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1.
Front Immunol ; 12: 657449, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34456901

RESUMO

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.


Assuntos
Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/metabolismo , Imunidade Inata , Hanseníase/imunologia , Hanseníase/metabolismo , Mycobacterium leprae/imunologia , Receptor Toll-Like 9/metabolismo , Células A549 , Biomarcadores , Células Cultivadas , Histonas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunomodulação , Hanseníase/microbiologia , NF-kappa B/metabolismo
2.
Immunol Rev ; 301(1): 193-208, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33913182

RESUMO

Leprosy is a much-feared incapacitating infectious disease caused by Mycobacterium leprae or M lepromatosis, annually affecting roughly 200,000 people worldwide. During host-pathogen interaction, M leprae subverts the immune response, leading to development of disease. Throughout the last few decades, the impact of energy metabolism on the control of intracellular pathogens and leukocytic differentiation has become more evident. Mitochondria play a key role in regulating newly-discovered immune signaling pathways by controlling redox metabolism and the flow of energy besides activating inflammasome, xenophagy, and apoptosis. Likewise, this organelle, whose origin is probably an alphaproteobacterium, directly controls the intracellular pathogens attempting to invade its niche, a feature conquered at the expense of billions of years of coevolution. In the present review, we discuss the role of reduced host cell mitochondrial activity during M leprae infection and the consequential fates of M leprae and host innate immunity. Conceivably, inhibition of mitochondrial energy metabolism emerges as an overlooked and novel mechanism developed by M leprae to evade xenophagy and the host immune response.


Assuntos
Hanseníase , Mycobacterium leprae , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Mitocôndrias
3.
Immunol Rev ; 301(1): 30-47, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33529407

RESUMO

Vaccination strategies against mycobacteria, focusing mostly on classical T- and B-cells, have shown limited success, encouraging the addition of alternative targets. Classically restricted T-cells recognize antigens presented via highly polymorphic HLA class Ia and class II molecules, while donor-unrestricted T-cells (DURTs), with few exceptions, recognize ligands via genetically conserved antigen presentation molecules. Consequently, DURTs can respond to the same ligands across diverse human populations. DURTs can be activated either through cognate TCR ligation or via bystander cytokine signaling. TCR-driven antigen-specific activation of DURTs occurs upon antigen presentation via non-polymorphic molecules such as HLA-E, CD1, MR1, and butyrophilin, leading to the activation of HLA-E-restricted T-cells, CD1-restricted T-cells, mucosal-associated invariant T-cells (MAITs), and TCRγδ T-cells, respectively. NK cells and innate lymphoid cells (ILCs), which lack rearranged TCRs, are activated through other receptor-triggering pathways, or can be engaged through bystander cytokines, produced, for example, by activated antigen-specific T-cells or phagocytes. NK cells can also develop trained immune memory and thus could represent cells of interest to mobilize by novel vaccines. In this review, we summarize the latest findings regarding the contributions of DURTs, NK cells, and ILCs in anti-M tuberculosis, M leprae, and non-tuberculous mycobacterial immunity and explore possible ways in which they could be harnessed through vaccines and immunotherapies to improve protection against Mtb.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Humanos , Imunidade Inata , Células Matadoras Naturais , Receptores de Antígenos de Linfócitos T gama-delta
4.
Bull Exp Biol Med ; 169(6): 836-839, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33098510

RESUMO

Leprosy was modeled in an experiment on BALB/c, BALB/cNude, CBA, and C57BL/6ТNF-/- mice using three Mycobacterium leprae strains obtained from patients with a diagnosis of A30 according to ICD-10 from different regions of the Russian Federation. Proliferation of M. leprae of the used strains showed a temporal-quantitative dependence on the used mouse line. CBA and BALB/cNude mice were optimal for strain R and BALB/c and BALB/cNude lines were optimal for strain I. BALB/cNude mice infected with strain I had low lifespan. M. leprae strain M showed low proliferation activity in BALB/cNude and C57BL/6ТNF-/- mice.


Assuntos
Imunidade Adaptativa , Imunidade Inata , Hanseníase/imunologia , Longevidade/imunologia , Mycobacterium leprae/patogenicidade , Fator de Necrose Tumoral alfa/imunologia , Animais , DNA Bacteriano/genética , Modelos Animais de Doenças , Especificidade de Hospedeiro , Humanos , Hanseníase/genética , Hanseníase/microbiologia , Hanseníase/patologia , Longevidade/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Camundongos Nus , Mycobacterium leprae/genética , Mycobacterium leprae/crescimento & desenvolvimento , Mycobacterium leprae/imunologia , Fator de Necrose Tumoral alfa/deficiência , Fator de Necrose Tumoral alfa/genética
5.
Front Immunol ; 11: 1811, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849645

RESUMO

Leprosy is a chronic infectious disease, caused by Mycobacterium leprae, that can lead to severe life-long disabilities. The transmission of M. leprae is continuously ongoing as witnessed by the stable new case detection rate. The majority of exposed individuals does, however, not develop leprosy and is protected from infection by innate immune mechanisms. In this study the relation between innate immune markers and M. leprae infection as well as the occurrence of leprosy was studied in household contacts (HCs) of leprosy patients with high bacillary loads. Serum proteins associated with innate immunity (ApoA1, CCL4, CRP, IL-1Ra, IL-6, IP-10, and S100A12) were determined by lateral flow assays (LFAs) in conjunction with the presence of M. leprae DNA in nasal swabs (NS) and/or slit-skin smears (SSS). The HCs displayed ApoA1 and S100A12 levels similar to paucibacillary patients and could be differentiated from endemic controls based on the levels of these markers. In the 31 households included the number (percentage) of HCs that were concomitantly diagnosed with leprosy, or tested positive for M. leprae DNA in NS and SSS, was not equally divided. Specifically, households where M. leprae infection and leprosy disease was not observed amongst members of the household were characterized by higher S100A12 and lower CCL4 levels in whole blood assays of HCs in response to M. leprae. Lateral flow assays provide a convenient diagnostic tool to quantitatively measure markers of the innate immune response and thereby detect individuals which are likely infected with M. leprae and at risk of developing disease or transmitting bacteria. Low complexity diagnostic tests measuring innate immunity markers can therefore be applied to help identify who should be targeted for prophylactic treatment.


Assuntos
Infecções Assintomáticas , Imunidade Inata/imunologia , Hanseníase/imunologia , Hanseníase/transmissão , Adolescente , Adulto , Biomarcadores/sangue , Criança , Doenças Endêmicas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
Front Immunol ; 11: 170, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32117300

RESUMO

Diseases due to mycobacteria, including tuberculosis, leprosy, and Buruli ulcer, rank among the top causes of death and disability worldwide. Animal studies have revealed the importance of T cells in controlling these infections. However, the specific antigens recognized by T cells that confer protective immunity and their associated functions remain to be definitively established. T cells that respond to mycobacterial peptide antigens exhibit classical features of adaptive immunity and have been well-studied in humans and animal models. Recently, innate-like T cells that recognize lipid and metabolite antigens have also been implicated. Specifically, T cells that recognize mycobacterial glycolipid antigens (mycolipids) have been shown to confer protection to tuberculosis in animal models and share some biological characteristics with adaptive and innate-like T cells. Here, we review the existing data suggesting that mycolipid-specific T cells exist on a spectrum of "innateness," which will influence how they can be leveraged to develop new diagnostics and vaccines for mycobacterial diseases.


Assuntos
Antígenos de Bactérias/imunologia , Glicolipídeos/imunologia , Imunidade Inata , Mycobacterium tuberculosis/imunologia , Linfócitos T/imunologia , Tuberculose/imunologia , Animais , Humanos , Memória Imunológica , Hanseníase/imunologia , Hanseníase/microbiologia , Ativação Linfocitária/imunologia , Fenótipo , Receptores de Antígenos de Linfócitos T/imunologia , Tuberculose/microbiologia
7.
Dev Comp Immunol ; 105: 103597, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31883447

RESUMO

Beta-glucans from yeast can induce trained immunity in in vitro and in vivo models. Intraperitoneal doses of ß-glucans in mammals have shown to induce trained immunity, but the training effects of orally administering ß-glucans are unknown. Newborn goats are susceptible to infections in the neonatal stage, so the induction of trained immunity could improve animal survival. This study aimed to describe the in vitro effects of immunological training by ß-glucan from Debaryomyces hansenii (ß-Dh) on caprine monocytes, as well as its in vivo effects using oral doses on newborn goats upon challenge with lipopolysaccharide (LPS). Hence in vitro, goat monocytes trained with ß-Dh up-regulated the gene expression of macrophage surface markers (CD11b and F4/80) whereas enhanced cell survival and high phagocytic ability was found upon LPS challenge. In the in vivo experiment, newborn goats stimulated with two doses (day -7 and - 4) of ß-Dh (50 mg/kg) and challenged (day 0) with LPS showed an increase in respiratory burst activity, IL-1ß, IL-6, and TNFα production in plasma, and transcription of the macrophage surface markers. This study has demonstrated for the first time that trained immunity was induced with oral doses of ß-glucan upon LPS challenge in mammals using newborn goats.


Assuntos
Debaryomyces/fisiologia , Cabras/imunologia , Macrófagos/imunologia , Monócitos/imunologia , beta-Glucanas/metabolismo , Administração Oral , Animais , Animais Recém-Nascidos , Células Cultivadas , Citocinas/metabolismo , Imunidade Inata , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/metabolismo , Fagocitose , Explosão Respiratória , beta-Glucanas/imunologia
8.
PLoS Negl Trop Dis ; 13(9): e0007368, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31504035

RESUMO

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.


Assuntos
Armadilhas Extracelulares/imunologia , Imunidade Inata , Hanseníase/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/imunologia , Doenças Autoimunes/microbiologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/patologia , Hanseníase/tratamento farmacológico , Hanseníase/patologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Mycobacterium leprae/patogenicidade , Neutrófilos/patologia , Talidomida/administração & dosagem , Talidomida/uso terapêutico
9.
Front Immunol ; 10: 1125, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231361

RESUMO

Free-ranging Atlantic bottlenose dolphins (n = 360) from two southeastern U.S. estuarine sites were given comprehensive health examinations between 2003 and 2015 as part of a multi-disciplinary research project focused on individual and population health. The study sites (and sample sizes) included the Indian River Lagoon (IRL), Florida, USA (n = 246) and Charleston harbor and associated rivers (CHS), South Carolina, USA (n = 114). Results of a suite of clinicoimmunopathologic tests revealed that both populations have a high prevalence of infectious and neoplastic disease and a variety of abnormalities of their innate and adaptive immune systems. Subclinical infections with cetacean morbillivirus and Chlamydiaceae were detected serologically. Clinical evidence of orogenital papillomatosis was supported by the detection of a new strain of dolphin papillomavirus and herpesvirus by molecular pathology. Dolphins with cutaneous lobomycosis/lacaziasis were subsequently shown to be infected with a novel, uncultivated strain of Paracoccidioides brasiliensis, now established as the etiologic agent of this enigmatic disease in dolphins. In this review, innate and adaptive immunologic responses are compared between healthy dolphins and those with clinical and/or immunopathologic evidence of infection with these specific viral, bacterial, and fungal pathogens. A wide range of immunologic host responses was associated with each pathogen, reflecting the dynamic and complex interplay between the innate, humoral, and cell-mediated immune systems in the dolphin. Collectively, these studies document the comparative innate and adaptive immune responses to various types of infectious diseases in free-ranging Atlantic bottlenose dolphins. Evaluation of the type, pattern, and degree of immunologic response to these pathogens provides novel insight on disease immunopathogenesis in this species and as a comparative model. Importantly, the data suggest that in some cases infection may be associated with subclinical immunopathologic perturbations that could impact overall individual and population health.


Assuntos
Golfinho Nariz-de-Garrafa/imunologia , Infecções por Chlamydiaceae/veterinária , Lobomicose/veterinária , Infecções por Morbillivirus/veterinária , Paracoccidioidomicose/veterinária , Imunidade Adaptativa , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Antifúngicos/sangue , Anticorpos Antivirais/sangue , Oceano Atlântico , Golfinho Nariz-de-Garrafa/sangue , Golfinho Nariz-de-Garrafa/microbiologia , Golfinho Nariz-de-Garrafa/virologia , Infecções por Chlamydiaceae/epidemiologia , Infecções por Chlamydiaceae/imunologia , Coinfecção/veterinária , Doenças Transmissíveis Emergentes/veterinária , Estuários , Imunidade Inata , Lobomicose/epidemiologia , Lobomicose/imunologia , Infecções por Morbillivirus/epidemiologia , Infecções por Morbillivirus/imunologia , Paracoccidioidomicose/epidemiologia , Paracoccidioidomicose/imunologia , South Carolina
10.
J Immunol ; 203(4): 911-921, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31235553

RESUMO

Th17 cells play a critical role in the adaptive immune response against extracellular bacteria, and the possible mechanisms by which they can protect against infection are of particular interest. In this study, we describe, to our knowledge, a novel IL-1ß dependent pathway for secretion of the antimicrobial peptide IL-26 from human Th17 cells that is independent of and more rapid than classical TCR activation. We find that IL-26 is secreted 3 hours after treating PBMCs with Mycobacterium leprae as compared with 48 hours for IFN-γ and IL-17A. IL-1ß was required for microbial ligand induction of IL-26 and was sufficient to stimulate IL-26 release from Th17 cells. Only IL-1RI+ Th17 cells responded to IL-1ß, inducing an NF-κB-regulated transcriptome. Finally, supernatants from IL-1ß-treated memory T cells killed Escherichia coli in an IL-26-dependent manner. These results identify a mechanism by which human IL-1RI+ "antimicrobial Th17 cells" can be rapidly activated by IL-1ß as part of the innate immune response to produce IL-26 to kill extracellular bacteria.


Assuntos
Imunidade Inata/imunologia , Interleucina-1beta/imunologia , Interleucinas/imunologia , Ativação Linfocitária/imunologia , Células Th17/imunologia , Infecções Bacterianas/imunologia , Humanos , Interleucina-1beta/metabolismo , Interleucinas/metabolismo , Células Th17/microbiologia
11.
Int J Paleopathol ; 26: 37-47, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31185376

RESUMO

OBJECTIVE: Our primary objective is to re-visit the tuberculosis and leprosy cross-immunity. hypothesis through the careful integration of immunology and paleopathology. METHODS: Using an integrated theoretical analysis that evaluates clinical literature on human innate immunological responses, paleomicrobiology, bioarchaeology, and paleopathology, we develop a multifactorial model. RESULTS: Past populations do not represent homogeneous immunological landscapes, and therefore it is likely that leprosy in Medieval Europe did not uniformly decline due to cross-immunity. CONCLUSIONS: We recommend that bioarchaeological reconstructions of past disease experience take into consideration models that include variation in immune function based on past environments and social contexts. This provides a unique opportunity to conduct comprehensive analyses on complex immunological processes. SIGNIFICANCE: Extrapolating results from experimental immunology to larger populations elucidates complexities of disease cross-immunity and highlights the importance of synthesizing archaeological, social, paleopathological and biological data as a means of understanding disease in the past. LIMITATIONS: All extrapolations from data produced from in vitro studies to past populations, using living donors, pose significant limitations where, among other factors, the full reconstruction of past environmental and social contexts can frequently be sparse or incomplete. SUGGESTIONS FOR FUTURE RESEARCH: To reduce the limitations of integrating experimental immunology with bioarchaeological reconstructions (i.e. how to use skeletal samples to reconstruct inflammatory phenotypes), we propose that osteoimmunology, or the study of the interplay between immune cells and bone cells, should be considered a vital discipline and perhaps the foundation for the expansion of paleoimmunology.


Assuntos
Alergia e Imunologia , Hanseníase/imunologia , Modelos Imunológicos , Paleopatologia , Tuberculose/imunologia , Arqueologia , Reações Cruzadas , História Medieval , Humanos , Imunidade Inata/imunologia , Tuberculose/história
12.
PLoS Negl Trop Dis ; 13(4): e0007318, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31017900

RESUMO

BACKGROUND: Leprosy, caused by Mycobacterium leprae, affects over 200,000 people annually worldwide and remains endemic in the ethnically diverse, mountainous and underdeveloped southwestern provinces of China. Delayed diagnosis of leprosy persists in China, thus, additional knowledge to support early diagnosis, especially early diagnosis of paucibacillary (PB) patients, based on the host immune responses induced by specific M. leprae antigens is needed. The current study aimed to investigate leprosy patients and controls in Southwest China by comparing supernatants after stimulation with specific M. leprae antigens in an overnight whole-blood assay (WBA) to determine whether host markers induced by specific M. leprae antigens improve the diagnosis or discrimination of PB patients with leprosy. METHODOLOGY/PRINCIPAL FINDINGS: Leprosy patients [13 multibacillary (MB) patients and 7 PB patients] and nonleprosy controls [21 healthy household contacts (HHCs), 20 endemic controls (ECs) and 19 tuberculosis (TB) patients] were enrolled in this study. The supernatant levels of ten host markers stimulated by specific M. leprae antigens were evaluated by overnight WBA and multiplex Luminex assays. The diagnostic value in PB patients and ECs and the discriminatory value between PB patients and HHCs or TB patients were evaluated by receiver operator characteristics (ROC) analysis. ML2044-stimulated CXCL8/IL-8 achieved the highest sensitivity of 100%, with a specificity of 73.68%, for PB diagnosis. Compared to single markers, a 3-marker combination model that included ML2044-induced CXCL8/IL-8, CCL4/MIP-1 beta, and IL-6 improved the diagnostic specificity to 94.7% for PB patients. ML2044-stimulated IL-4 and CXCL8/IL-8 achieved the highest sensitivity (85.71% and 100%) and the highest specificity (95.24% and 84.21%) for discriminating PB patients from HHCs and TB patients, respectively. CONCLUSIONS: Our findings suggest that the host markers induced by specific M. leprae antigens in an overnight WBA increase diagnostic and discriminatory value in PB patients with leprosy, with a particularly strong association with interleukin 8.


Assuntos
Antígenos de Bactérias/imunologia , Sangue/imunologia , Imunidade Inata , Imunoensaio/métodos , Hanseníase Paucibacilar/diagnóstico , Hanseníase Paucibacilar/imunologia , Mycobacterium leprae/imunologia , Adulto , China , Citocinas/análise , Testes Diagnósticos de Rotina/métodos , Feminino , Humanos , Masculino , Curva ROC , Sensibilidade e Especificidade , Adulto Jovem
13.
Appl Microbiol Biotechnol ; 103(5): 2339-2352, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30656393

RESUMO

Several marine Debaryomyces hansenii strains have shown probiotic effects on aquatic animals, and D. hansenii-derived ß-glucans have recently provided immunostimulant effects on goat leukocytes. This study assessed the probiotic effects of live yeast D. hansenii CBS 8339 on newborn goats administered orally, and subsequently challenged in vitro with Escherichia coli. D. hansenii CBS 8339 demonstrated the capacity to survive gastrointestinal tract conditions (bile salts and acid pH tolerance) and adhere to goat intestine. Twelve Saanen × Nubian crossbred newborn goats (2.9 ± 0.47 kg) were fed with a controlled diet or D. hansenii (0.7 g/kg body weight per day)-supplemented milk for 30 days. Blood samples of newborn goats were taken at days 15 and 30, and peripheral blood leukocytes were isolated for bacterial challenge, and immunological and antioxidant analyses. Despite cell viability was higher in leukocytes of goat kids fed with the yeast supplement, protection against E. coli challenge was not significantly affected. On the other hand, at day 15, oral administration of D. hansenii enhanced respiratory burst and catalase activity and increased superoxide dismutase activity after challenge. In contrast, at day 30, administration of the yeast supplement increased peroxidase activity and enhanced nitric oxide production and catalase activity after challenge. Finally, the yeast-supplemented diet upregulated the expression of the receptor genes TLR (2, 4, 6), modulator genes Raf.1, Syk, and Myd88, transcription factor gene AP-1, and cytokine genes IL-1ß and TNF-α only at day 15 in leukocytes from unchallenged goat kids. These results demonstrated that a short time (15 days) of orally administering the probiotic D. hansenii CBS 8339 to newborn goats stimulated innate immune and antioxidant parameters and the expression of immune-related gene signaling pathways.


Assuntos
Animais Recém-Nascidos/microbiologia , Antioxidantes/metabolismo , Debaryomyces/metabolismo , Cabras/microbiologia , Imunidade Inata/imunologia , Probióticos/metabolismo , Animais , Catalase/metabolismo , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/fisiologia , Leucócitos/citologia , Óxido Nítrico/metabolismo , Explosão Respiratória/fisiologia , Superóxido Dismutase/metabolismo , beta-Glucanas/metabolismo
14.
Front Immunol ; 10: 2913, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31921172

RESUMO

Mycobacterium leprae, the causative agent of leprosy, is unique amongst human pathogens in its capacity to produce the virulence factor phenolic glycolipid (PGL)-I. In addition to mediating bacterial tropism for neurons, PGL-I interacts with Complement Receptor (CR)3 on macrophages (MPs) to promote infection. We demonstrate here that PGL-I binding to CR3 also enhances bacterial invasion of both polymorphonuclear neutrophils (PMNs) and dendritic cells (DCs). Moreover, in all cell types CR3 engagement by PGL-I activates the Syk tyrosine kinase, inducing calcineurin-dependent nuclear translocation of the transcription factor NFATc. This selectively augments the production of IL-2 by DCs, IL-10 by PMNs and IL-1ß by MPs. In intranasally-infected mice PGL-I binding to CR3 heightens mycobacterial phagocytosis by lung PMNs and MPs, and stimulates NFATc-controlled production of Syk-dependent cytokines. Our study thus identifies the CR3-Syk-NFATc axis as a novel signaling pathway activated by PGL-I in innate immune cells, rewiring host cytokine responses to M. leprae.


Assuntos
Antígenos de Bactérias/imunologia , Calcineurina/imunologia , Glicolipídeos/imunologia , Imunidade Inata , Hanseníase/imunologia , Antígeno de Macrófago 1/imunologia , Mycobacterium leprae/imunologia , Fatores de Transcrição NFATC/imunologia , Transdução de Sinais/imunologia , Quinase Syk/imunologia , Animais , Calcineurina/genética , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/imunologia , Hanseníase/genética , Antígeno de Macrófago 1/genética , Masculino , Camundongos , Camundongos Knockout , Fatores de Transcrição NFATC/genética , Neutrófilos/imunologia , Fagocitose , Transdução de Sinais/genética , Quinase Syk/genética
15.
PLoS One ; 13(10): e0205234, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30289892

RESUMO

Leprosy is an infectious disease with a complex genetic and immunological background. Polymorphisms in genes that encode cytokines and receptors involved in the immune response, such as the Toll-like receptor 1 (TLR1), may be associated with disease risk. We hypothesized that polymorphisms in innate immunity genes confer susceptibility to leprosy that differs between women and men. In this study, we investigate sex differences in the association between a single nucleotide polymorphism (SNP) in TLR1 and Nucleotide-binding oligomerization domain containing 2 (NOD2) genes and leprosy susceptibility in 256 clinically classified leprosy patients and 233 control subjects in a Brazilian population. Our results showed no association between the SNP rs8057341 in NOD2 and leprosy in this population. However, the heterozygous genotype of the TLR1 SNP (rs4833095) showed a statistically significant association in women (OR = 0.54, P = 0.02). Our findings suggest that the TLR1 polymorphism was associated with an increased protection from leprosy in women.


Assuntos
Predisposição Genética para Doença , Imunidade Inata/genética , Hanseníase/genética , Proteína Adaptadora de Sinalização NOD2/genética , Receptor 1 Toll-Like/genética , Adulto , Idoso , Biópsia , Brasil , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Hanseníase/imunologia , Hanseníase/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Fatores Sexuais , Pele/patologia , Receptor 1 Toll-Like/imunologia
16.
PLoS Negl Trop Dis ; 12(10): e0006815, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30300363

RESUMO

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


Assuntos
Evasão da Resposta Imune , Fatores Imunológicos/farmacologia , Interferon Tipo I/metabolismo , Macrófagos/imunologia , Macrófagos/microbiologia , Mycobacterium leprae/fisiologia , Vitamina D/farmacologia , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/biossíntese , Humanos , Imunidade Inata , Mycobacterium leprae/imunologia , Regulação para Cima
17.
Microb Pathog ; 125: 230-239, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30195647

RESUMO

The aim of this study was to identify phenotypic and functional biomarkers associated with distinct clinical status of leprosy or leprosy reactions. The study included tuberculoid/borderline (BB/BT/T) and lepromatous (BL/L) leprosy poles as well as Type-1 and Type-2 leprosy reactions along with healthy controls (NI). A range of peripheral blood biomarkers of innate (neutrophils - NEU and monocytes - MON) and adaptive immunity (CD4+ and CD8+ T-cells) were evaluated ex vivo and upon in vitro stimuli with M. leprae antigen. Data analysis allowed the selection of NEUTLR4+ (ex vivo) and CD4+IL-10+ (in vitro) as universal biomarkers increased in all leprosy patients and those exhibiting leprosy reactions. A range of biomarkers were commonly found in both poles of leprosy patients, including decreased levels of MONTGF-ß+ (ex vivo) and increased levels of MONTNF-α+, CD4+TGF-ß+, CD8+TLR2+, CD8+TNF-α+, CD8+IL-4+ and CD8+TGF-ß+ (in vitro). Noteworthy was that MONHLA-DR+ (ex vivo) and CD8+IL-10+ (in vitro) were particularly found in BL/L patients. Leprosy patients with Type-1 reaction exhibited a larger list of altered biomarkers, mainly involving activation markers (TLR2, TLR4, HLA-DR and DAF-2T) in NEU and MON along with CD4+ and CD8+ cells. In summary, this study provided insights about immunological features of leprosy poles and leprosy reactional episodes with putative applicability, including novel biomarkers for complementary diagnosis and future therapeutic approaches in clinical studies.


Assuntos
Imunidade Adaptativa , Biomarcadores/análise , Imunidade Inata , Hanseníase/patologia , Adolescente , Adulto , Antígenos de Bactérias/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Adulto Jovem
18.
BMC Infect Dis ; 18(1): 422, 2018 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-30143000

RESUMO

BACKGROUND: The major factors contributing for nerve damage and permanent disabilities in leprosy are type 1 or reversal reactions (RR) and type 2 or erythema nodosum leprosum (ENL). Gene profiling of leprosy reactions have shown that different pathways are activated during the course of reactions, which is consistent with the exacerbated immune response exhibited by these patients. METHODS: We used qPCR to screen a panel of 90 genes related to the immune response in leprosy in RNA-derived peripheral leukocytes of patients with (N = 94) and without leprosy reactions (N = 57) in order to define expression signatures correlated to RR or ENL. RESULTS: Our results show that there is a marked signature for RR in the blood, comprising genes mostly related to the innate immune responses, including type I IFN components, autophagy, parkins and Toll like receptors. On the other hand, only Parkin was differentially expressed in the ENL group. CONCLUSIONS: The data put together corroborates previous work that brings evidence that an acute uncontrolled exacerbated immune response designed to contain the spread of M. leprae antigens might be cause of RR pathogenesis. Identifying a blood profile useful to predict leprosy reactions prior to its development might help to reduce the morbidity associated to this disabling disease.


Assuntos
Imunidade Inata/genética , Hanseníase/genética , Mycobacterium leprae/imunologia , Adulto , Análise Química do Sangue/métodos , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Humanos , Hanseníase/sangue , Hanseníase/imunologia , Leucócitos/metabolismo , Leucócitos/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real
19.
Dev Comp Immunol ; 88: 173-182, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30031015

RESUMO

Debaryomyces hansenii-derived ß-glucan has shown immunostimulant effect on aquaculture species and recently on goat peripheral blood leukocytes. Moreover, the marine yeast D. hansenii CBS 8339 has demonstrated to enhance fish immune response. Nonetheless, the associated immune signaling pathways induced by ß-glucan from this marine yeast have not been characterized yet. This study described the effects of ß-glucan from D. hansenii CBS 8339 against challenge with Escherichia coli and activation of possible mechanisms on goat peripheral blood leukocytes. The proton nuclear magnetic resonance spectra showed that D. hansenii had ß-(1,3)(1,6)-glucan. The phagocytic ability enhanced after E. coli challenge, and nitric oxide production increased before and after challenge in leukocytes stimulated with D. hansenii ß-glucan. In addition, an early gene expression stimulation was found related to ß-glucan recognition by TLR2 and Dectin-1 receptors, intracellular regulation by Syk, TRAF6, MyD88 and transcription factor NFκB, and effector functions of pro-inflammatory cytokine, such as IL-1ß and TNF-α. Interestingly, simulation with D. hansenii-derived ß-glucan increased leukocyte viability after E. coli challenge. In conclusion, ß-glucan from D. hansenii CBS 8339 reduced cytotoxic effects of E. coli and modulated signaling pathways and innate immune response in goat peripheral blood leukocytes.


Assuntos
Debaryomyces/química , Cabras/imunologia , Fatores Imunológicos/farmacologia , Leucócitos/imunologia , beta-Glucanas/farmacologia , Animais , Organismos Aquáticos/química , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Células Cultivadas , Citocinas/imunologia , Escherichia coli/imunologia , Cabras/microbiologia , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/isolamento & purificação , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Leucócitos/microbiologia , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , beta-Glucanas/isolamento & purificação
20.
Front Immunol ; 9: 1223, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29915584

RESUMO

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


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