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The recent explosion in the number of predatory journals has led to the appearance of questionable websites providing fake or spurious impact factors, which are analyzed and discussed here. We believe that academic associations, universities, and research funding bodies must take action to stop these questionable practices.
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Bibliometria , Fator de Impacto de Revistas , Pesquisa Biomédica/normasRESUMO
Programmed death-1 (PD-1) plays an important role in mediating immune tolerance through mechanisms that remain unclear. Herein, we investigated whether PD-1 prevents excessive host tissue damage during infection with the protozoan parasite, Toxoplasma gondii. Surprisingly, our results demonstrate that PD-1-deficient mice have increased susceptibility to T. gondii, with increased parasite cyst counts along with reduced type-1 cytokine responses (IL-12 and IFN-γ). PD-1â»/â» DCs showed no cell intrinsic defect in IL-12 production in vitro. Instead, PD-1 neutralization via genetic or pharmacological approaches resulted in a striking increase in IL-10 release, which impaired type-1-inflammation during infection. Our results indicate that the absence of PD-1 increases IL-10 production even in the absence of infection. Although the possibility that such increased IL-10 protects against autoimmune damage is speculative, our results show that IL-10 suppresses the development of protective Th1 immune response after T. gondii infection.
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Interleucina-10/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Toxoplasmose Animal/metabolismo , Animais , Inflamação/imunologia , Inflamação/metabolismo , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-10/imunologia , Interleucina-12/imunologia , Interleucina-12/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Toxoplasma/imunologia , Toxoplasma/metabolismo , Toxoplasmose Animal/imunologiaRESUMO
Statins are pharmacological inhibitors of the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), an enzyme responsible for the synthesis of cholesterol. Some recent experimental studies have shown that besides their effects on the primary and secondary prevention of cardiovascular diseases, statins may also have beneficial anti-inflammatory effects through diverse mechanisms. On the other hand, the induction and activity of regulatory T cells (Treg) are key processes in the prevention of pathology during chronic inflammatory and autoimmune diseases. Hence, strategies oriented towards the therapeutic expansion of Tregs are gaining special attention among biomedical researchers. The potential effects of statins on the biology of Treg are of particular importance because of their eventual application as in vivo inducers of Treg in the treatment of multiple conditions. In this paper we review the experimental evidence pointing out to a potential effect of statins on the role of regulatory T cells in different conditions and discuss its potential clinical significance.
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Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Células Apresentadoras de Antígenos/citologia , Doenças Autoimunes/metabolismo , Movimento Celular/efeitos dos fármacos , Colesterol/sangue , Células Dendríticas/citologia , Regulação da Expressão Gênica , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inflamação/metabolismo , Camundongos , Fenótipo , Células Th1/efeitos dos fármacosRESUMO
INTRODUCTION: The KEYNOTE-054 trial found that adjuvant treatment with pembrolizumab improved recurrence-free survival versus placebo in completely resected high-risk stage III melanoma patients. We assessed the cost-effectiveness of adjuvant pembrolizumab in Colombia compared with watchful waiting, a widely used strategy despite the high risk of recurrence with surgery alone. METHODS: A four-health state [recurrence-free (RF), locoregional recurrence (LR), distant metastases (DM), and death) Markov model was developed to assess the lifetime medical costs and outcomes (3% annual discount), along with cost-effectiveness ratios (ICERs). The transitions from the RF and LR states were modeled using KEYNOTE-054 data, and those from the DM state were modeled using data from the KEYNOTE-006 trial and a network meta-analysis of advanced treatments received after adjuvant pembrolizumab and watchful waiting. The health state utilities were derived from KEYNOTE-054 Euro-QoL data and literature. Costs are expressed in 2021 Colombian pesos (COP). RESULTS: Over a 46-year time horizon, patients on adjuvant pembrolizumab and watchful waiting were estimated to gain 9.69 and 7.56 quality-adjusted life-years (QALYs), 10.83 and 8.65 life-years (LYs), and incur costs of COP 663,595,726 and COP 563,237,206, respectively. The proportion of LYs spent in RF state was 84.63% for pembrolizumab and 72.13% for watchful waiting, yielding lower subsequent treatment, disease management, and terminal care costs for pembrolizumab. Adjuvant pembrolizumab improved survival by 2.18 LYs and 2.13 QALYs versus watchful waiting. The ICER per QALY was COP 47,081,917, primarily driven by recurrence rates and advanced melanoma treatments. The deterministic sensitivity analysis results were robust and consistent across various reasonable inputs and alternative scenarios. At a willingness-to-pay threshold of COP 69,150,201 per QALY, the probability of pembrolizumab being cost-effective was 65.70%. CONCLUSION: Pembrolizumab is cost-effective as an adjuvant treatment compared to watchful waiting among patients with high-risk stage III melanoma after complete resection in Colombia.
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Melanoma , Qualidade de Vida , Humanos , Análise Custo-Benefício , Colômbia , Recidiva Local de Neoplasia/tratamento farmacológico , Melanoma/tratamento farmacológico , Melanoma/cirurgia , Anos de Vida Ajustados por Qualidade de Vida , Adjuvantes Imunológicos/uso terapêutico , Linfonodos/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma Maligno CutâneoRESUMO
An effective innate immune recognition of the intracellular protozoan parasite Trypanosoma cruzi is critical for host resistance against Chagas disease, a severe and chronic illness that affects millions of people in Latin America. In this study, we evaluated the participation of nucleotide-binding oligomerization domain (Nod)-like receptor proteins in host response to T. cruzi infection and found that Nod1-dependent, but not Nod2-dependent, responses are required for host resistance against infection. Bone marrow-derived macrophages from Nod1(-/-) mice showed an impaired induction of NF-kappaB-dependent products in response to infection and failed to restrict T. cruzi infection in presence of IFN-gamma. Despite normal cytokine production in the sera, Nod1(-/-) mice were highly susceptible to T. cruzi infection, in a similar manner to MyD88(-/-) and NO synthase 2(-/-) mice. These studies indicate that Nod1-dependent responses account for host resistance against T. cruzi infection by mechanisms independent of cytokine production.
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Doença de Chagas/imunologia , Imunidade Inata , Proteína Adaptadora de Sinalização NOD1/fisiologia , Trypanosoma cruzi/imunologia , Animais , Doença de Chagas/genética , Doença de Chagas/metabolismo , Predisposição Genética para Doença , Imunidade Inata/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/fisiologia , Proteína Adaptadora de Sinalização NOD1/deficiência , Proteína Adaptadora de Sinalização NOD1/genética , Proteína Adaptadora de Sinalização NOD2/deficiência , Proteína Adaptadora de Sinalização NOD2/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptores Toll-Like/fisiologiaRESUMO
Trypanosoma cruzi infection causes intense myocarditis, leading to cardiomyopathy and severe cardiac dysfunction. Protective adaptive immunity depends on balanced signaling through a T cell receptor and coreceptors expressed on the T cell surface. Such coreceptors can trigger stimulatory or inhibitory signals after binding to their ligands in antigen-presenting cells (APC). T. cruzi modulates the expression of coreceptors in lymphocytes after infection. Deregulated inflammation may be due to unbalanced expression of these molecules. Programmed death cell receptor 1 (PD-1) is a negative T cell coreceptor that has been associated with T cell anergy or exhaustion and persistent intracellular infections. We aimed to study the role of PD-1 during T. cruzi-induced acute myocarditis in mice. Cytometry assays showed that PD-1 and its ligands are strongly upregulated in lymphocytes and APC in response to T. cruzi infection in vivo and in vitro. Lymphocytes infiltrating the myocardium exhibited high levels of expression of these molecules. An increased cardiac inflammatory response was found in mice treated with blocking antibodies against PD-1, PD-L1, and to a lesser extent, PD-L2, compared to that found in mice treated with rat IgG. Similar results in PD-1(-/-) mice were obtained. Moreover, the PD-1 blockade/deficiency led to reduced parasitemia and tissue parasitism but increased mortality. These results suggest the participation of a PD-1 signaling pathway in the control of acute myocarditis induced by T. cruzi and provide additional insight into the regulatory mechanisms in the pathogenesis of Chagas' disease.
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Antígenos de Superfície/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Cardiomiopatia Chagásica/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Trypanosoma cruzi/imunologia , Animais , Antígenos de Superfície/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Separação Celular , Cardiomiopatia Chagásica/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Morte Celular Programada 1 , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Neospora caninum is an apicomplexan parasite responsible for major economic losses due to abortions in cattle. Toll-like receptors (TLRs) sense specific microbial products and direct downstream signaling pathways in immune cells, linking innate, and adaptive immunity. Here, we analyze the role of TLR2 on innate and adaptive immune responses during N. caninum infection. Inflammatory peritoneal macrophages and bone marrow-derived dendritic cells exposed to N. caninum-soluble antigens presented an upregulated expression of TLR2. Increased receptor expression was correlated to TLR2/MyD88-dependent antigen-presenting cell maturation and pro-inflammatory cytokine production after stimulation by antigens. Impaired innate responses observed after infection of mice genetically deficient for TLR2((-/-)) was followed by downregulation of adaptive T helper 1 (Th1) immunity, represented by diminished parasite-specific CD4(+) and CD8(+) T-cell proliferation, IFN-γ:interleukin (IL)-10 ratio, and IgG subclass synthesis. In parallel, TLR2(-/-) mice presented higher parasite burden than wild-type (WT) mice at acute and chronic stages of infection. These results show that initial recognition of N. caninum by TLR2 participates in the generation of effector immune responses against N. caninum and imply that the receptor may be a target for future prophylactic strategies against neosporosis.
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Coccidiose/imunologia , Células Dendríticas/metabolismo , Macrófagos Peritoneais/metabolismo , Neospora/imunologia , Receptor 2 Toll-Like/metabolismo , Animais , Medula Óssea/patologia , Bovinos , Diferenciação Celular/genética , Processos de Crescimento Celular/genética , Células Cultivadas , Coccidiose/genética , Coccidiose/metabolismo , Citocinas/genética , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/parasitologia , Células Dendríticas/patologia , Regulação da Expressão Gênica , Mediadores da Inflamação/metabolismo , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/parasitologia , Macrófagos Peritoneais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neospora/patogenicidade , Equilíbrio Th1-Th2 , Receptor 2 Toll-Like/genéticaRESUMO
Trypanosoma cruzi infection triggers substantial production of nitric oxide (NO), which has been shown to have protective and toxic effects on the host's immune system. Sensing of trypomastigotes by phagocytes activates the inducible NO-synthase (NOS2) pathway, which produces NO and is largely responsible for macrophage-mediated killing of T. cruzi. NO is also responsible for modulating virtually all steps of innate and adaptive immunity. However, NO can also cause oxidative stress, which is especially damaging to the host due to increased tissue damage. The cytokines IFN-gamma and TNF-alpha, as well as chemokines, are strong inducers of NOS2 and are produced in large amounts during T. cruzi acute infection. Conversely, TGF-beta and IL-10 negatively regulate NO production. Here we discuss the recent evidence describing the mechanisms by which NO is able to exert its antimicrobial and immune regulatory effects, the mechanisms involved in the oxidative stress response during infection and the implications of NO for the development of therapeutic strategies against T. cruzi.
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Doença de Chagas/imunologia , Sistema Imunitário/metabolismo , Óxido Nítrico Sintase Tipo II/imunologia , Óxido Nítrico/imunologia , Trypanosoma cruzi/imunologia , Doença de Chagas/metabolismo , Humanos , Sistema Imunitário/parasitologia , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse OxidativoRESUMO
INTRODUCTION: Infection by Trypanosoma cruzi is challenging to blood bank supplies in terms of accurate diagnosis, mostly due to its clinical complexity. Infected individuals may remain asymptomatic for years, albeit they may have circulating parasites potentially transferable to eventual receptors of a transfusion. OBJECTIVE: Although risk donors are systematically excluded through a survey, an important residual risk for transmission remains, evidencing the need to implement additional actions for the detection of T. cruzi in blood banks. METHOD: A review of the scientific literature is presented with the objective of identifying relevant publications on this subject. RESULTS: We discuss the diagnostic considerations of this chronic infection on transfusion medicine and some recent advances in the processing of blood and derivatives units. CONCLUSION: Finally, recommendations are made on how the transmission of T. cruzi can be avoided through the implementation of better diagnostic and pathogen control measures at blood banks.
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The infection with Trypanosoma cruzi leads to a vigorous and apparently uncontrolled inflammatory response in the heart. Although the parasites trigger specific immune response, the infection is not completely cleared out, a phenomenon that in other parasitic infections has been attributed to CD4+CD25+ T cells (Tregs). Then, we examined the role of natural Tregs and its signaling through CD25 and GITR in the resistance against infection with T. cruzi. Mice were treated with mAb against CD25 and GITR and the parasitemia, mortality and heart pathology analyzed. First, we demonstrated that CD4+CD25+GITR+Foxp3+ T cells migrate to the heart of infected mice. The treatment with anti-CD25 or anti-GITR resulted in increased mortality of these infected animals. Moreover, the treatment with anti-GITR enhanced the myocarditis, with increased migration of CD4+, CD8+, and CCR5+ leukocytes, TNF-alpha production, and tissue parasitism, although it did not change the systemic nitric oxide synthesis. These data showed a limited role for CD25 signaling in controlling the inflammatory response during this protozoan infection. Also, the data suggested that signaling through GITR is determinant to control of the heart inflammation, parasite replication, and host resistance against the infection.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Doença de Chagas/imunologia , Linfócitos T Reguladores/imunologia , Trypanosoma cruzi/imunologia , Animais , Linfócitos T CD4-Positivos/química , Linfócitos T CD8-Positivos/imunologia , Feminino , Fatores de Transcrição Forkhead/análise , Proteína Relacionada a TNFR Induzida por Glucocorticoide , Subunidade alfa de Receptor de Interleucina-2/análise , Subunidade alfa de Receptor de Interleucina-2/antagonistas & inibidores , Subunidade alfa de Receptor de Interleucina-2/imunologia , Camundongos , Miocárdio/patologia , Parasitemia , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Receptores de Fator de Crescimento Neural/imunologia , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Receptores do Fator de Necrose Tumoral/imunologia , Análise de Sobrevida , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/química , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Introduction: Chagas disease (CD) is caused by a parasitic infection. The disease usually occurs after decades of the primary infection and can involve the myocardium or the digestive system. Of note, around 30% of T. cruzi infected patients develop CD while the other 70% may remain asymptomatic for their entire life. CD is usually observed as familial clustered phenomena. Moreover, individuals with chronic Chagas heart disease (CCHD) usually present a strong, deregulated immune response, which strongly suggests an immunogenetic effect.Areas covered: In this article we review and discuss the information currently available from the published scientific literature regarding the genetic variants of molecules of the immune system that contribute to the clinical presentation of the disease.Expert commentary: Of note, the most promissory results are found on the polymorphisms of chemokine receptors, particularly CCR5 and CCR2. Additional investigations are required, particularly with a focus on the genes that regulate the immune system.
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ABSTRACT Introduction: Infection by Trypanosoma cruzi is challenging to blood bank supplies in terms of accurate diagnosis, mostly due to its clinical complexity. Infected individuals may remain asymptomatic for years, albeit they may have circulating parasites potentially transferable to eventual receptors of a transfusion. Objective: Although risk donors are systematically excluded through a survey, an important residual risk for transmission remains, evidencing the need to implement additional actions for the detection of T. cruzi in blood banks. Method: A review of the scientific literature is presented with the objective of identifying relevant publications on this subject. Results: We discuss the diagnostic considerations of this chronic infection on transfusion medicine and some recent advances in the processing of blood and derivatives units. Conclusion: Finally, recommendations are made on how the transmission of T. cruzi can be avoided through the implementation of better diagnostic and pathogen control measures at blood banks.
Assuntos
Trypanosoma cruzi , Bancos de Sangue , Fatores Epidemiológicos , Doença de Chagas/diagnóstico , Segurança do SangueRESUMO
Infectious myocarditis (IM) is a commonly undiagnosed condition that may cause several heart diseases, including dilated cardiomyopathy and chronic heart failure. The understanding of the physiopathology of myocardial inflammation is crucial for a timely diagnosis and for the control of the tissue damage, which may occur in some cases of IM. Of note, some experimental studies suggest that dilated cardiomyopathy could be a consequence of untreated IM. However, further research is required to address the molecular mechanisms that may link these two clinical entities. Here we review the mechanisms involved in the regulation at different levels of the immune response during IM, with a special focus on diagnostic and therapeutic perspectives of molecules that have been linked to the development of IM and the resulting chronic heart diseases.
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Cardiomiopatia Dilatada/etiologia , Insuficiência Cardíaca/etiologia , Miocardite/imunologia , Animais , Cardiomiopatia Dilatada/imunologia , Cardiomiopatia Dilatada/fisiopatologia , Doença Crônica , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Inflamação/etiologia , Inflamação/imunologia , Inflamação/fisiopatologia , Miocardite/complicações , Miocardite/diagnóstico , Fatores de TempoRESUMO
The infection with Trypanosoma cruzi induces a robust cardiac inflammation that plays a pathogenic role in the development of Chagas heart disease. In this study, we aimed at investigating the effects of Haem Oxygenase (HO) during experimental infection by T. cruzi in BALB/c and C57BL/6 mice. HO has recently emerged as a key factor modulating the immune response in diverse models of inflammatory diseases. In mice with two different genetic backgrounds, the pharmacologic inhibition of HO activity with zinc-protoporphyrin IX (ZnPPIX) induced enhanced myocarditis and reduced parasitaemia, which was accompanied by an amplified production of nitric oxide and increased influx of CD4(+), CD8(+) and IFN-γ(+) cells to the myocardium in comparison with the control group. Conversely, treatment with haemin (an activator of HO) lead to a decreased number of intracardiac CD4(+) (but not CD8(+)) cells compared to the control group. The mechanism involved in these observations is a modulation of the induction of regulatory T cells, because the stimulation or inhibition of HO was parallelled by an enhanced or reduced frequency of regulatory T cells, respectively. Hence, HO may be involved in the regulation of heart tissue inflammation and could be a potential target in conceiving future therapeutic approaches for Chagas disease.
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Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/metabolismo , Heme Oxigenase-1/metabolismo , Inflamação/metabolismo , Animais , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Feminino , Hemina/administração & dosagem , Hemina/farmacologia , Inflamação/patologia , Camundongos , Óxido Nítrico/biossíntese , Protoporfirinas/administração & dosagem , Protoporfirinas/farmacologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Trypanosoma cruziRESUMO
The development of Chagas disease is determined by a complex interaction between the genetic traits of both the protozoan parasite, T. cruzi, and the infected host. This process is regulated by multiple genes that control different aspects of the host-parasite interaction. While determination of the relevant genes in humans is extremely difficult, it is feasible to use inbred mouse strains to determine the genes and loci responsible for host resistance to infection. In this study, we investigated the susceptibility of several inbred mouse strains to infection with the highly virulent Y strain of T. cruzi and found a considerable difference in susceptibility between A/J and C57BL/6 mice. We explored the differences between these two mouse strains and found that the A/J strain presented higher mortality, exacerbated and uncontrolled parasitemia and distinct histopathology in the target organs, which were associated with a higher parasite burden and more extensive tissue lesions. We then employed a genetic approach to assess the pattern of inheritance of the resistance phenotype in an F1 population and detected a strong parent-of-origin effect determining the susceptibility of the F1 male mice. This effect is unlikely to result from imprinted genes because the inheritance of this susceptibility was affected by the direction of the parental crossing. Collectively, our genetic approach of using the F1 population suggests that genes contained in the murine chromosome X contribute to the natural resistance against T. cruzi infection. Future linkage studies may reveal the locus and genes participating on the host resistance process reported herein.
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Doença de Chagas/genética , Hibridização Genética , Trypanosoma cruzi/fisiologia , Animais , Suscetibilidade a Doenças , Feminino , Loci Gênicos/genética , Masculino , Camundongos , Fenótipo , Caracteres Sexuais , Especificidade da Espécie , Cromossomo X/genéticaRESUMO
BACKGROUND: Chagas disease affects approximately 10 million people mainly in Latin America. The immune regulation by the host seems to be an essential factor for disease evolution, and immune system inhibitory molecules such as CTLA-4 and PD-1 favor the maintenance of peripheral tolerance. Considering that polymorphisms at the immunoregulatory CTLA-4 and PDCD1 genes may alter their inhibitory function, we investigated the association of alleles, genotypes and haplotypes of polymorphic sites observed at the CTLA-4 and PDCD1 genes with different clinical manifestations of chronic Chagas disease (indeterminate, cardiac, digestive and mixed). METHODS: The polymorphisms at the CTLA-4 (-1722T/C, -318C/T and +49A/G) and PDCD1 (PD-1.3G/A) genes were typed using TaqMan methodology in 277 chronic Chagas disease patients classified into four groups, according to clinical characteristics, and 326 non-infected controls. RESULTS: Our results showed that CTLA-4 -1722CC genotype (22%), -1722C allele (27%) and CTLA-4 TCG (8.6%), TCA (26%) and CCA (15%) haplotypes were strongly associated with the indeterminate form, while the CTLA-4-318CT genotype (82%) and CTLA-4-318T allele (47%) were found mainly in patients with the mixed form of the disease. The CTLA-4 TCG haplotype (10.2%) was associated with the digestive form. On the other hand, the PD-1.3G/A polymorphism was not associated with chronic Chagas disease and its clinical manifestations. CONCLUSIONS: Here, we showed that alleles, genotypes and haplotypes reported to increase the expression of the regulatory molecule CTLA-4 were associated with the indeterminate form of the disease. Taken together, our data support the idea that polymorphic sites at immunoregulatory genes may influence the development of Chagas disease variants.
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Doença de Chagas/genética , Predisposição Genética para Doença/genética , Haplótipos/genética , Proteínas de Membrana Transportadoras/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Estudos de Casos e Controles , Doença Crônica , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genéticaRESUMO
Parasites of the Leishmania genus are the causative agents of leishmaniasis in humans, a disease that affects more than 12 million people worldwide. These parasites replicate intracellularly in macrophages, and the primary mechanisms underlying host resistance involve the production of nitric oxide (NO). In this study we show that the Nlrp3 inflammasome is activated in response to Leishmania infection and is important for the restriction of parasite replication both in macrophages and in vivo as demonstrated through the infection of inflammasome-deficient mice with Leishmania amazonensis, Leishmania braziliensis and Leishmania infantum chagasi. Inflammasome-driven interleukin-1ß (IL-1ß) production facilitated host resistance to infection, as signaling through IL-1 receptor (IL-1R) and MyD88 was necessary and sufficient to trigger inducible nitric oxide synthase (NOS2)-mediated production of NO. In this manuscript we identify a major signaling platform for host resistance to Leishmania spp. infection and describe the molecular mechanisms underlying Leishmania-induced NO production.
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Resistência à Doença/efeitos dos fármacos , Inflamassomos/imunologia , Interleucina-1beta/metabolismo , Leishmania , Óxido Nítrico/imunologia , Animais , Proteínas Reguladoras de Apoptose , Proteínas Adaptadoras de Sinalização CARD , Proteínas de Transporte/genética , Caspase 1/genética , Células Cultivadas , Proteínas do Citoesqueleto/genética , Resistência à Doença/genética , Resistência à Doença/imunologia , Feminino , Leishmaniose/genética , Leishmaniose/imunologia , Leishmaniose/metabolismo , Leishmaniose/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Óxido Nítrico Sintase Tipo II/genéticaRESUMO
Evaluation of: Bua J, Volta BJ, Velazquez EB et al. Vertical transmission of Trypanosoma cruzi infection: quantification of parasite burden in mothers and their children by parasite DNA amplification. Trans. R. Soc. Trop. Med. Hyg. 106(10), 623-628 (2012). The congenital transmission of Trypanosoma cruzi has gained epidemiological importance because it is partially responsible for the spread of Chagas disease worldwide. The feasibility of a cure when infected children are treated early makes the detection of congenital infection a valuable goal toward the control of the disease. Here, the authors review and discuss the findings of Bua et al., who quantified the parasitemia of infected women and their newborns by quantitative PCR. The authors demonstrate that the maternal parasite burden is directly related to the risk of neonatal infection. This study points out the importance of a quantitative screen for T. cruzi in pregnant women who live in, or have traveled to, endemic areas for improving the diagnosis of infected newborns and providing prompt treatment.
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Chagas disease affects 7.7 million people and 28 million people are at risk of acquiring the disease in 15 endemic countries of Latin America. Benznidazole and nifurtimox are drugs that have been used to treat the disease. However, both drugs induce severe side effects. Treatment with benznidazole has been recommended for the acute phase (0-4 months after infection), recent chronic phase (children 0-14 years of age, treated 4 months after infection) and congenital infection. Average cure rates for Chagas disease patients obtained from clinical trials were 97.9% (congenital infection, treatment performed 0-6 months of age), 71.5% (acute phase), 57.6% (recent chronic phase, children 0-13 years of age) and 5.9% (late chronic phase, great majority of patients between 15 and 69 years of age). Clinical evidence about the capacity of antiparasitic treatment to avoid, stop or revert heart pathology in indeterminate and cardiac chronic patients is contradictory. The investigation of novel therapeutic strategies against Chagas disease remains a priority in the research of tropical diseases. Unfortunately, Chagas disease remains neglected in the formulation of strategies toward control of this disease. This article focuses on current therapeutic approaches to Chagas disease.
Assuntos
Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Miocardite/etiologia , Tripanossomicidas/efeitos adversos , Trypanosoma cruzi/fisiologia , Adulto , Animais , Doença de Chagas/complicações , Doença de Chagas/mortalidade , Criança , Ensaios Clínicos como Assunto , Esquema de Medicação , Humanos , América Latina/epidemiologia , Camundongos , Miocardite/mortalidade , Miocardite/parasitologia , Miocardite/fisiopatologia , Nifurtimox/efeitos adversos , Nifurtimox/uso terapêutico , Nitroimidazóis/efeitos adversos , Nitroimidazóis/uso terapêutico , Análise de Sobrevida , Tripanossomicidas/uso terapêuticoRESUMO
Ticks (Acari: Ixodidae) are bloodsucking ectoparasitic arthropods of human and veterinary medical importance. Tick saliva has been shown to contain a wide range of bioactive molecules with vasodilatory, antihemostatic, and immunomodulatory activities. We have previously demonstrated that saliva from Rhipicephalus sanguineus ticks inhibits the maturation of dendritic cells (DCs) stimulated with LPS. Here we examined the mechanism of this immune subversion, evaluating the effect of tick saliva on Toll-like receptor (TLR)-4 signalling pathway in bone marrow-derived DCs. We demonstrated that R. sanguineus tick saliva impairs maturation of DCs stimulated with LPS, a TLR-4 ligand, leading to increased production of interleukin (IL)-10 and reduced synthesis of IL-12p70 and TNF-alpha. The immunomodulatory effect of the tick saliva on the production of pro-inflammatory cytokines by DCs stimulated with LPS was associated with the observation that tick saliva inhibits the activation of the ERK 1/2 and p38 MAP kinases. These effects were independent of the expression of TLR-4 on the surface of DCs. Additionally, saliva-treated DCs also presented a similar pattern of cytokine modulation in response to other TLR ligands. Since the recent literature reports that several parasites evade immune responses through TLR-2-mediated production of IL-10, we evaluated the effect of tick saliva on the percentage of TLR-2(+) DCs stimulated with the TLR-2 ligand lipoteicoic acid (LTA). The data showed that the population of DCs expressing TLR-2 was significantly increased in DCs treated with LTA plus saliva. In addition, tick saliva alone increased the expression of TLR-2 in a dose- and time-dependent manner. Our data suggest that tick saliva induces regulatory DCs, which secrete IL-10 and low levels of IL-12 and TNF-alpha when stimulated by TLR ligands. Such regulatory DCs are associated with expression of TLR-2 and inhibition of ERK and p38, which promotes the production of IL-10 and thus down-modulates the host's immune response, possibly favouring susceptibility to tick infestations.