patients based on the hypothesis that the excessive NETs formation would play a major role in T2R pathogenesis. Abundant NETs were found in T2R skin lesions, and increased spontaneous NETs formation was observed in T2R peripheral neutrophils. Both the M. leprae whole-cell sonicate and the CpG-Hlp complex, mimicking a mycobacterial TLR9 ligand, were able to induce NETs production in vitro. Moreover, TLR9 expression was shown to be higher in T2R neutrophils, suggesting that DNA recognition via TLR9 may be one of the pathways triggering this process during T2R. Finally, treatment of T2R patients with thalidomide for 7 consecutive days resulted in a decrease in all of the evaluated in vivo and ex vivo NETosis parameters. Altogether, our findings shed light on the pathogenesis of T2R, which, it is hoped, will contribute to the emergence of novel alternative therapies and the identification of prognostic reactional markers in the near future.


Asunto(s)
Trampas Extracelulares/inmunología , Inmunidad Innata , Lepra/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/microbiología , Femenino , Humanos , Inflamación/inmunología , Inflamación/patología , Lepra/tratamiento farmacológico , Lepra/patología , Masculino , Persona de Mediana Edad , Mycobacterium leprae/inmunología , Mycobacterium leprae/patogenicidad , Neutrófilos/patología , Talidomida/administración & dosificación , Talidomida/uso terapéutico
5.
Mem Inst Oswaldo Cruz ; 114: e180579, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30970080

RESUMEN

BACKGROUND: CD64 (FcγR1) is a high-affinity receptor for monomeric IgG1 and IgG3. Circulating neutrophils express very low amounts of CD64 on their surface. OBJECTIVES: Our primary aim was to investigate the utility of neutrophil CD64 surface expression as a biomarker of active pulmonary tuberculosis (TB). We hypothesised that elevated neutrophil CD64 expression in TB infection would be associated with interferon gamma (IFN-γ) as an inducer of CD64 expression. METHODS: The expression level of CD64 per neutrophil (PMN CD64 index) was quantitatively measured with flow cytometry using a Leuko64 kit in samples from patients with TB and latent TB infection (LTBI) as well as healthy controls, as part of a prospective cohort study in Brazil. FINDINGS: The PMN CD64 index in patients with TB was higher than that in healthy controls and LTBI. Receiver operating characteristic curve analyses determined that the PMN CD64 index could discriminate patients with TB from those with LTBI and healthy individuals. PMN CD64 index levels returned to baseline levels after treatment. CONCLUSIONS: The positive regulation of CD64 expression in circulating neutrophils of patients with active TB could represent an additional biomarker for diagnosis of active TB and could be used for monitoring individuals with LTBI before progression of TB disease.


Asunto(s)
Tuberculosis Latente/diagnóstico , Neutrófilos/inmunología , Receptores de IgG/inmunología , Adulto , Biomarcadores/análisis , Estudios de Casos y Controles , Femenino , Citometría de Flujo , Humanos , Ensayos de Liberación de Interferón gamma , Tuberculosis Latente/inmunología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Curva ROC , Receptores de IgG/metabolismo , Sensibilidad y Especificidad
6.
Mem. Inst. Oswaldo Cruz ; 114: e180579, 2019. tab, graf
Artículo en Inglés | LILACS | ID: biblio-1002686

RESUMEN

BACKGROUND CD64 (FcγR1) is a high-affinity receptor for monomeric IgG1 and IgG3. Circulating neutrophils express very low amounts of CD64 on their surface. OBJECTIVES Our primary aim was to investigate the utility of neutrophil CD64 surface expression as a biomarker of active pulmonary tuberculosis (TB). We hypothesised that elevated neutrophil CD64 expression in TB infection would be associated with interferon gamma (IFN-γ) as an inducer of CD64 expression. METHODS The expression level of CD64 per neutrophil (PMN CD64 index) was quantitatively measured with flow cytometry using a Leuko64 kit in samples from patients with TB and latent TB infection (LTBI) as well as healthy controls, as part of a prospective cohort study in Brazil. FINDINGS The PMN CD64 index in patients with TB was higher than that in healthy controls and LTBI. Receiver operating characteristic curve analyses determined that the PMN CD64 index could discriminate patients with TB from those with LTBI and healthy individuals. PMN CD64 index levels returned to baseline levels after treatment. CONCLUSIONS The positive regulation of CD64 expression in circulating neutrophils of patients with active TB could represent an additional biomarker for diagnosis of active TB and could be used for monitoring individuals with LTBI before progression of TB disease.


Asunto(s)
Humanos , Biomarcadores/análisis , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/inmunología , Citometría de Flujo , Estudios de Casos y Controles , Estudios Prospectivos , Ensayos de Liberación de Interferón gamma , Neutrófilos/inmunología
7.
PLoS Negl Trop Dis ; 12(12): e0007001, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30566440

RESUMEN

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


Asunto(s)
Vectores Arácnidos/fisiología , Ixodes/microbiología , Ixodidae/microbiología , Lepra/transmisión , Mycobacterium leprae/fisiología , Animales , Vectores Arácnidos/microbiología , Línea Celular , Femenino , Humanos , Ixodes/fisiología , Ixodidae/fisiología , Lepra/microbiología , Masculino , Mycobacterium leprae/genética , Conejos
8.
Cytokine ; 112: 87-94, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30017389

RESUMEN

The disease leprosy is caused by Mycobacterium leprae. The disease displays a spectrum of clinical manifestations relating to the stage of the infection and the pathogen-specific immune response. The most frequent M. leprae-specific hypersensitivity reactions are erythema nodosum leprosum (ENL) and type-1 (reversal) reaction (T1R). Omega-3 and omega-6 fatty acid-derived lipid mediators are involved in the regulation of these M. leprae-specific inflammatory and immune responses. Studies on lipid mediators showed their presence during different manifestations of leprosy-before and after multidrug therapy (MDT) and during T1R. This review aims to compare the lipid mediators at different stages of the disease. This review also presents new data on the significance of lipid mediators (cysteinyl leukotrienes and leukotriene B4, prostaglandin E2 and D2, lipoxin A4 and resolvin D1) on ENL.


Asunto(s)
Ácidos Grasos Omega-3/sangre , Ácidos Grasos Omega-6/sangre , Lepra/sangre , Animales , Quimioterapia Combinada , Eritema Nudoso/sangre , Eritema Nudoso/tratamiento farmacológico , Humanos , Leprostáticos/farmacología , Lepra/tratamiento farmacológico , Mycobacterium leprae/efectos de los fármacos
9.
PLoS Pathog ; 14(7): e1007151, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29979790

RESUMEN

Mycobacterium leprae, an obligate intracellular bacillus, infects Schwann cells (SCs), leading to peripheral nerve damage, the most severe leprosy symptom. In the present study, we revisited the involvement of phenolic glycolipid I (PGL I), an abundant, private, surface M. leprae molecule, in M. leprae-SC interaction by using a recombinant strain of M. bovis BCG engineered to express this glycolipid. We demonstrate that PGL I is essential for bacterial adhesion and SC internalization. We also show that live mycobacterium-producing PGL I induces the expression of the endocytic mannose receptor (MR/CD206) in infected cells in a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent manner. Of note, blocking mannose recognition decreased bacterial entry and survival, pointing to a role for this alternative recognition pathway in bacterial pathogenesis in the nerve. Moreover, an active crosstalk between CD206 and the nuclear receptor PPARγ was detected that led to the induction of lipid droplets (LDs) formation and prostaglandin E2 (PGE2), previously described as fundamental players in bacterial pathogenesis. Finally, this pathway was shown to induce IL-8 secretion. Altogether, our study provides evidence that the entry of live M. leprae through PGL I recognition modulates the SC phenotype, favoring intracellular bacterial persistence with the concomitant secretion of inflammatory mediators that may ultimately be involved in neuroinflammation.


Asunto(s)
Antígenos Bacterianos/metabolismo , Glucolípidos/metabolismo , Lectinas Tipo C/metabolismo , Lepra/metabolismo , Lectinas de Unión a Manosa/metabolismo , PPAR gamma/metabolismo , Receptores de Superficie Celular/metabolismo , Células de Schwann/virología , Humanos , Mycobacterium leprae/metabolismo , Receptor Cross-Talk/fisiología
10.
Front Immunol ; 9: 518, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29643852

RESUMEN

Leprosy is an infectious disease that may present different clinical forms depending on host immune response to Mycobacterium leprae. Several studies have clarified the role of various T cell populations in leprosy; however, recent evidences suggest that local innate immune mechanisms are key determinants in driving the disease to its different clinical manifestations. Leprosy is an ideal model to study the immunoregulatory role of innate immune molecules and its interaction with nervous system, which can affect homeostasis and contribute to the development of inflammatory episodes during the course of the disease. Macrophages, dendritic cells, neutrophils, and keratinocytes are the major cell populations studied and the comprehension of the complex networking created by cytokine release, lipid and iron metabolism, as well as antimicrobial effector pathways might provide data that will help in the development of new strategies for leprosy management.


Asunto(s)
Inmunidad Innata , Lepra/inmunología , Animales , Humanos , Lepra/patología , Lepra/transmisión , Mycobacterium leprae/fisiología
11.
PLoS Negl Trop Dis ; 12(3): e0006214, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29565968

RESUMEN

BACKGROUND: Leprosy is a chronic dermato-neurological disease caused by Mycobacterium leprae infection. In 2016, more than 200,000 new cases of leprosy were detected around the world, representing the most frequent cause of infectious irreversible deformities and disabilities. PRINCIPAL FINDINGS: In the present work, we demonstrate a consistent procoagulant profile on 40 reactional and non-reactional multibacillary leprosy patients. A retrospective analysis in search of signs of coagulation abnormalities among 638 leprosy patients identified 35 leprosy patients (5.48%) which displayed a characteristic lipid-like clot formed between blood clot and serum during serum harvesting, herein named 'leprosum clot'. Most of these patients (n = 16, 45.7%) belonged to the lepromatous leprosy pole of the disease. In addition, formation of the leprosum clot was directly correlated with increased plasma levels of soluble tissue factor and von Willebrand factor. High performance thin layer chromatography demonstrated a high content of neutral lipids in the leprosum clot, and proteomic analysis demonstrated that the leprosum clot presented in these patients is highly enriched in fibrin. Remarkably, differential 2D-proteomics analysis between leprosum clots and control clots identified two proteins present only in leprosy patients clots: complement component 3 and 4 and inter-alpha-trypsin inhibitor family heavy chain-related protein (IHRP). In agreement with those observations we demonstrated that M. leprae induces hepatocytes release of IHRP in vitro. CONCLUSIONS: We demonstrated that leprosy MB patients develop a procoagulant status due to high levels of plasmatic fibrinogen, anti-cardiolipin antibodies, von Willebrand factor and soluble tissue factor. We propose that some of these components, fibrinogen for example, presents potential as predictive biomarkers of leprosy reactions, generating tools for earlier diagnosis and treatment of these events.


Asunto(s)
Trastornos de la Coagulación Sanguínea/microbiología , Eritema Nudoso/sangre , Lepra Lepromatosa/sangre , Piel/microbiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Brasil , Niño , Electroforesis en Gel Bidimensional , Electroforesis en Gel de Poliacrilamida , Eritema Nudoso/complicaciones , Femenino , Humanos , Lepra Lepromatosa/complicaciones , Modelos Lineales , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Mycobacterium leprae/aislamiento & purificación , Estudios Prospectivos , Proteómica/métodos , Estudios Retrospectivos , Adulto Joven
12.
s.l; s.n; 2018. 25 p. ilu, tab, graf.
No convencional en Inglés | Sec. Est. Saúde SP, HANSEN, SESSP-ILSLPROD, Sec. Est. Saúde SP, SESSP-ILSLACERVO, Sec. Est. Saúde SP | ID: biblio-1025298

RESUMEN

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


Asunto(s)
Humanos , Animales , Masculino , Femenino , Conejos , Vectores Arácnidos/fisiología , Vectores Arácnidos/microbiología , Línea Celular , Ixodes/fisiología , Ixodes/microbiología , Ixodidae/fisiología , Ixodidae/microbiología , Lepra/microbiología , Lepra/transmisión , Mycobacterium leprae/fisiología , Mycobacterium leprae/genética
13.
s.l; s.n; 2018. 20 p. ilus, tab, graf.
No convencional en Inglés | Sec. Est. Saúde SP, HANSEN, SESSP-ILSLPROD, Sec. Est. Saúde SP, SESSP-ILSLACERVO, Sec. Est. Saúde SP | ID: biblio-1023805

RESUMEN

Hemostatic illnesses are frequently associated with acute and chronic infections. In the present work we demonstrated that leprosy patients developed hemostatic abnormalities, like the formation of an atypical lipid clot mass during sera harvesting, a phenomenon previously observed and never unraveled. We characterize the nature of the "leprosum clot", formed during a protrombotic state developed by some patients. During the proteomic analysis of the leprosum clot we discovered a set of potential serum biomarkers to leprosy reactional episodes diagnosis, which at this moment is based only in clinical features. Taking together, our data suggest that leprosy patients are suffering from a procoagulant status, being beneficiated by the introduction of routine coagulation tests during their treatment, which will aloud physicians to prevent some of the acute clinical symptoms related with superficial vein thrombosis such as cyanosis and tissue necrosis observed during severe cases of leprosy reactional episodes. (AU)


Asunto(s)
Humanos , Masculino , Femenino , Niño , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Adulto Joven , Piel/microbiología , Espectrometría de Masas , Trastornos de la Coagulación Sanguínea/microbiología , Biomarcadores/sangre , Electroforesis en Gel Bidimensional , Lepra Lepromatosa/complicaciones , Lepra Lepromatosa/sangre , Modelos Lineales , Proteómica/métodos , Electroforesis en Gel de Poliacrilamida , Eritema Nudoso/complicaciones , Eritema Nudoso/sangre , Mycobacterium leprae/aislamiento & purificación , Estudios Prospectivos , Estudios Retrospectivos
14.
PLoS Negl Trop Dis ; 11(5): e0005560, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28467415

RESUMEN

Household contacts of multibacillary leprosy patients (HCMB) constitute the group of individuals at the highest risk of developing leprosy. Early diagnosis and treatment of their index cases combined with Bacille Calmette-Guerin (BCG) immunization remain important strategies adopted in Brazil to prevent HCMB from evolving into active disease. In the present study, we assessed the impact of these measures on the immune response to Mycobacterium leprae in HCMB. Peripheral blood mononuclear cells (PBMC) from HCMB (n = 16) were obtained at the beginning of leprosy index case treatment (T0). At this time point, contacts were vaccinated (n = 13) or not (n = 3) in accordance with their infancy history of BCG vaccination and PBMCs were recollected at least 6 months later (T1). As expected, a significant increase in memory CD4 and CD8 T cell frequencies responsive to M. leprae whole-cell sonicate was observed in most contacts. Of note, higher frequencies of CD4+ T cells that recognize M. leprae specific epitopes were also detected. Moreover, increased production of the inflammatory mediators IL1-ß, IL-6, IL-17, TNF, IFN-γ, MIP1-ß, and MCP-1 was found at T1. Interestingly, the increment in these parameters was observed even in those contacts that were not BCG vaccinated at T0. This result reinforces the hypothesis that the continuous exposure of HCMB to live M. leprae down regulates the specific cellular immune response against the pathogen. Moreover, our data suggest that BCG vaccination of HCMB induces activation of T cell clones, likely through "trained immunity", that recognize M. leprae specific antigens not shared with BCG as an additional protective mechanism besides the expected boost in cell-mediated immunity by BCG homologues of M. leprae antigens.


Asunto(s)
Antígenos Bacterianos/inmunología , Vacuna BCG/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Inmunidad Celular , Lepra Multibacilar/inmunología , Adulto , Anticuerpos Antibacterianos/sangre , Brasil , Linfocitos T CD8-positivos/inmunología , Citocinas/metabolismo , Epítopos de Linfocito T/inmunología , Composición Familiar , Femenino , Humanos , Inmunoglobulina M/sangre , Lepra Multibacilar/prevención & control , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Mycobacterium leprae , Estudios Prospectivos , Adulto Joven
15.
J Infect Dis ; 215(3): 431-439, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-27932613

RESUMEN

Background: Type 1 reaction (T1R) is an acute T-helper type 1 (Th1) inflammatory episode in patients with leprosy. While immunological responses associated with T1R have been investigated, the corresponding metabolic responses that could contribute to T1R pathology have received little attention. Methods: Metabolomics-based analyses of sera from 7 patients with and 9 without T1R were conducted via liquid chromatography-mass spectrometry. Serum metabolites present at levels that significantly differed (P < .05) with a log2 fold change of ≥ 1.0 between patient groups were interrogated against known metabolic pathways. The structural identification of targeted metabolites was confirmed and abundance changes validated by mass spectrometry and enzyme-linked immunoassay. Results: Forty metabolic pathways were perturbed in patients with T1R, with 71 dysregulated metabolites mapping to pathways for lipid mediators of inflammation. Of note was an increase in the abundance of the proinflammatory leukotriene B4 (LTB4) and a corresponding decrease in the level of proresolving resolvin D1 (RvD1). Also, levels of prostaglandin D2 (PGD2) and lipoxin A4 (LXA4) in patients with T1R were significantly increased, while the level of prostaglandin E2 (PGE2) was decreased. Conclusions: The dysregulation of metabolic pathways leading to abundance shifts between proinflammatory and proresolving lipid mediators provides a link between metabolic and cellular immune responses that result in the Th1-mediated pathology of T1R.


Asunto(s)
Mediadores de Inflamación/metabolismo , Lepra/inmunología , Lípidos/inmunología , Células TH1/inmunología , Adulto , Anciano , Antígenos Bacterianos/inmunología , Cromatografía Liquida , Ácidos Grasos Insaturados/inmunología , Femenino , Glucolípidos/inmunología , Humanos , Lepra/metabolismo , Masculino , Espectrometría de Masas , Redes y Vías Metabólicas , Metabolómica , Persona de Mediana Edad , Mycobacterium leprae/inmunología
17.
J Biol Chem ; 291(41): 21375-21387, 2016 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-27555322

RESUMEN

Mycobacterium leprae, the intracellular etiological agent of leprosy, infects Schwann promoting irreversible physical disabilities and deformities. These cells are responsible for myelination and maintenance of axonal energy metabolism through export of metabolites, such as lactate and pyruvate. In the present work, we observed that infected Schwann cells increase glucose uptake with a concomitant increase in glucose-6-phosphate dehydrogenase (G6PDH) activity, the key enzyme of the oxidative pentose pathway. We also observed a mitochondria shutdown in infected cells and mitochondrial swelling in pure neural leprosy nerves. The classic Warburg effect described in macrophages infected by Mycobacterium avium was not observed in our model, which presented a drastic reduction in lactate generation and release by infected Schwann cells. This effect was followed by a decrease in lactate dehydrogenase isoform M (LDH-M) activity and an increase in cellular protection against hydrogen peroxide insult in a pentose phosphate pathway and GSH-dependent manner. M. leprae infection success was also dependent of the glutathione antioxidant system and its main reducing power source, the pentose pathway, as demonstrated by a 50 and 70% drop in intracellular viability after treatment with the GSH synthesis inhibitor buthionine sulfoximine, and aminonicotinamide (6-ANAM), an inhibitor of G6PDH 6-ANAM, respectively. We concluded that M. leprae could modulate host cell glucose metabolism to increase the cellular reducing power generation, facilitating glutathione regeneration and consequently free-radical control. The impact of this regulation in leprosy neuropathy is discussed.


Asunto(s)
Metabolismo Energético , Glucosa/metabolismo , Glucosafosfato Deshidrogenasa/metabolismo , Ácido Láctico/metabolismo , Lepra Tuberculoide/metabolismo , Mycobacterium leprae/metabolismo , Células de Schwann/metabolismo , Línea Celular , Humanos , Metionina/análogos & derivados , Metionina/farmacología , Mitocondrias/metabolismo , Células de Schwann/microbiología
18.
Sci Rep ; 6: 27632, 2016 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-27282338

RESUMEN

Mycobacterium leprae (ML), the etiologic agent of leprosy, can subvert macrophage antimicrobial activity by mechanisms that remain only partially understood. In the present study, the participation of hormone insulin-like growth factor I (IGF-I) in this phenomenum was investigated. Macrophages from the dermal lesions of the disseminated multibacillary lepromatous form (LL) of leprosy expressed higher levels of IGF-I than those from the self-limited paucibacillary tuberculoid form (BT). Higher levels of IGF-I secretion by ML-infected macrophages were confirmed in ex vivo and in vitro studies. Of note, the dampening of IGF-I signaling reverted the capacity of ML-infected human and murine macrophages to produce antimicrobial molecules and promoted bacterial killing. Moreover, IGF-I was shown to inhibit the JAK/STAT1-dependent signaling pathways triggered by both mycobacteria and IFN-γ most probably through its capacity to induce the suppressor of cytokine signaling-3 (SOCS3). Finally, these in vitro findings were corroborated by in vivo observations in which higher SOCS3 expression and lower phosphorylation of STAT1 levels were found in LL versus BT dermal lesions. Altogether, our data strongly suggest that IGF-I contributes to the maintenance of a functional program in infected macrophages that suits ML persistence in the host, reinforcing a key role for IGF-I in leprosy pathogenesis.


Asunto(s)
Factor I del Crecimiento Similar a la Insulina/metabolismo , Lepra/inmunología , Macrófagos/inmunología , Mycobacterium leprae/patogenicidad , Adulto , Animales , Línea Celular , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Quinasas Janus/metabolismo , Lepra/microbiología , Macrófagos/microbiología , Masculino , Ratones , Factor de Transcripción STAT1/metabolismo
19.
J Infect Dis ; 214(2): 311-20, 2016 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-27190175

RESUMEN

Cytosolic detection of nucleic acids elicits a type I interferon (IFN) response and plays a critical role in host defense against intracellular pathogens. Herein, a global gene expression profile of Mycobacterium leprae-infected primary human Schwann cells identified the genes differentially expressed in the type I IFN pathway. Among them, the gene encoding 2'-5' oligoadenylate synthetase-like (OASL) underwent the greatest upregulation and was also shown to be upregulated in M. leprae-infected human macrophage cell lineages, primary monocytes, and skin lesion specimens from patients with a disseminated form of leprosy. OASL knock down was associated with decreased viability of M. leprae that was concomitant with upregulation of either antimicrobial peptide expression or autophagy levels. Downregulation of MCP-1/CCL2 release was also observed during OASL knock down. M. leprae-mediated OASL expression was dependent on cytosolic DNA sensing mediated by stimulator of IFN genes signaling. The addition of M. leprae DNA enhanced nonpathogenic Mycobacterium bovis bacillus Calmette-Guerin intracellular survival, downregulated antimicrobial peptide expression, and increased MCP-1/CCL2 secretion. Thus, our data uncover a promycobacterial role for OASL during M. leprae infection that directs the host immune response toward a niche that permits survival of the pathogen.


Asunto(s)
2',5'-Oligoadenilato Sintetasa/metabolismo , Interacciones Huésped-Patógeno , Proteínas de la Membrana/metabolismo , Viabilidad Microbiana , Mycobacterium leprae/fisiología , Células de Schwann/microbiología , Células Cultivadas , Células Epiteliales/microbiología , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Lepra/microbiología , Lepra/patología , Macrófagos/microbiología , Mycobacterium bovis/fisiología
20.
PLoS One ; 11(5): e0156037, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27203082

RESUMEN

Leprosy is a chronic dermato-neurological disease caused by infection with Mycobacterium leprae. In 2013 almost 200,000 new cases of leprosy were detected around the world. Since the first symptoms take from years to decades to appear, the total number of asymptomatic patients is impossible to predict. Although leprosy is one of the oldest records of human disease, the mechanisms involved with its transmission and epidemiology are still not completely understood. In the present work, we experimentally investigated the hypothesis that the mosquitoes Aedes aegypti and Culex quinquefasciatus and the hemiptera Rhodnius prolixus act as leprosy vectors. By means of real-time PCR quantification of M. leprae 16SrRNA, we found that M. leprae remained viable inside the digestive tract of Rhodnius prolixus for 20 days after oral infection. In contrast, in the gut of both mosquito species tested, we were not able to detect M. leprae RNA after a similar period of time. Inside the kissing bug Rhodnius prolixus digestive tract, M. leprae was initially restricted to the anterior midgut, but gradually moved towards the hindgut, in a time course reminiscent of the life cycle of Trypanosoma cruzi, a well-known pathogen transmitted by this insect. The maintenance of M. leprae infectivity inside the digestive tract of this kissing bug is further supported by successful mice footpad inoculation with feces collected 20 days after infection. We conclude that Rhodnius prolixus defecate infective M. leprae, justifying the evaluation of the presence of M. leprae among sylvatic and domestic kissing bugs in countries endemic for leprosy.


Asunto(s)
Lepra/microbiología , Lepra/transmisión , Mycobacterium leprae/patogenicidad , Rhodnius/microbiología , Animales , Heces/microbiología , Humanos , Lepra/genética , Microscopía Fluorescente , ARN Ribosómico 16S/genética , Reacción en Cadena en Tiempo Real de la Polimerasa
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