Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.482
Filtrar
1.
Adv Protein Chem Struct Biol ; 123: 73-93, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33485489

RESUMO

Autophagy is a self-destructing mechanism of cell via lysosomal degradation, which helps to degrade/destroy hazardous substances, proteins, degenerating organelles and recycling nutrients. It plays an important role is cellular homeostasis and regulates internal environment of cell, moreover, when needed causes non-apoptotic programmed death of cell. Autophagy has been observed as one of the major factors in parasite clearance in leishmaniasis. Being an intra-cellular pathogen, the cell mediated response is the only alternative for adaptive immunity against Leishmania in host. Pro-inflammatory cytokines IL12 and TNFα generate Th2 response which helps in active phagocytosis of parasite whereas an anti-inflammatory cytokine like IL10 mediate parasite promotion by blocking autophagic pathways and inhibiting phagocytic actions. In the present chapter, through systems biology approach, we are trying to decipher the role of pro-inflammatory and anti-inflammatory cytokine in autophagy during leishmanial infection. TLR2/6 mediated signaling stimulated by LPG produces many pro-inflammatory cytokines like IL12, TNFα and IL6 etc. Among them TNFα, causes the activation of PI3P through a series of events, which results in activation of autophagic machinery, whereas, IL10 through ATG9 and mTOR activation, inhibits autophagy. The mathematical modeling of these pathways shows that, ATG9-PI3P act as a negative feedback loop in autophagic machinery of leishmaniasis.


Assuntos
Proteínas Relacionadas à Autofagia/imunologia , Autofagia/imunologia , Homeostase/imunologia , Leishmania/imunologia , Leishmaniose/imunologia , Modelos Imunológicos , Células Th2/imunologia , Citocinas/imunologia , Humanos
2.
Mol Immunol ; 127: 95-106, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32949849

RESUMO

Leishmania infantum infection may cause visceral leishmaniasis (VL), a fatal disease having worldwide distribution, that may be silent or asymptomatic. The latter indicates that immunity is naturally developed in some individuals, and, therefore, a vaccine against VL would be possible. Molecular mechanisms of gene expression are being understood in Leishmania, and this knowledge may be useful for vaccine development. The aim of this study was developing an attenuated strain by regulating the expression of toxic proteins in a stage specific manner. For that purpose, the 3' UTR of an amastin gene, known by its increased expression in the amastigote phase, was selected for direct the expression of exogenous proteins. This construct (pFL-AMA), firstly, was proved effective for the expression of mCherry specifically in the intracellular form of L. infantum, as demonstrated by fluorescence microscopy, flow cytometry and Western blotting. Afterwards, mCherry coding sequence was replaced, in the pFL-AMA plasmid, by either egg avidin or the active form of bovine trypsin. Viability of transfected parasites was evaluated in promastigote axenic cultures and in in vitro infection of macrophages. Both lines of transfected parasites showed a limited capacity to multiply inside macrophages. BALB/c mice were inoculated intraperitoneally (i.p.) with a single dose consisting of 2 × 106L. infantum promastigotes transfected with plasmids bearing the toxic genes. After 10 weeks post-inoculation, no parasites were recovered by limiting dilution in either liver or spleen, but a specific immunological response was detected. The immunization with transfected parasites induced cellular and humoral immune responses with activation of TCD4+, TCD8+ and B cells, having a TH1-type response with increased levels of pro-inflammatory cytokines such as IFN-γ, TNF-α and IL-6. In parallel groups of mice, a challenge consisting on 1 × 106 virulent parasites of either L. infantum (inoculated i.p.) or L. amazonensis subcutaneously (s.c.) was performed. Vaccinated mice, challenged with L. infantum, showed lower parasite burdens in liver, spleen and bone marrow than infected mice with WT L. infantum (non-vaccinated); similarly, vaccinated mice developed smaller footpad inflammation than control group. These data support this strategy as an efficient immunization system aimed to the development of vaccines against different forms of leishmaniasis.


Assuntos
Leishmania infantum/fisiologia , Leishmania/fisiologia , Leishmaniose/prevenção & controle , Leishmaniose/parasitologia , Plasmídeos/metabolismo , Toxinas Biológicas/metabolismo , Transfecção , Animais , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade Celular , Imunidade Humoral , Imunização , Leishmania/patogenicidade , Leishmania infantum/crescimento & desenvolvimento , Leishmania infantum/patogenicidade , Leishmaniose/imunologia , Estágios do Ciclo de Vida , Camundongos Endogâmicos BALB C , Parasitos/metabolismo , Parasitos/patogenicidade , Proteínas de Protozoários/metabolismo , Virulência
3.
PLoS One ; 15(9): e0238933, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32966326

RESUMO

Serum levels of interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 17 (IL-17), interferon gamma (IFN-γ), tumor necrosis factor α (TNF-α), and interleukin 1ß (IL-1ß), cytokines involved in the immune response, were investigated in 75 Leishmania-positive blood donors living in endemic areas. Based on their status in 2011 and 2015, the subjects were clustered into three groups: positive for at least one diagnostic method in both years, but lacking clinical progression to disease (G1); positive on at least one method in 2011 but negative in 2015 (G2); negative on all methods in both years (G3). Donors were interviewed for sociodemographic data collection and underwent clinical evaluation and laboratory tests. Serum cytokines were quantified using a CBA Flex set (BD Biosciences). Significant differences were found for all the cytokines evaluated, with lower concentrations in consistently Leishmania-negative individuals. The exception was IFN-γ, with similar levels among all donors. No changes consistent with active disease were observed in the laboratory results for Leishmania-positive donors who underwent clinical evaluation, none of whom progressed to disease. This suggests that infection control is associated with serum IL-17 levels. Resolution of Leishmania infection in positive donors may be related to high levels of IL-17 and low levels of IL-10, highlighting the role played by IL-17 in asymptomatic Leishmania-infected individuals.


Assuntos
Doadores de Sangue/estatística & dados numéricos , Citocinas/sangue , Leishmania/imunologia , Leishmaniose/imunologia , Adulto , Doenças Assintomáticas , Feminino , Humanos , Interleucina-10/sangue , Interleucina-17/sangue , Leishmaniose/sangue , Masculino , Pessoa de Meia-Idade , Regulação para Cima , Adulto Jovem
4.
Mol Immunol ; 125: 104-114, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32659595

RESUMO

Leishmania are obligate protozoan parasites responsible for substantial public health problems in tropical and subtropical regions around the world, with L. braziliensis being one of the causative agents of American Tegumentary Leishmaniasis. Macrophages, fundamental cells in the innate inflammatory response against Leishmania, constitute a heterogeneous group with multiple activation phenotypes and functions. The outcome of this infection depends largely on the activation status of macrophages, the first line of mammalian defense and the major target cells for parasite replication. The importance of lipids, the major components of cell membranes, goes beyond their basic structural functions. Lipid bioactive molecules have been described in Leishmania spp., and in the recent years the knowledge about the biological relevance of lipids in particular and their relationship with the immune response is expanding. The present work analyzes the biological effects of L. braziliensis lipids from lysed promastigotes (PRO) to mimic rapid modulatory processes that could occur in the initial steps of infection or the effects of lipids from lysed and incubated promastigotes (PROinc), simulating the parasite lipid degradation processes triggered after parasite lysis that might occur in the mammalian host. To perform these studies, lipid profiles of PRO and PROinc were compared with lipids from amastigotes under similar conditions (AMA and AMAinc), and the effect of these lipid extracts were analyzed on the induction of an inflammatory response in murine peritoneal macrophages: LB induction, COX-2, iNOS and Arginase expression, TNF-α, IL-10 and NO production, Arginase activity and M1/M2 markers mRNA induction.


Assuntos
Antígenos de Protozoários/imunologia , Leishmania braziliensis/imunologia , Leishmaniose/imunologia , Lipídeos/imunologia , Ativação de Macrófagos/imunologia , Animais , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C
5.
Artigo em Inglês | MEDLINE | ID: mdl-32401957

RESUMO

Immunosuppression is an important risk factor for leishmaniasis. We assessed the clinical profile, geographic distribution and prevalence of leishmaniasis in patients undergoing immunosuppressive therapy for dermatological, rheumatological or gastroenterological autoimmune diseases. We identified relevant studies in PubMed, EMBASE, Scopus, Web of Science and LILACS on July 3rd, 2018. We included articles that reported at least one case of leishmaniasis in patients undergoing immunosuppressive treatment for dermatological, rheumatological or gastroenterological diseases. Our protocol was registered in PROSPERO (CRD42018103050). We assessed the quality of the included studies with the Joanna Briggs Institute Critical Appraisal Tool. After the removal of duplicates, 5,431 articles were collected and screened. We included 138 articles; the prevalence of leishmaniasis in six methodologically similar studies varied from three to 1,282 cases per 100,000 patients using anti-TNFα drugs, but the results were significantly heterogeneous . Leishmaniasis in patients treated with immunosuppressive drugs is a health problem mostly reported in European countries bordering the Mediterranean Sea; sporadic activities, such as travelling, seem not to be associated with a significant risk of leishmaniasis, although effective control measures must always be observed.


Assuntos
Hospedeiro Imunocomprometido/imunologia , Imunossupressores/efeitos adversos , Leishmaniose/imunologia , Gastroenteropatias/tratamento farmacológico , Humanos , Imunossupressores/imunologia , Imunossupressores/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , Dermatopatias/tratamento farmacológico
6.
Parasite Immunol ; 42(7): e12722, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32294247

RESUMO

Leishmaniasis is a neglected infectious disease with clinical presentations ranging from asymptomatic or mild symptoms to chronic infection and eventual death. The mechanisms of disease susceptibility and pathology have been extensively studied, but there are no steadfast rules regarding leishmaniasis. A Th1 response is usually associated with infection control, while a predominant Th2 response is detrimental to the patient. In this scenario, the enzymes arginase and inducible nitric oxide synthase represent two possible pathways of immune response. While the former contributes to parasite replication, the latter is crucial for its control. In the present review, we collected study results that associate arginase expression in patients and in experimental models with disease susceptibility/chronicity and show some proposed mechanisms that explain the role of arginase in maintaining Leishmania infection, including polyamine and thiol synthesis, tissue-resident macrophage (TRM) proliferation and activation and T-cell suppression and exhaustion.


Assuntos
Arginase/metabolismo , Leishmania/imunologia , Leishmaniose/imunologia , Macrófagos/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunidade Inata/imunologia , Leishmaniose/parasitologia , Neutrófilos/imunologia , Células Th1/imunologia , Células Th2/imunologia
7.
Parasite Immunol ; 42(9): e12718, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32249437

RESUMO

AIM: To characterize several anti-Leishmania tropica nanobodies and to investigate their effect on Leishmania infection. METHODS: Several immunological tests were implied to characterize five different (as confirmed by sequencing) anti-L tropica nanobodies (NbLt05, NbLt06, NbLt14, NbLt24 and NbLt36) against parasite lysates or intact cells from different stages, promastigotes and amastigotes. Direct inhibitory effect of these nanobodies on parasite infection cycle on macrophages was tested in cell culture. RESULTS: All the five nanobodies (with distinguished characteristics) were more specific to L tropica than to L major, but could equally recognize the lysate and the outer surface of the intact cells from the two main stages of the parasite. Nanobodies recognized several leishmania antigens (majorly between 75 and 63 kDa), and their proteinaceous nature was confirmed. Because of its role in leishmania life cycle, gp63 was considered a potential antigen candidate for nanobodies, and bioinformatics predicted such interaction. All nanobodies have a negative effect on the infectivity of L tropica, as they decreased the number of infected macrophages and the amastigotes inside those macrophages. CONCLUSION: Such anti-leishmania nanobodies, with outstanding characteristics and important target, can be of great use in the development of promising treatment strategies against leishmaniasis.


Assuntos
Camelus/imunologia , Cadeias Pesadas de Imunoglobulinas/uso terapêutico , Leishmania tropica , Leishmaniose/terapia , Anticorpos de Domínio Único/uso terapêutico , Animais , Células Cultivadas , Humanos , Cadeias Pesadas de Imunoglobulinas/imunologia , Leishmania tropica/efeitos dos fármacos , Leishmania tropica/crescimento & desenvolvimento , Leishmania tropica/imunologia , Leishmaniose/imunologia , Estágios do Ciclo de Vida , Macrófagos/imunologia , Macrófagos/parasitologia , Anticorpos de Domínio Único/imunologia
8.
Trends Parasitol ; 36(5): 459-472, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32298633

RESUMO

Inflammasomes are cytosolic complexes that assemble in response to cellular stress or upon sensing microbial molecules, culminating in cytokine processing and an inflammatory form of cell death called pyroptosis. Inflammasomes are usually composed of a sensor molecule, an adaptor protein, and an inflammatory caspase, such as Caspase-1, which cleaves and activates multiple substrates, including Gasdermin-D, pro-IL-1ß, and pro-IL-18. Ultimately, inflammasome activation promotes inflammation and restriction of the microbial infection. In recent years, many studies have addressed the role of inflammasomes during fungal, bacterial, viral, and parasitic diseases, revealing sophisticated aspects of the host-pathogen interaction. In this review, we summarize recent advances on inflammasome activation in response to intracellular parasites, including Leishmania spp., Plasmodium spp., Trypanosoma cruzi, and Toxoplasma gondii.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Inflamassomos/imunologia , Infecções por Protozoários/imunologia , Animais , Eucariotos/imunologia , Humanos , Leishmaniose/imunologia , Leishmaniose/parasitologia , Malária/imunologia , Malária/parasitologia , Infecções por Protozoários/parasitologia , Pesquisa/tendências , Toxoplasmose/imunologia , Toxoplasmose/parasitologia , Tripanossomíase/imunologia , Tripanossomíase/parasitologia
9.
Acta Trop ; 207: 105456, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32222362

RESUMO

Leishmania are obligate intracellular parasites of mononuclear phagocytes transmitted by Phlebotomine sandflies. Monocytes are one of the main cell types recruited to the site of the bite having an important role in the defense against Leishmania parasites in the first hours of infection. In the tissue, macrophages play a pivotal role as both the primary replication sites and the major effector cells responsible for parasite elimination. Many authors have reviewed the monocyte/macrophage-Leishmania interactions from results derived in mice, however, given the important differences between mice an humans we considered vital to discuss the role of these cells in human leishmaniasis. In this review, we recapitulated the most important studies carried out to understand the different roles of human monocyte/macrophages in Leishmania infection and how they can participate in both control and the immunopathogenesis of the disease.


Assuntos
Leishmania/imunologia , Leishmaniose/imunologia , Macrófagos/fisiologia , Monócitos/fisiologia , Óxido Nítrico/metabolismo , Animais , Humanos , Leishmaniose/parasitologia , Camundongos , Espécies Reativas de Oxigênio
10.
Parasite Immunol ; 42(6): e12713, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32173875

RESUMO

Canine leishmaniasis (CanL) is caused by the intracellular parasite Leishmania infantum. Prostaglandin E2 (PGE2 ) exerts potent regulatory effects on the immune system in experimental model Leishmania infection, but this influence has not yet been studied in CanL. In this study, PGE2 and PGE2 receptor levels and the regulatory effect of PGE2 on arginase activity, NO2 , IL-10, IL-17, IFN-γ, TNF-α and parasite load were evaluated in cultures of splenic leucocytes obtained from dogs with CanL in the presence of agonists and inhibitors. Our results showed that splenic leucocytes from dogs with CanL had lower EP2 receptor levels than those of splenic leucocytes from healthy animals. We observed that NO2 levels decreased when the cells were treated with a PGE2 receptor agonist (EP1/EP2/EP3) or COX-2 inhibitor (NS-398) and that TNF-α, IL-17 and IFN-γ cytokine levels decreased when the cells were treated with a PGE2 receptor agonist (EP2) or PGE2 itself. The parasite load in splenic leucocyte cell cultures from dogs with CanL decreased after stimulation of the cells with PGE2 . We conclude that Leishmania infection of dogs modulates PGE2 receptors and speculate that the binding of PGE2 to its receptors may activate the microbicidal capacity of cells.


Assuntos
Citocinas/imunologia , Dinoprostona/metabolismo , Doenças do Cão/tratamento farmacológico , Leishmania infantum/imunologia , Leishmaniose/veterinária , Receptores de Prostaglandina E/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/agonistas , Dinoprostona/antagonistas & inibidores , Doenças do Cão/imunologia , Doenças do Cão/parasitologia , Cães , Leishmaniose/tratamento farmacológico , Leishmaniose/imunologia , Óxido Nítrico/análise , Nitrobenzenos/farmacologia , Carga Parasitária , Receptores de Prostaglandina E/agonistas , Receptores de Prostaglandina E/fisiologia , Sulfonamidas/farmacologia , Fator de Necrose Tumoral alfa/imunologia
11.
Hum Genet ; 139(6-7): 813-819, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32055998

RESUMO

Identifying genetic risk factors for parasitic infections such as the leishmaniases could provide important leads for improved therapies and vaccines. Until recently most genetic studies of human leishmaniasis were underpowered and/or not replicated. Here, we focus on recent genome-wide association studies of visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL). For VL, analysis across 2287 cases and 2692 controls from three cohorts identified a single major peak of genome-wide significance (Pcombined = 2.76 × 10-17) at HLA-DRB1-HLA-DQA1. HLA-DRB1*1501 and DRB1*1404/DRB1*1301 were the most significant protective versus risk alleles, respectively, with specific residues at amino acid positions 11 and 13 unique to protective alleles. Epitope-binding studies showed higher frequency of basic AAs in DRB1*1404-/*1301-specific epitopes compared to hydrophobic and polar AAs in DRB1*1501-specific epitopes at anchor residues P4 and P6 which interact with residues at DRB1 positions 11 and 13. For CL, genome-wide significance was not achieved in combined analysis of 2066 cases and 2046 controls across 2 cohorts. Rather, multiple top hits at P < 5 × 10-5 were observed, amongst which IFNG-AS1 was of specific interest as a non-coding anti-sense RNA known to influence responses to pathogens by increasing IFN-γ secretion. Association at LAMP3 encoding dendritic cell lysosomal associated membrane protein 3 was also interesting. LAMP3 increases markedly upon activation of dendritic cells, localizing to the MHC Class II compartment immediately prior to translocation of Class II to the cell surface. Together these GWAS results provide firm confirmation for the importance of antigen presentation and the regulation of IFNγ in determining the outcome of Leishmania infections.


Assuntos
Predisposição Genética para Doença , Antígenos HLA/genética , Genética Humana , Leishmania/imunologia , Leishmaniose/genética , Leishmaniose/imunologia , Polimorfismo de Nucleotídeo Único , Regulação da Expressão Gênica , Antígenos HLA/imunologia , Humanos , Leishmania/genética , Leishmaniose/parasitologia
12.
Wien Klin Wochenschr ; 132(1-2): 47-49, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31912288

RESUMO

Leishmaniasis is a severe vector-borne disease with two main clinical forms, visceral leishmaniasis and cutaneous leishmaniasis. Both forms of leishmaniasis are also endemic in Mediterranean countries including the Balkan region from where mainly visceral leishmaniasis is reported. Austrian soldiers returning from Kosovo were screened for anti-Leishmania antibodies to assess the risk of infection during operations. Anti-Leishmania antibodies were detected in more than 20% of the soldiers investigated, which indicates a considerable risk of infection during missions in this area and thus suggests the application of protective measures.


Assuntos
Leishmania , Leishmaniose , Militares , Animais , Áustria , Humanos , Insetos Vetores , Kosovo , Leishmania/imunologia , Leishmaniose/diagnóstico , Leishmaniose/imunologia , Testes Sorológicos
13.
PLoS Negl Trop Dis ; 14(1): e0007949, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961876

RESUMO

Leishmaniasis is caused by intracellular parasites transmitted to vertebrates by sandfly bites. Clinical manifestations include cutaneous, mucosal or visceral involvement depending upon the host immune response and the parasite species. To assure their survival inside macrophages, these parasites developed a plethora of highly successful strategies to manipulate various immune system pathways. Considering that inflammasome activation is critical for the establishment of a protective immune response in many parasite infections, in this study we determined the transcriptome of THP-1 cells after infection with L. infantum, with a particular focus on the inflammasome components. To this end, the human cell line THP-1, previously differentiated into macrophages by PMA treatment, was infected with L. infantum promastigotes. Differentiated THP-1 cells were also stimulated with LPS to be used as a comparative parameter. The gene expression signature was determined 8 hours after by RNA-seq technique. Infected or uninfected THP-1 cells were stimulated with nigericin (NIG) to measure active caspase-1 and TNF-α, IL-6 and IL-1ß levels in culture supernatants after 8, 24 and 48 hours. L. infantum triggered a gene expression pattern more similar to non-infected THP-1 cells and very distinct from LPS-stimulated cells. Some of the most up-regulated genes in L. infantum-infected cells were CDC20, CSF1, RPS6KA1, CD36, DUSP2, DUSP5, DUSP7 and TNFAIP3. Some up-regulated GO terms in infected cells included cell coagulation, regulation of MAPK cascade, response to peptide hormone stimulus, negative regulation of transcription from RNA polymerase II promoter and nerve growth factor receptor signaling pathway. Infection was not able to induce the expression of genes associated with the inflammasome signaling pathway. This finding was confirmed by the absence of caspase-1 activation and IL-1ß production after 8, 24 and 48 hours of infection. Our results indicate that L. infantum was unable to activate the inflammasomes during the initial interaction with THP-1 cells.


Assuntos
Inflamassomos/imunologia , Leishmania infantum/fisiologia , Leishmaniose/genética , Monócitos/imunologia , Monócitos/parasitologia , Caspase 1/genética , Caspase 1/imunologia , Fosfatases de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/imunologia , Humanos , Inflamassomos/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Leishmaniose/imunologia , Leishmaniose/parasitologia , Células THP-1 , Transcriptoma , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
14.
Microb Pathog ; 139: 103892, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31778755

RESUMO

BACKGROUND: Leishmania is a protozoan parasite that nests in macrophages and is responsible for the Leishmaniasis disease. In spite of different defense pathways, last strategy of macrophage for killing parasite is apoptosis process. By permeableizing the mitochondrial outer membrane (MOM). As breaching MOM releases apoptogenic factors like cytochrome-c which activate caspases that result in the destruction of the cell. In this review, we summarized the appropriate manuscripts regarding the bax includes, its different types and the effect of bax on the apoptosis of Leishmania and parasite-infected macrophages. METHODS: Information about the role of BAX in the apoptosis of parasite-infected macrophage of recent articles were surveyed by searching computerized bibliographic database PubMed and Google Scholar entering the keywords BAX and leishmaniasis. RESULTS: The common studies revealed Leishmania use different survival strategies for inhibiting macrophage apoptosis. As Leishmania by preventing homooligomerization or upregulating the anti-apoptotic molecule Bcl-2 can prohibits proteins of host-cell apoptosis such as Bax that is required for mitochondrial permeabilisation during apoptosis. CONCLUSION: With regard to the supportive role of bax in apoptosis and the preventive role of Leishmania in its function, it seems that expression of bax gene in parasite by technologies like transgenic or down regulating of anti-apoptotic molecule Bcl-2 by miRNA could be prompted the apoptosis process of infected-macrophages and inhibited extensive spread of Leishmania and the resulting lesions.


Assuntos
Apoptose , Leishmania/fisiologia , Leishmaniose/metabolismo , Leishmaniose/parasitologia , Macrófagos/imunologia , Macrófagos/metabolismo , Proteína X Associada a bcl-2/metabolismo , Animais , Apoptose/genética , Apoptose/imunologia , Dano ao DNA , Regulação da Expressão Gênica , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Humanos , Leishmaniose/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/genética
15.
Infect Immun ; 88(3)2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31818959

RESUMO

The immune mechanisms that contribute to the efficacy of treatment of cutaneous leishmaniasis (CL) are not fully understood. The aim of this study was to define immune correlates of the outcome of treatment of CL caused by Leishmania (Viannia) species during standard of care treatment with pentavalent antimonials. We conducted a comparative expression profiling of immune response genes in peripheral blood mononuclear cells (PBMCs) and lesion biopsy specimens obtained from CL patients before and at the end of treatment (EoT) with meglumine antimoniate. The ex vivo response of PBMCs to L (V) panamensis partially reflected that of lesion microenvironments. Significant downregulation of gene expression profiles consistent with local innate immune responses (monocyte and neutrophil activation and chemoattractant molecules) was observed at EoT in biopsy specimens of patients who cured (n = 8), compared to those from patients with treatment failure (n = 8). Among differentially expressed genes, pretreatment expression of CCL2 was significantly predictive of the therapeutic response (receiver operating characteristic [ROC] curve, area under the curve [AUC] = 0.82, P = 0.02). Polymorphisms in regulatory regions of the CCL2 promoter were analyzed in a pilot cohort of DNA samples from CL patients (cures, n = 20, and treatment failure, n = 20), showing putative association of polymorphisms rs13900(C/T) and rs2857656(G/C) with treatment outcome. Our data indicate that dampening gene expression profiles of monocyte and neutrophil activation characterize clinical cure after treatment of CL, supporting participation of parasite-sustained inflammation or deregulated innate immune responses in treatment failure.


Assuntos
Antiprotozoários/uso terapêutico , Citocinas/metabolismo , Imunidade Inata/fisiologia , Leishmania/imunologia , Leishmaniose/tratamento farmacológico , Leishmaniose/imunologia , Antimoniato de Meglumina/uso terapêutico , Perfilação da Expressão Gênica , Humanos , Leishmaniose/metabolismo , Leucócitos Mononucleares/metabolismo , Proteínas Quimioatraentes de Monócitos/metabolismo , Monócitos/metabolismo
16.
Parasitol Int ; 74: 101997, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31626986

RESUMO

B-cell activating factor (BAFF) is known as a cytokine responsible for survival and activation of B cells. However, involvement of the molecule in IgG antibody production during infection remains elusive. In this study, dependency of antibody production in Leishmania infection on BAFF was examined by using BAFF-knockout (BAFF-KO) mice. When BAFF-KO mice were infected with L. major, there was no significant difference in lesion development or parasite burden from those in infected wildtype mice. In contrast, levels of IgG antibodies to Leishmania crude antigen were lower in BAFF-KO mice, suggesting that antibody production during L. major infection is BAFF-dependent. ELISA using defined leishmanial antigens demonstrated that the influence of BAFF on antibody production during L. major varies depending on antigens; IgG production to tandem repeat proteins were more affected by BAFF than non-repeat antigens. On the contrary, all of the defined antigens tested were strongly affected by BAFF for IgG antibody production during L. donovani infection. These results suggest degree of BAFF contribution to antibody production during infection is variable depending on the type of infection and even on the type of antigen in a given infection. These results may explain contradictory roles of BAFF in antibody production in previous works.


Assuntos
Anticorpos Antiprotozoários/imunologia , Fator Ativador de Células B/imunologia , Imunoglobulina G/imunologia , Leishmaniose/imunologia , Animais , Antígenos de Protozoários/imunologia , Fator Ativador de Células B/genética , Feminino , Leishmania donovani/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout
17.
PLoS One ; 14(12): e0225588, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31841511

RESUMO

Macrophages can reprogram their metabolism in response to the surrounding stimuli, which affects their capacity to kill intracellular pathogens. We have investigated the metabolic and immune status of human macrophages after infection with the intracellular trypanosomatid parasites Leishmania donovani, L. amazonensis and T. cruzi and their capacity to respond to a classical polarizing stimulus (LPS and IFN-γ). We found that macrophages infected with Leishmania preferentially upregulate oxidative phosphorylation, which could be contributed by both host cell and parasite, while T. cruzi infection did not significantly increase glycolysis or oxidative phosphorylation. Leishmania and T. cruzi infect macrophages without triggering a strong inflammatory cytokine response, but infection does not prevent a potent response to LPS and IFN-γ. Infection appears to prime macrophages, since the cytokine response to activation with LPS and IFN-γ is more intense in infected macrophages compared to uninfected ones. Metabolic polarization in macrophages can influence infection and immune evasion of these parasites since preventing macrophage cytokine responses would help parasites to establish a persistent infection. However, macrophages remain responsive to classical inflammatory stimuli and could still trigger inflammatory cytokine secretion by macrophages.


Assuntos
Doença de Chagas/imunologia , Citocinas/metabolismo , Leishmaniose/imunologia , Ativação de Macrófagos , Macrófagos/imunologia , Células 3T3 , Animais , Células Cultivadas , Doença de Chagas/sangue , Doença de Chagas/parasitologia , Citocinas/imunologia , Voluntários Saudáveis , Humanos , Leishmania donovani/imunologia , Leishmania donovani/isolamento & purificação , Leishmania mexicana/imunologia , Leishmania mexicana/isolamento & purificação , Leishmaniose/sangue , Leishmaniose/parasitologia , Macrófagos/metabolismo , Metaboloma/imunologia , Camundongos , Fosforilação Oxidativa , Cultura Primária de Células , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/isolamento & purificação , Regulação para Cima
18.
Parasit Vectors ; 12(1): 575, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31806038

RESUMO

BACKGROUND: Canine leishmaniosis (CanL) caused by Leishmania infantum can have several dermatological manifestations. The type of immune response elicited against the parasite appears to be at the basis for such clinical variability. Much of the work in CanL has focused on adaptive immune response and there are scarce data on the importance of the innate immune responses. Moreover, few studies have evaluated the immunological response in the cutaneous lesions in dogs naturally infected with L. infantum and with different degrees of disease severity, and no study has compared clinically-lesioned with normal-looking skin. METHODS: We determined and compared the transcription of toll like receptors (TLRs) 2, 4 and 7, interferon gamma (IFN-γ), interleukin (IL) 10 and programmed cell death protein ligand (PD-L) 1 by real-time PCR in paired clinically-lesioned and normal-looking skin from 25 diseased dogs (mild disease-stage I (n = 11) and moderate to severe disease-stages II and III (n = 14) as well as in normal-looking skin from healthy dogs (n = 10) from a non-endemic area. We also assessed the association between the transcripts in clinically-lesioned and normal-looking skin of dogs with leishmaniosis with clinicopathological, immunological and parasitological findings. RESULTS: Clinically-lesioned skin from mildly affected dogs was characterized by a significant upregulation of TLR2 (P < 0.0001) and IL-10 (P = 0.021) and downregulation of TLR7 (P = 0.004) when compared with more severely affected dogs. Normal-looking skin of mildly affected dogs was characterized by a significant lower expression of TLR7 (P = 0.003), IFN-γ (P < 0.0001) and PD-L1 (P = 0.001) when compared with more severely affected dogs. TLR2, TLR4, IL-10 and IFN-γ upregulation in clinically-lesioned skin was correlated with lower disease severity while TLR7 upregulation was correlated with markers of disease severity. Upregulation of TLR7, IL-10, IFN-γ and PD-L1 in normal-looking skin was correlated with disease severity. CONCLUSIONS: This study demonstrated different expression profiles of immune genes in clinically-lesioned and normal-looking skin among mildly and more severely affected dogs. These immunological conditions might favor the maintenance and replication of the parasite in the skin of more severely affected dogs.


Assuntos
Antígeno B7-H1/genética , Interferon gama/genética , Interleucina-10/genética , Leishmaniose/veterinária , Dermatopatias Parasitárias/veterinária , Receptores Toll-Like/genética , Animais , Antígeno B7-H1/imunologia , Biópsia , Doenças do Cão/imunologia , Doenças do Cão/parasitologia , Cães , Regulação para Baixo , Feminino , Interferon gama/imunologia , Interleucina-10/imunologia , Leishmania infantum , Leishmaniose/imunologia , Masculino , Pele/imunologia , Pele/parasitologia , Pele/patologia , Dermatopatias Parasitárias/imunologia , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Receptores Toll-Like/imunologia , Regulação para Cima
19.
Sci Rep ; 9(1): 19841, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882833

RESUMO

The fate of Leishmania infection can be strongly influenced by the host genetic background. In this work, we describe gene expression modulation of the immune system based on dual global transcriptome profiles of bone marrow-derived macrophages (BMDMs) from BALB/c and C57BL/6 mice infected with Leishmania amazonensis. A total of 12,641 host transcripts were identified according to the alignment to the Mus musculus genome. Differentially expressed genes (DEGs) profiling revealed a differential modulation of the basal genetic background between the two hosts independent of L. amazonensis infection. In addition, in response to early L. amazonensis infection, 10 genes were modulated in infected BALB/c vs. non-infected BALB/c macrophages; and 127 genes were modulated in infected C57BL/6 vs. non-infected C57BL/6 macrophages. These modulated genes appeared to be related to the main immune response processes, such as recognition, antigen presentation, costimulation and proliferation. The distinct gene expression was correlated with the susceptibility and resistance to infection of each host. Furthermore, upon comparing the DEGs in BMDMs vs. peritoneal macrophages, we observed no differences in the gene expression patterns of Jun, Fcgr1 and Il1b, suggesting a similar activation trends of transcription factor binding, recognition and phagocytosis, as well as the proinflammatory cytokine production in response to early L. amazonensis infection. Analysis of the DEG profile of the parasite revealed only one DEG among the 8,282 transcripts, indicating that parasite gene expression in early infection does not depend on the host genetic background.


Assuntos
Perfilação da Expressão Gênica/métodos , Leishmania/imunologia , Leishmaniose/imunologia , Macrófagos Peritoneais/metabolismo , Macrófagos/metabolismo , Transcriptoma , Animais , Interações Hospedeiro-Parasita , Leishmania/fisiologia , Leishmaniose/genética , Leishmaniose/parasitologia , Macrófagos/parasitologia , Macrófagos Peritoneais/parasitologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Front Immunol ; 10: 2523, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31736955

RESUMO

In recent decades, studies have shown that, depending on parasite species and host background, autophagy can either favor infection or promote parasite clearance. To date, relatively few studies have attempted to assess the role played by autophagy in Leishmania infection. While it has been consistently shown that Leishmania spp. induce autophagy in a variety of cell types, published results regarding the effects of autophagic modulation on Leishmania survival are contradictory. The present review, after a short overview of the general aspects of autophagy, aims to summarize the current body of knowledge surrounding how Leishmania spp. adaptively interact with macrophages, the host cells mainly involved in controlling leishmaniasis. We then explore the scarce studies that have investigated interactions between these parasite species and the autophagic pathway, and finally present a critical perspective on how autophagy influences infection outcome.


Assuntos
Autofagia , Leishmaniose/imunologia , Macrófagos/imunologia , Animais , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...