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1.
Front Immunol ; 9: 2791, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30559742

RESUMO

Chagas disease is caused by infection with the protozoan Trypanosoma cruzi and affects over 8 million people worldwide. In spite of a powerful innate and adaptive immune response in acute infection, the parasite evades eradication, leading to a chronic persistent infection with low parasitism. Chronically infected subjects display differential patterns of disease progression. While 30% develop chronic Chagas disease cardiomyopathy (CCC)-a severe inflammatory dilated cardiomyopathy-decades after infection, 60% of the patients remain disease-free, in the asymptomatic/indeterminate (ASY) form, and 10% develop gastrointestinal disease. Infection of genetically deficient mice provided a map of genes relevant for resistance to T. cruzi infection, leading to the identification of multiple genes linked to survival to infection. These include pathogen resistance genes (PRG) needed for intracellular parasite destruction, and genes involved in disease tolerance (protection against tissue damage and acute phase death-DTG). All identified DTGs were found to directly or indirectly inhibit IFN-γ production or Th1 differentiation. We hypothesize that the absolute need for DTG to control potentially lethal IFN-γ PRG activity leads to T. cruzi persistence and establishment of chronic infection. IFN-γ production is higher in CCC than ASY patients, and is the most highly expressed cytokine in CCC hearts. Key DTGs that downmodulate IFN-γ, like IL-10, and Ebi3/IL27p28, are higher in ASY patients. Polymorphisms in PRG and DTG are associated with differential disease progression. We thus hypothesize that ASY patients are disease tolerant, while an imbalance of DTG and IFN-γ PRG activity leads to the inflammatory heart damage of CCC.


Assuntos
Cardiomiopatia Chagásica/imunologia , Doença de Chagas/imunologia , Tolerância Imunológica/imunologia , Trypanosoma cruzi/imunologia , Progressão da Doença , Coração/parasitologia , Humanos , Interferon gama/imunologia , Interleucina-10/imunologia , Células Th1/imunologia , Células Th1/parasitologia
2.
Nat Commun ; 9(1): 1513, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29666415

RESUMO

Chagas disease is caused by infection with the protozoan Trypanosoma cruzi (T. cruzi) and is an important cause of severe inflammatory heart disease. However, the mechanisms driving Chagas disease cardiomyopathy have not been completely elucidated. Here, we show that the canonical PI3Kγ pathway is upregulated in both human chagasic hearts and hearts of acutely infected mice. PI3Kγ-deficient mice and mutant mice carrying catalytically inactive PI3Kγ are more susceptible to T. cruzi infection. The canonical PI3Kγ signaling in myeloid cells is essential to restrict T. cruzi heart parasitism and ultimately to avoid myocarditis, heart damage, and death of mice. Furthermore, high PIK3CG expression correlates with low parasitism in human Chagas' hearts. In conclusion, these results indicate an essential role of the canonical PI3Kγ signaling pathway in the control of T. cruzi infection, providing further insight into the molecular mechanisms involved in the pathophysiology of chagasic heart disease.


Assuntos
Cardiomiopatia Chagásica/imunologia , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Transdução de Sinais/imunologia , Trypanosoma cruzi/imunologia , Adulto , Animais , Biópsia , Linhagem Celular , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Modelos Animais de Doenças , Feminino , Coração/parasitologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Células Mieloides/imunologia , Células Mieloides/metabolismo , Miocárdio/imunologia , Miocárdio/patologia , Quinoxalinas/farmacologia , Tiazolidinedionas/farmacologia , Trypanosoma cruzi/patogenicidade , Regulação para Cima
3.
Sci Rep ; 7(1): 17990, 2017 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-29269773

RESUMO

Chagas disease, caused by the parasite Trypanosoma cruzi, is endemic in Latin America. Its acute phase is associated with high parasitism, myocarditis and profound myocardial gene expression changes. A chronic phase ensues where 30% develop severe heart lesions. Mouse models of T. cruzi infection have been used to study heart damage in Chagas disease. The aim of this study was to provide an interactome between miRNAs and their targetome in Chagas heart disease by integrating gene and microRNA expression profiling data from hearts of T. cruzi infected mice. Gene expression profiling revealed enrichment in biological processes and pathways associated with immune response and metabolism. Pathways, functional and upstream regulator analysis of the intersections between predicted targets of differentially expressed microRNAs and differentially expressed mRNAs revealed enrichment in biological processes and pathways such as IFNγ, TNFα, NF-kB signaling signatures, CTL-mediated apoptosis, mitochondrial dysfunction, and Nrf2-modulated antioxidative responses. We also observed enrichment in other key heart disease-related processes like myocarditis, fibrosis, hypertrophy and arrhythmia. Our correlation study suggests that miRNAs may be implicated in the pathophysiological processes taking place the hearts of acutely T. cruzi-infected mice.


Assuntos
Doença de Chagas/metabolismo , MicroRNAs/fisiologia , Trypanosoma cruzi/metabolismo , Animais , Doença de Chagas/imunologia , Doença de Chagas/patologia , Feminino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Transcriptoma
4.
Front Immunol ; 8: 1213, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29033934

RESUMO

The identification of anti-inflammatory mediators can reveal important targetable molecules capable of counterbalancing Trypanosoma cruzi-induced myocarditis. Composed of Ebi3 and IL-27p28 subunits, IL-27 is produced by myeloid cells and is able to suppress inflammation by inducing IL-10-producing Tr1 cells, thus emerging as a potential candidate to ameliorate cardiac inflammation induced by T. cruzi. Although IL-27 has been extensively characterized as a suppressive cytokine that prevents liver immunopathogenesis after T. cruzi infection, the mechanisms underlying its effects on T. cruzi-induced myocarditis remain largely unknown. Here, wild-type (WT) and Ebi3-deficient animals were intraperitoneally infected with trypomastigotes of T. cruzi Y strain and used to evaluate the potential anti-inflammatory properties of Ebi3 during T. cruzi infection. The survival rates of mice were daily recorded, the frequency of inflammatory cells was analyzed by flow cytometry and inflammatory mediators were measured by ELISA, real-time PCR and PCR array. We reported that T. cruzi-induced myocarditis was prevented by Ebi3. Stressors mainly recognized by TLR2 and TLR4 receptors on myeloid cells were essential to trigger IL-27p28 production. In addition, Ebi3 regulated IFN-γ-mediated myocarditis by promoting an anti-inflammatory environment through IL-10, which was most likely produced by Tr1 cells rather than classical regulatory T cells (Tregs), in the heart tissue of T. cruzi-infected animals. Furthermore, in vivo IFN-γ blockade ameliorated the host survival without compromising the parasite control in the bloodstream. In humans, IL-27p28 was correlated with cardiac protection during Chagas disease. Patients with mild clinical forms of the disease produced high levels of IL-27p28, whereas lower levels were found in those with severe forms. In addition, polymorphic sites at Ebi3 gene were associated with severe cardiomyopathy in patients with Chagas disease. Collectively, we describe a novel regulatory mechanism where Ebi3 dampens cardiac inflammation by modulating the overproduction of IFN-γ, the bona fide culprit of Chagas disease cardiomyopathy.

5.
Clin Infect Dis ; 65(7): 1103-1111, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575239

RESUMO

Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects 10 million people worldwide. Approximately 12000 deaths attributable to Chagas disease occur annually due to chronic Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy presenting with heart failure and arrythmia; 30% of infected subjects develop CCC years after infection. Genetic mechanisms play a role in differential progression to CCC, but little is known about the role of epigenetic modifications in pathological gene expression patterns in CCC patients' myocardium. DNA methylation is the most common modification in the mammalian genome. Methods: We investigated the impact of genome-wide cardiac DNA methylation on global gene expression in myocardial samples from end-stage CCC patients, compared to control samples from organ donors. Results: In total, 4720 genes were differentially methylated between CCC patients and controls, of which 399 were also differentially expressed. Several of them were related to heart function or to the immune response and had methylation sites in their promoter region. Reporter gene and in silico transcription factor binding analyses indicated promoter methylation modified expression of key genes. Among those, we found potassium channel genes KCNA4 and KCNIP4, involved in electrical conduction and arrythmia, SMOC2, involved in matrix remodeling, as well as enkephalin and RUNX3, potentially involved in the increased T-helper 1 cytokine-mediated inflammatory damage in heart. Conclusions: Results support that DNA methylation plays a role in the regulation of expression of pathogenically relevant genes in CCC myocardium, and identify novel potential disease pathways and therapeutic targets in CCC.


Assuntos
Cardiomiopatia Chagásica/genética , Doença de Chagas/genética , Metilação de DNA/genética , Adolescente , Adulto , Idoso , Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/parasitologia , Doença Crônica , Impressões Digitais de DNA/métodos , Feminino , Expressão Gênica/genética , Coração/parasitologia , Humanos , Inflamação/genética , Inflamação/parasitologia , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Canais de Potássio/genética , Regiões Promotoras Genéticas/genética , Trypanosoma cruzi/patogenicidade , Adulto Jovem
6.
J Infect Dis ; 214(1): 161-5, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-26951817

RESUMO

Long noncoding RNAs (lncRNAs) modulate gene expression at the epigenetic, transcriptional, and posttranscriptional levels. Dysregulation of the lncRNA known as myocardial infarction-associated transcript (MIAT) has been associated with myocardial infarction. Chagas disease causes a severe inflammatory dilated chronic cardiomyopathy (CCC). We investigated the role of MIAT in CCC. A whole-transcriptome analysis of heart biopsy specimens and formalin-fixed, paraffin-embedded samples revealed that MIAT was overexpressed in patients with CCC, compared with subjects with noninflammatory dilated cardiomyopathy and controls. These results were confirmed in a mouse model. Results suggest that MIAT is a specific biomarker of CCC.


Assuntos
Doença de Chagas/complicações , Doença de Chagas/genética , Perfilação da Expressão Gênica , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/genética , RNA Longo não Codificante , Animais , Doença de Chagas/fisiopatologia , Feminino , Humanos , Masculino , Camundongos , Fatores de Transcrição
7.
PLoS Negl Trop Dis ; 9(6): e0003828, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26086673

RESUMO

Chagas disease is caused by the parasite Trypanosoma cruzi, and it begins with a short acute phase characterized by high parasitemia followed by a life-long chronic phase with scarce parasitism. Cardiac involvement is the most prominent manifestation, as 30% of infected subjects will develop abnormal ventricular repolarization with myocarditis, fibrosis and cardiomyocyte hypertrophy by undefined mechanisms. Nevertheless, follow-up studies in chagasic patients, as well as studies with murine models, suggest that the intensity of clinical symptoms and pathophysiological events that occur during the acute phase of disease are associated with the severity of cardiac disease observed during the chronic phase. In the present study we investigated the role of microRNAs (miRNAs) in the disease progression in response to T. cruzi infection, as alterations in miRNA levels are known to be associated with many cardiovascular disorders. We screened 641 rodent miRNAs in heart samples of mice during an acute infection with the Colombiana T.cruzi strain and identified multiple miRNAs significantly altered upon infection. Seventeen miRNAs were found significantly deregulated in all three analyzed time points post infection. Among these, six miRNAs had their expression correlated with clinical parameters relevant to the disease, such as parasitemia and maximal heart rate-corrected QT (QTc) interval. Computational analyses identified that the gene targets for these six miRNAs were involved in networks and signaling pathways related to increased ventricular depolarization and repolarization times, important factors for QTc interval prolongation. The data presented here will guide further studies about the contribution of microRNAs to Chagas heart disease pathogenesis.


Assuntos
Cardiomiopatia Chagásica/metabolismo , Coração/fisiopatologia , MicroRNAs/metabolismo , Miocárdio/metabolismo , Transdução de Sinais/fisiologia , Transcriptoma/genética , Trypanosoma cruzi , Animais , Cardiomiopatia Chagásica/patologia , Eletrocardiografia , Feminino , Perfilação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Análise de Componente Principal , Transdução de Sinais/genética
9.
Cytokine ; 73(1): 79-83, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25743241

RESUMO

BACKGROUND: Chronic Chagas Disease cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy, affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi, the rest of the infected subjects remaining asymptomatic (ASY). The Th1 T cell-rich myocarditis plays a pivotal role in CCC pathogenesis. Local expression of IL-18 in CCC myocardial tissue has recently been described. IL-18 could potentially amplify the process by inducing increased expression of IFN-γ which in turn can increase the production of IL-18, thereby creating a positive feedback mechanism. In order to assess the contribution of the IL-18 to susceptibility to Chronic Chagas Disease, we investigated the association between a single nucleotide polymorphism (SNP) located in the IL-18 gene with the risk of developing Chagas cardiomyopathy. METHODS AND RESULTS: We analyzed the rs2043055 marker in the IL18 gene in a cohort of Chagas disease cardiomyopathy patients (n=849) and asymptomatic subjects (n=202). We found a significant difference in genotype frequencies among moderate and severe CCC patients with ventricular dysfunction. CONCLUSIONS: Our analysis suggests that the IL18 rs2043055 polymorphism- or a SNP in tight linkage disequilibrium with it- may contribute to modulating the Chagas cardiomyopathy outcome.


Assuntos
Cardiomiopatia Chagásica/genética , Predisposição Genética para Doença , Interleucina-18/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Cardiomiopatia Chagásica/fisiopatologia , Doença Crônica , Estudos de Coortes , Feminino , Estudos de Associação Genética , Humanos , Masculino , Volume Sistólico
10.
Cytokine ; 73: 79-83, 2015. tab
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-31265

RESUMO

Background: Chronic Chagas Disease cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy,affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi, the restof the infected subjects remaining asymptomatic (ASY). The Th1 T cell-rich myocarditis plays a pivotalrole in CCC pathogenesis. Local expression of IL-18 in CCC myocardial tissue has recently been described.IL-18 could potentially amplify the process by inducing increased expression of IFN-c which in turn canincrease the production of IL-18, thereby creating a positive feedback mechanism. In order to assess thecontribution of the IL-18 to susceptibility to Chronic Chagas Disease, we investigated the associationbetween a single nucleotide polymorphism (SNP) located in the IL-18 gene with the risk of developingChagas cardiomyopathy.Methods and results: We analyzed the rs2043055 marker in the IL18 gene in a cohort of Chagas diseasecardiomyopathy patients (n = 849) and asymptomatic subjects (n = 202). We found a significant differencein genotype frequencies among moderate and severe CCC patients with ventricular dysfunction.Conclusions: Our analysis suggests that the IL18 rs2043055 polymorphism- or a SNP in tight linkagedisequilibrium with it- may contribute to modulating the Chagas cardiomyopathy outcome. (AU)


Assuntos
Doença de Chagas , Miocardite , Disfunção Ventricular
11.
Mediators Inflamm ; 2014: 683230, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25210230

RESUMO

Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects ca. 10 million people worldwide. About 30% of Chagas disease patients develop chronic Chagas disease cardiomyopathy (CCC), a particularly lethal inflammatory cardiomyopathy that occurs decades after the initial infection, while most patients remain asymptomatic. Mortality rate is higher than that of noninflammatory cardiomyopathy. CCC heart lesions present a Th1 T-cell-rich myocarditis, with cardiomyocyte hypertrophy and prominent fibrosis. Data suggest that the myocarditis plays a major pathogenetic role in disease progression. Major unmet goals include the thorough understanding of disease pathogenesis and therapeutic targets and identification of prognostic genetic factors. Chagas disease thus remains a neglected disease, with no vaccines or antiparasitic drugs proven efficient in chronically infected adults, when most patients are diagnosed. Both familial aggregation of CCC cases and the fact that only 30% of infected patients develop CCC suggest there might be a genetic component to disease susceptibility. Moreover, previous case-control studies have identified some genes associated to human susceptibility to CCC. In this paper, we will review the immunopathogenesis and genetics of Chagas disease, highlighting studies that shed light on the differential progression of Chagas disease patients to CCC.


Assuntos
Cardiomiopatia Chagásica/genética , Cardiomiopatia Chagásica/patologia , Animais , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/metabolismo , Humanos
12.
World J Cardiol ; 6(8): 782-90, 2014 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-25228957

RESUMO

Chagas disease cardiomyopathy (CCC), the main consequence of Trypanosoma cruzi (T.cruzi) infection, is an inflammatory cardiomyopathy that develops in up to 30% of infected individuals. The heart inflammation in CCC patients is characterized by a Th1 T cell-rich myocarditis with increased production of interferon (IFN)-γ, produced by the CCC myocardial infiltrate and detected at high levels in the periphery. IFN-γ has a central role in the cardiomyocyte signaling during both acute and chronic phases of T.cruzi infection. In this review, we have chosen to focus in its pleiotropic mode of action during CCC, which may ultimately be the strongest driver towards pathological remodeling and heart failure. We describe here the antiparasitic protective and pathogenic dual role of IFN-γ in Chagas disease.

13.
Int J Cardiol ; 175(3): 409-17, 2014 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-24910366

RESUMO

BACKGROUND/METHODS: Chagas disease is caused by an intracellular parasite, Trypanosoma cruzi, and it is a leading cause of heart failure in Latin America. The main clinical consequence of the infection is the development of a Chronic Chagas disease Cardiomyopathy (CCC), which is characterized by myocarditis, hypertrophy and fibrosis and affects about 30% of infected patients. CCC has a worse prognosis than other cardiomyopathies, like idiopathic dilated cardiomyopathy (DCM). It is well established that myocardial gene expression patterns are altered in CCC, but the molecular mechanisms underlying these differences are not clear. MicroRNAs are recently discovered regulators of gene expression, and are recognized as important factors in heart development and cardiovascular disorders (CD). We analyzed the expression of nine different miRNAs in myocardial tissue samples of CCC patients in comparison to DCM patients and samples from heart transplant donors. Using the results of a cDNA microarray database on CCC and DCM myocardium, signaling networks were built and nodal molecules were identified. RESULTS: We observed that five miRNAs were significantly altered in CCC and three in DCM; importantly, three miRNAs were significantly reduced in CCC as compared to DCM. We observed that multiple gene targets of the differentially expressed miRNAs showed a concordant inverse expression in CCC. Significantly, most gene targets and involved networks belong to crucial disease-related signaling pathways. CONCLUSION: These results suggest that miRNAs may play a major role in the regulation of gene expression in CCC pathogenesis, with potential implication as diagnostic and prognostic tools.


Assuntos
Cardiomiopatia Chagásica/metabolismo , MicroRNAs/biossíntese , Adolescente , Adulto , Biomarcadores/metabolismo , Cardiomiopatia Chagásica/diagnóstico , Cardiomiopatia Chagásica/genética , Doença Crônica , Feminino , Redes Reguladoras de Genes/fisiologia , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miocárdio/patologia , Adulto Jovem
14.
PLoS One ; 8(12): e83446, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24367596

RESUMO

AIMS: Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America, and may lead to a life-threatening inflammatory dilated, chronic Chagas cardiomyopathy (CCC). One third of T. cruzi-infected individuals progress to CCC while the others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Since mutations in multiple sarcomeric genes, including alpha-cardiac actin (ACTC1) have been involved in hereditary dilated cardiomyopathy, we investigated the involvement of the ACTC1 gene in CCC pathogenesis. METHODS AND RESULTS: We conducted a proteomic and genetic study on a Brazilian study population. The genetic study was done on a main cohort including 118 seropositive asymptomatic subjects and 315 cases and the replication was done on 36 asymptomatic and 102 CCC cases. ACTC1 protein and mRNA levels were lower in myocardial tissue from patients with end-stage CCC than those found in hearts from organ donors. Genotyping a case-control cohort of CCC and ASY subjects for all informative single nucleotide polymorphism (SNP) in the ACTC1 gene identified rs640249 SNP, located at the 5' region, as associated to CCC. Associations are borderline after correction for multiple testing. Correlation and haplotype analysis led to the identification of a susceptibility haplotype. Functional assays have shown that the rs640249A/C polymorphism affects the binding of transcriptional factors in the promoter regions of the ACTC1 gene. Confirmation of the detected association on a larger independent replication cohort will be useful. CONCLUSIONS: Genetic variations at the ACTC1 gene may contribute to progression to chronic Chagas Cardiomyopathy among T. cruzi-infected patients, possibly by modulating transcription factor binding to ACTC1 promoter regions.


Assuntos
Actinas/genética , Cardiomiopatia Chagásica/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Actinas/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Miocárdio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
15.
BMC Infect Dis ; 13: 587, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24330528

RESUMO

BACKGROUND: Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. The others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Migration of Th1-type T cells play a major role in myocardial damage. METHODS: Our genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects. RESULTS: The CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%. CONCLUSIONS: Our data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets.


Assuntos
Cardiomiopatia Chagásica/genética , Quimiocina CCL2/genética , Predisposição Genética para Doença , Imunidade Inata , Glicoproteínas de Membrana/genética , Receptores CCR5/genética , Receptores de Interleucina-1/genética , Trypanosoma cruzi/fisiologia , Adulto , Idoso , Brasil , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/prevenção & controle , Quimiocina CCL2/imunologia , Feminino , Genótipo , Humanos , Masculino , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores CCR5/imunologia , Receptores de Interleucina-1/imunologia
16.
PLOS ONE ; 8(12): 1-16, 2013. ilus
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-29744

RESUMO

Aims: Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America, and may lead to alife-threatening inflammatory dilated, chronic Chagas cardiomyopathy (CCC). One third of T. cruzi-infectedindividuals progress to CCC while the others remain asymptomatic (ASY). A possible genetic component to diseaseprogression was suggested by familial aggregation of cases and the association of markers of innate and adaptiveimmunity genes with CCC development. Since mutations in multiple sarcomeric genes, including alpha-cardiac actin(ACTC1) have been involved in hereditary dilated cardiomyopathy, we investigated the involvement of the ACTC1gene in CCC pathogenesis.Methods and Results: We conducted a proteomic and genetic study on a Brazilian study population. The geneticstudy was done on a main cohort including 118 seropositive asymptomatic subjects and 315 cases and thereplication was done on 36 asymptomatic and 102 CCC cases. ACTC1 protein and mRNA levels were lower inmyocardial tissue from patients with end-stage CCC than those found in hearts from organ donors. Genotyping acase-control cohort of CCC and ASY subjects for all informative single nucleotide polymorphism (SNP) in the ACTC1gene identified rs640249 SNP, located at the 5’ region, as associated to CCC. Associations are borderline aftercorrection for multiple testing. Correlation and haplotype analysis led to the identification of a susceptibility haplotype.Functional assays have shown that the rs640249A/C polymorphism affects the binding of transcriptional factors in thepromoter regions of the ACTC1 gene. Confirmation of the detected association on a larger independent replicationcohort will be useful.Conclusions: Genetic variations at the ACTC1 gene may contribute to progression to chronic ChagasCardiomyopathy among T. cruzi-infected patients, possibly by modulating transcription factor binding to ACTC1promoter regions. (AU)


Assuntos
Doença de Chagas , Variação Genética , Cardiomiopatia Chagásica
17.
J Rheumatol ; 37(2): 351-8, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20032097

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) is a life-threatening autoimmune disease characterized by chronic fibrosis of the skin and internal organs. Connective tissue growth factor (CTGF) is believed to be a primary mediator of chronic fibrosis. We assessed the possible association between 7 single-nucleotide polymorphisms (SNP) in the CTGF gene and scleroderma in a French population (registration number 2006/0182). METHODS: We conducted a case-control study with 241 scleroderma patients and 269 controls. Seven SNP were genotyped using the TaqMan system. Univariate and multivariate analyses were performed. In silico electrophoretic mobility shift assay (EMSA), and reverse transcriptase polymerase chain reaction analyses were done to assess the effect of the SNP on CTGF gene expression. RESULTS: The frequency of the rs9399005TT genotype was significantly lower in SSc patients than in controls. This association remained significant after adjustment for gender. An association was detected between the rs9399005 and the diffuse and limited cutaneous forms. Multivariate analysis between SSc patients and controls taking into account all 7 SNP and sex revealed that only sex and the rs9399005 SNP were associated with disease. DNA analysis by EMSA indicated that the T allele bound nuclear factors that were also bound by the C allele. The binding affinity was higher for the T allele. Analysis of the human database and experiments with human hepatocyte cell line indicated the existence of an alternative transcript containing the rs9399005 polymorphism in its 3'UTR region. In silico analysis indicated that this polymorphism may alter the structure of CTGF messenger RNA. CONCLUSION: These findings suggest that CTGF gene polymorphisms may contribute to susceptibility to scleroderma.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Escleroderma Sistêmico/genética , Alelos , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , França , Genótipo , Humanos , Masculino , Análise de Regressão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores Sexuais
18.
J Exp Med ; 206(11): 2321-8, 2009 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-19822645

RESUMO

Abnormal fibrosis occurs during chronic hepatic inflammations and is the principal cause of death in hepatitis C virus and schistosome infections. Hepatic fibrosis (HF) may develop either slowly or rapidly in schistosome-infected subjects. This depends, in part, on a major genetic control exerted by genes of chromosome 6q23. A gene (connective tissue growth factor [CTGF]) is located in that region that encodes a strongly fibrogenic molecule. We show that the single nucleotide polymorphism (SNP) rs9402373 that lies close to CTGF is associated with severe HF (P = 2 x 10(-6); odds ratio [OR] = 2.01; confidence interval of OR [CI] = 1.51-2.7) in two Chinese samples, in Sudanese, and in Brazilians infected with either Schistosoma japonicum or S. mansoni. Furthermore, SNP rs12526196, also located close to CTGF, is independently associated with severe fibrosis (P = 6 x 10(-4); OR = 1.94; CI = 1.32-2.82) in the Chinese and Sudanese subjects. Both variants affect nuclear factor binding and may alter gene transcription or transcript stability. The identified variants may be valuable markers for the prediction of disease progression, and identify a critical step in the development of HF that could be a target for chemotherapy.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/genética , Predisposição Genética para Doença , Cirrose Hepática/genética , Cirrose Hepática/parasitologia , Polimorfismo de Nucleotídeo Único/genética , Esquistossomose/complicações , Esquistossomose/genética , Grupo com Ancestrais do Continente Africano/genética , Agricultura , Grupo com Ancestrais Nativos do Continente Americano/genética , Animais , Grupo com Ancestrais do Continente Asiático/genética , Brasil , Linhagem Celular , China , Ensaio de Desvio de Mobilidade Eletroforética , Pesqueiros , Humanos , Cirrose Hepática/complicações , Proteínas Nucleares , Ligação Proteica , Estabilidade de RNA , Schistosoma/fisiologia , Esquistossomose/parasitologia , Sudão , Transcrição Genética , Recursos Humanos
19.
Eur J Intern Med ; 20(3): 242-52, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19393491

RESUMO

BACKGROUND: Systemic sclerosis is a rare autoimmune disease mainly characterized by vascular alteration and fibrosis involving skin but also visceral organs such as lungs, digestive tract, and heart. This disease leads to high morbidity and mortality. Its pathogenesis remains unclear, but recent attention has focus on genetic factors. OBJECTIVE: We first recall the main manifestations associated with systemic sclerosis and leading to its diagnosis and prognosis. Then we propose an overview on human genetics studies, as a number of genetic loci have been identified that appear to be associated with the disease. METHODS: Articles concerning association studies with candidate genes encoding for extracellular matrix proteins, cytokines, growth factors, chemokines, and proteins involved in vascular tone and immune regulations are presented and discussed. RESULTS/CONCLUSION: Systemic sclerosis is a multigenic complex disorder. Genetic associations are observed in distinct phenotypes such as the diffuse cutaneous form or the limited form, or in association with specific autoantibody pattern. Promising candidate genes are those involved in pathways that lead to the vascular damage and fibrosis. A better knowledge of crucial mediators involved in systemic sclerosis could in the future provide new therapeutic strategies to control the disease.


Assuntos
Predisposição Genética para Doença , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Humanos , Polimorfismo Genético , Fatores de Risco , Escleroderma Sistêmico/epidemiologia
20.
J Immunol ; 180(9): 6139-48, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18424735

RESUMO

In populations exposed to Leishmania braziliensis, certain subjects develop skin ulcers, whereas others are naturally protected against cutaneous leishmaniasis. We have evaluated which cytokines are most crucial in the development of skin lesions. We found that active lesions occur in subjects with polarized Th2 or mixed Th1/Th2 responses, both associated with elevated IL-10 production. IL-10 was strongly associated (p = 0.004, odd ratio (OR) = 6.8, confidence interval = 1.9-25) with lesions, excluding IFN-gamma, IL-12, TNF, IL-13, and IL-4 from the regression model. IL-10 was produced by blood monocytes and CD4(+)CD25(+) T lymphocytes (mostly Foxp3(+)). However, we did not observe any difference between the number of these cells present in the blood of subjects with active lesions and those present in resistant subjects. Genetic analysis of the IL10-819C/T polymorphism, located in the IL10 promoter, showed that the C allele increased the risk of lesions (OR = 2.5 (1.12-5.7), p = 0.003). Functional analysis of these variants showed allele-specific binding of nuclear factors. The IL10-819C/C genotype was associated with higher levels of IL-10 than C/T and T/T genotypes. These observations demonstrate an important role for IL-10 in skin lesions in humans infected with L. braziliensis, and identify circulating monocytes and Tregs as principal sources of IL-10 in these patients.


Assuntos
Interleucina-10/genética , Interleucina-10/imunologia , Leishmania braziliensis/imunologia , Leishmaniose Cutânea/genética , Leishmaniose Cutânea/imunologia , Monócitos/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Animais , Citocinas/genética , Citocinas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/imunologia , Regiões Promotoras Genéticas/genética , Regiões Promotoras Genéticas/imunologia , Fatores de Risco , Células Th1/imunologia , Células Th2/imunologia
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