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1.
Trends Parasitol ; 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33082090

RESUMO

Neglected tropical diseases annually account for several million infections worldwide. Efficacious treatment for these poorly understood infectious diseases is often limited to ineffective, expensive, and toxic therapies such as the SbV used for leishmaniasis patients. Here, we review the latest discoveries and literature on the molecular pathways, cell types, and immune mediators involved in the immune response to infection with New World Leishmania spp. in humans and their interaction with the adaptive and innate immune system. Novel developments in the field of trained innate immunity and the recently described role of IL-32 are emphasized as potential immunotherapeutic treatments for the management of leishmaniasis.

2.
Trop Anim Health Prod ; 52(6): 3889-3892, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32594353

RESUMO

The aim of this study was to evaluate the population structure of Brazilian buffaloes using of pedigree information. The pedigree used in the analyses included records of 16,915 animals. The population parameters were obtained through the ENDOG software. The estimates of mean of inbreeding (F) and average relatedness (AR) coefficients were 3.22% and 5.99%, respectively. The average generation interval was 6.39 years. The effective number of founders and ancestors was 28 and 22, respectively. In this study, we concluded that the selection of individuals with lower AR is necessary to avoid an increase in matings between inbreeding individuals in this population, in order to obtain greater genetic gain by selection.

3.
PLoS Negl Trop Dis ; 14(2): e0008029, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32023240

RESUMO

Interleukin-32 is a novel inflammatory mediator that has been described to be important in the immunopathogenesis and control of infections caused by Leishmania parasites. By performing experiments with primary human cells in vitro, we demonstrate that the expression of IL-32 isoforms is dependent on the time exposed to L. amazonensis and L. braziliensis antigens. Moreover, for the first time we show the functional consequences of three different genetic variations in the IL32 (rs4786370, rs4349147, rs1555001) modulating IL-32γ expression, influencing innate and adaptive cytokine production after Leishmania exposure. Using a Brazilian cohort of 107 American Tegumentary Leishmaniasis patients and a control cohort of 245 healthy individuals, the IL32 rs4786370 genetic variant was associated with protection against ATL, whereas the IL32 rs4349147 was associated with susceptibility to the development of localized cutaneous and mucosal leishmaniasis. These novel insights may help improve therapeutic strategies and lead to benefits for patients suffering from Leishmania infections.


Assuntos
Predisposição Genética para Doença , Variação Genética , Interleucinas/genética , Leishmania/classificação , Leishmaniose Cutânea/genética , Adulto , Idoso , Brasil/epidemiologia , Citocinas/genética , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Leishmaniose Cutânea/epidemiologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/metabolismo , Masculino , Pessoa de Meia-Idade , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Isoformas de Proteínas , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
4.
Cell Rep ; 28(10): 2659-2672.e6, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484076

RESUMO

American tegumentary leishmaniasis is a vector-borne parasitic disease caused by Leishmania protozoans. Innate immune cells undergo long-term functional reprogramming in response to infection or Bacillus Calmette-Guérin (BCG) vaccination via a process called trained immunity, conferring non-specific protection from secondary infections. Here, we demonstrate that monocytes trained with the fungal cell wall component ß-glucan confer enhanced protection against infections caused by Leishmania braziliensis through the enhanced production of proinflammatory cytokines. Mechanistically, this augmented immunological response is dependent on increased expression of interleukin 32 (IL-32). Studies performed using a humanized IL-32 transgenic mouse highlight the clinical implications of these findings in vivo. This study represents a definitive characterization of the role of IL-32γ in the trained phenotype induced by ß-glucan or BCG, the results of which improve our understanding of the molecular mechanisms governing trained immunity and Leishmania infection control.


Assuntos
Imunidade , Interleucinas/metabolismo , Leishmania braziliensis/fisiologia , Leishmaniose Cutânea/prevenção & controle , beta-Glucanas/farmacologia , Adulto , Idoso , Animais , Vacina BCG/imunologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunidade/efeitos dos fármacos , Interleucina-1/metabolismo , Leishmania braziliensis/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Masculino , Camundongos Transgênicos , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Vacinação , Adulto Jovem
5.
Neuroimmunomodulation ; 26(2): 77-83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30897575

RESUMO

OBJECTIVE: Multiple sclerosis (MS) is a multifactorial chronic disease that affects the central nervous system (CNS). Toll-like receptors (TLRs) play a central role in cytokine production after pathogen- and danger-associated molecular patterns (PAMPs and DAMPs) and contribute to CNS damage in MS patients. Here, we evaluated the effects of interferon (IFN)-ß treatment in TLR2 and TLR4-dependent cytokine production and mRNA expression in whole-blood cell cultures from MS patients. METHODS: We evaluated cytokine production by ELISA from whole-blood cell culture supernatants and mRNA expression by real-time polymerase chain reaction in peripheral blood mononuclear cells (PBMCs). RESULTS: In patients treated with IFN-ß, tumor necrosis factor (TNF)-α production after exposure to TLR2 agonist (Pam3Cys) was lower than in healthy controls and untreated MS patients. However, IFN-ß treatment had no significant effect on TNF-α production after TLR4 agonist (LPS) stimulation. On the other hand, interleukin (IL)-10 production was increased in TLR4- but not in TLR2-stimulated whole-blood cell culture from MS patients under IFN-ß treatment when compared to the controls. No differences in TNF-α or IL-10 mRNA expression in PBMCs from healthy controls and untreated or treated MS patients were detected, although PBMCs from treated patients presented higher levels of IL-32γ mRNA than those from controls. CONCLUSIONS: Our data suggest that IFN-ß treatment alters the TLR-dependent immune response of PBMCs from MS patients. This may contribute to the beneficial effects of IFN-ß treatment.


Assuntos
Interferon beta/uso terapêutico , Interleucina-10/biossíntese , Esclerose Múltipla/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Adulto , Citocinas/biossíntese , Citocinas/efeitos dos fármacos , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia
6.
Atherosclerosis ; 271: 193-202, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29524862

RESUMO

BACKGROUND AND AIMS: The role of interleukin (IL-)32 in inflammatory conditions is well-established, however, the mechanism behind its role in atherosclerosis remains unexplained. Our group reported a promoter single nucleotide polymorphism in IL-32 associated with higher high-density lipoprotein (HDL) concentrations. We hypothesize that endogenous IL-32 in liver cells, a human monocytic cell line and carotid plaque tissue, can affect atherosclerosis by regulating (HDL) cholesterol homeostasis via expression of cholesterol transporters/mediators. METHODS: Human primary liver cells were stimulated with recombinant human (rh)TNFα and poly I:C to study the expression of IL-32 and mediators in cholesterol pathways. Additionally, IL-32 was overexpressed in HepG2 cells and overexpressed and silenced in THP-1 cells to study the direct effect of IL-32 on cholesterol transporters expression and function. RESULTS: Stimulation of human primary liver cells resulted in induction of IL-32α, IL-32ß and IL-32γ mRNA expression (p < 0.01). A strong correlation between the expression of IL-32γ and ABCA1, ABCG1, LXRα and apoA1 was observed (p < 0.01), and intracellular lipid concentrations were reduced in the presence of endogenous IL-32 (p < 0.05). Finally, IL32γ and ABCA1 mRNA expression was upregulated in carotid plaque tissue and when IL-32 was silenced in THP-1 cells, mRNA expression of ABCA1 was strongly reduced. CONCLUSIONS: Regulation of IL-32 in human primary liver cells, HepG2 and THP-1 cells strongly influences the mRNA expression of ABCA1, ABCG1, LXRα and apoA1 and affects intracellular lipid concentrations in the presence of endogenous IL-32. These data, for the first time, show an important role for IL32 in cholesterol homeostasis.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , HDL-Colesterol/metabolismo , Hepatócitos/metabolismo , Interleucinas/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Doenças das Artérias Carótidas/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Homeostase , Humanos , Interleucinas/genética , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Poli I-C/farmacologia , Cultura Primária de Células , Células THP-1 , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima
7.
Infect Immun ; 86(5)2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29483288

RESUMO

Visceral leishmaniasis (VL) is a chronic parasitic disease caused by Leishmania infantum in the Americas. During VL, several proinflammatory cytokines are produced in spleen, liver, and bone marrow. However, the role of interleukin-32 (IL-32) has not been explored in this disease. IL-32 can induce production of proinflammatory cytokines in innate immune cells and polarize the adaptive immune response. Herein, we discovered that L. infantum antigens induced expression of mRNA mainly for the IL-32γ isoform but also induced low levels of the IL-32ß transcript in human peripheral blood mononuclear cells. Furthermore, infection of human IL-32γ transgenic mice (IL-32γTg mice) with L. infantum promastigote forms increased IL-32γ expression in the spleen and liver. Interestingly, IL-32γTg mice harbored less parasitism in the spleen and liver than wild-type (WT) mice. In addition, IL-32γTg mice showed increased granuloma formation in the liver compared to WT mice. The protection against VL was associated with increased production of nitric oxide (NO), interferon gamma (IFN-γ), IL-17A, and tumor necrosis factor alpha by splenic cells restimulated ex vivo with L. infantum antigens. In parallel, there was an increase in the number of Th1 and Th17 T cells in the spleens of IL-32γTg mice infected with L. infantum IL-32γ induction of IFN-γ and IL-17A expression was found to be essential for NO production by splenic cells of infected animals. These data indicate that IL-32γ potentiates the Th1/Th17 immune response during experimental VL, thus contributing to the control of L. infantum infection.


Assuntos
Imunidade Inata/imunologia , Imunidade Inata/fisiologia , Interleucinas/imunologia , Interleucinas/fisiologia , Leishmania infantum/imunologia , Leishmaniose Visceral/imunologia , Fatores de Proteção , Animais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Modelos Animais
8.
Sci Rep ; 7(1): 15219, 2017 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-29123157

RESUMO

American Tegumentary Leishmaniasis is a chronic infection caused by Leishmania protozoan. It is not known whether genetic variances in NOD-like receptor (NLR) family members influence the immune response towards Leishmania parasites and modulate intracellular killing. Using functional genomics, we investigated whether genetic variants in NOD1 or NOD2 influence the production of cytokines by human PBMCs exposed to Leishmania. In addition, we examined whether recognition of Leishmania by NOD2 contributes to intracellular killing. Polymorphisms in the NOD2 gene decreased monocyte- and lymphocyte-derived cytokine production after stimulation with L. amazonensis or L. braziliensis compared to individuals with a functional NOD2 receptor. The phagolysosome formation is important for Leishmania-induced cytokine production and upregulation of NOD2 mRNA expression. NOD2 is crucial to control intracellular infection caused by Leishmania spp. NOD2 receptor is important for Leishmania recognition, the control of intracellular killing, and the induction of innate and adaptive immune responses.


Assuntos
Leishmania/imunologia , Leishmaniose Cutânea/imunologia , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Polimorfismo Genético , Adulto , Idoso , Sobrevivência Celular , Células Cultivadas , Citocinas/metabolismo , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Países Baixos , Fagossomos/metabolismo , Adulto Jovem
9.
Parasit Vectors ; 10(1): 336, 2017 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-28709468

RESUMO

BACKGROUND: Interleukin 32 (IL-32) is a pro-inflammatory cytokine induced in patients with American tegumentary leishmaniasis (ATL) caused by Leishmania braziliensis. Here, we investigated whether IL-32 is also expressed in patient lesions caused by L. amazonensis. In addition, we evaluated experimental L. amazonensis and L. braziliensis infections in C57BL/6 transgenic mice for human IL-32γ (IL-32γTg) in comparison with wild-type (WT) mice that do not express the IL-32 gene. RESULTS: Human cutaneous lesions caused by L. amazonensis express higher levels of IL-32 than healthy control skin. In mice, the presence of IL-32γ promoted the control of cutaneous lesions caused by L. braziliensis, but not lesions caused by L. amazonensis in an ear dermis infection model. In addition, IL-32γTg mice displayed less tissue parasitism and inflammation in IL-32γTg than WT mice during the healing phase of L. braziliensis infection. Production of antigen-specific pro-inflammatory cytokines was higher in IL-32γTg mice than in WT mice during L. braziliensis infection but not during L. amazonensis infection. CONCLUSIONS: Human cutaneous lesions caused by L. amazonensis express high levels of IL-32. In mice, the presence of IL-32γ contributes to the lesion healing caused by L. braziliensis but not by L. amazonensis. Data suggest that despite the ability for both species to induce IL-32 in humans, the connections between this cytokine and other immune players induced by related species of parasites can lead to distinct outcomes of the murine infections.


Assuntos
Interleucinas/metabolismo , Leishmania braziliensis/imunologia , Leishmania mexicana/imunologia , Leishmaniose Cutânea/imunologia , Cicatrização , Animais , Modelos Animais de Doenças , Humanos , Interleucinas/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pele/parasitologia , Pele/patologia
10.
PLoS Negl Trop Dis ; 11(2): e0005413, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28241012

RESUMO

BACKGROUND: Interleukin-32 (IL-32) is expressed in lesions of patients with American Tegumentary Leishmaniasis (ATL), but its precise role in the disease remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, silencing and overexpression of IL-32 was performed in THP-1-derived macrophages infected with Leishmania (Viannia) braziliensis or L. (Leishmania) amazonensis to investigate the role of IL-32 in infection. We report that Leishmania species induces IL-32γ, and show that intracellular IL-32γ protein production is dependent on endogenous TNFα. Silencing or overexpression of IL-32 demonstrated that this cytokine is closely related to TNFα and IL-8. Remarkably, the infection index was augmented in the absence of IL-32 and decreased in cells overexpressing this cytokine. Mechanistically, these effects can be explained by nitric oxide cathelicidin and ß-defensin 2 production regulated by IL-32. CONCLUSIONS: Thus, endogenous IL-32 is a crucial cytokine involved in the host defense against Leishmania parasites.


Assuntos
Citocinas/metabolismo , Interleucinas/metabolismo , Leishmania braziliensis/imunologia , Leishmania mexicana/imunologia , Macrófagos/imunologia , Macrófagos/parasitologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Linhagem Celular , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Óxido Nítrico/metabolismo , beta-Defensinas/metabolismo
11.
J Leukoc Biol ; 101(1): 39-52, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27793959

RESUMO

Interleukin 32 (IL-32) is a proinflammatory cytokine, expressed as 9 distinct isoforms. The most active isoform is the predominantly intracellular-functioning IL-32γ. Involvement of IL-32 in infectious diseases is increasingly being appreciated. Production of IL-32 promotes pathways that serve to control bacterial infection, especially those caused by mycobacteria. A similar role for this cytokine is observed in the cellular response to viral infections. In addition to its protective effects against microorganisms, IL-32 is involved in immunopathogenesis of some infectious diseases. In parasitic diseases, it has been demonstrated that this cytokine is induced by Leishmania infection. In this review, we summarize the present data on the role of IL-32 in infectious diseases, highlighting this cytokine as new target for control of infections.


Assuntos
Doenças Transmissíveis/metabolismo , Interleucinas/metabolismo , Animais , Infecções Bacterianas/metabolismo , Humanos , Modelos Biológicos , Transdução de Sinais , Viroses/metabolismo
12.
Cytokine ; 88: 184-192, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27649507

RESUMO

While the role of Toll-like receptors (TLRs) has been investigated in murine models of tegumentary leishmaniasis caused by Leishmania (Viannia) braziliensis, the interaction between TLRs and Leishmania sp. has not been investigated in human cells. The aim of this study was to evaluate the involvement of TLR4 in cytokine production of human peripheral blood mononuclear cells (PBMCs) induced by L. braziliensis, and whether the parasite alters the expression of TLR4 on monocytes/macrophages. Amastigote forms were obtained from mice lesions and PBMCs were isolated from healthy donors. PBMCs were cultured in absence or presence of IFNγ, TLR4 neutralizing antibodies, natural antagonist of TLR4 (Bartonella LPS), TLR4 agonist (E. coli LPS), and amastigote forms. The concentrations of tumor necrosis factor (TNFα) and interleukin 10 (IL-10) were assayed by ELISA and TLR4 expression by flow cytometry. Amastigotes forms of L. braziliensis induced TNFα and IL-10 production only in IFNγ-primed PBMCs. The TNFα and IL-10 production was inhibited by TLR4 neutralization, both with anti-TLR4 antibodies and Bartonella LPS. Interestingly, addition of E. coli LPS further increased TNFα but not IL-10 production induced by L. braziliensis amastigotes. Amastigotes of L. braziliensis strongly reduced membrane TLR4 expression on monocytes/macrophages, apparently by internalization after the infection. The present study reveals that TLR4 drives the production of TNFα and IL-10 induced by L. braziliensis amastigotes and that the parasites decrease TLR4 expression on monocyte surface.


Assuntos
Interleucina-10/imunologia , Leishmania braziliensis/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/imunologia , Adolescente , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade
13.
PLoS One ; 9(7): e99284, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25036025

RESUMO

INTRODUCTION: The central nucleus of amygdala plays an important role mediating fear and anxiety responses. It is known that oxytocin microinjections into the central nucleus of amygdala induce hypergrooming, an experimental model of compulsive behavior. We evaluated the behavioral and cardiorespiratory responses of conscious rats microinjected with oxytocin into the central nucleus of amygdala. METHODS: Male Wistar rats were implanted with guide cannulae into the central nucleus of amygdala and microinjected with oxytocin (0.5 µg, 1 µg) or saline. After 24 h, rats had a catheter implanted into the femoral artery for pulsatile arterial pressure measurement. The pulsatile arterial pressure was recorded at baseline conditions and data used for cardiovascular variability and baroreflex sensitivity analysis. Respiratory and behavioral parameters were assessed during this data collection session. RESULTS: Microinjections of oxytocin (0.5 µg) into the central nucleus of amygdala produced hypergrooming behavior but did not change cardiorespiratory parameters. However, hypergrooming evoked by microinjections of oxytocin (1 µg) into the central nucleus of amygdala was accompanied by increase in arterial pressure, heart rate and ventilation and augmented the power of low and high (respiratory-related) frequency bands of the systolic arterial pressure spectrum. No changes were observed in power of the low and high frequency bands of the pulse interval spectrum. Baroreflex sensitivity was found lower after oxytocin microinjections, demonstrating that the oxytocin-induced pressor response may involve an inhibition of baroreflex pathways and a consequent facilitation of sympathetic outflow to the cardiovascular system. CONCLUSIONS: The microinjection of oxytocin (1 µg) into the central nucleus of amygdala not only induces hypergrooming but also changes cardiorespiratory parameters. Moreover, specific oxytocin receptor antagonism attenuated hypergrooming but did not affect pressor, tachycardic and ventilatory responses to oxytocin, suggesting the involvement of distinct neural pathways.


Assuntos
Núcleo Central da Amígdala/efeitos dos fármacos , Comportamento Compulsivo/fisiopatologia , Asseio Animal/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Ocitocina/farmacologia , Respiração/efeitos dos fármacos , Animais , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Núcleo Central da Amígdala/fisiologia , Asseio Animal/fisiologia , Hemodinâmica/fisiologia , Masculino , Microinjeções , Ocitocina/administração & dosagem , Ratos , Ratos Wistar , Receptores de Ocitocina/agonistas , Receptores de Ocitocina/fisiologia , Sistema Nervoso Simpático/fisiologia
14.
ISRN Inflamm ; 2014: 563628, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24563803

RESUMO

Snake venom has been the subject of numerous studies in an attempt to find properties and biological effects that may be beneficial to man. In this study we evaluated in vitro the effects of Crotalus durissus terrificus (Cdt) and Crotalus durissus collilineatus (Cdc) venom in human peripheral blood mononuclear cells (PBMCs). At 24 h, a significant decrease of viable cells was observed in cells stimulated with the Cdc venom at 0.0005 mg/mL and 0.005 mg/mL compared to the negative control. At 48 h, a significant decrease of viable cells was observed only in cells stimulated with Cdc venom at 0.005 mg/mL. A significant increase of TNF- α and IL-10 was detected 48 hours after culture of PBMC with Cdc, but not with Cdt venom. The expression of CD69 and PD1 (programmed death-1), activation and regulatory cell markers, on CD8+ and CD8- T cells did not change in the presence of Cdt and Cdc venom. Our results suggest the presence of proinflammatory and anti-inflammatory components in the Cdc venom. Further analysis should be done to identify those Cdc venom components as it has been done for the Cdt venom by other authors, indicating that modulatory components are found in the venom of different species of Crotalus snakes.

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