Innate immune receptors over expression correlate with chronic chagasic cardiomyopathy and digestive damage in patients.

Chronic chagasic cardiomyopathy (CCC) is observed in 30% to 50% of the individuals infected by Trypanosoma cruzi and heart failure is the important cause of death among patients in the chronic phase of Chagas disease. Although some studies have elucidated the role of adaptive immune responses involving T and B lymphocytes in cardiac pathogenesis, the role of innate immunity receptors such as Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in CCC pathophysiology has not yet been determined. In this study, we evaluated the association among innate immune receptors (TLR1-9 and nucleotide-binding domain-like receptor protein 3/NLRP3), its adapter molecules (Myd88, TRIF, ASC and caspase-1) and cytokines (IL-1β, IL-6, IL-12, IL-18, IL-23, TNF-α, and IFN-β) with clinical manifestation, digestive and cardiac function in patients with different clinical forms of chronic Chagas disease. The TLR8 mRNA expression levels were enhanced in the peripheral blood mononuclear cells (PBMC) from digestive and cardiodigestive patients compared to indeterminate and cardiac patients. Furthermore, mRNA expression of IFN-β (cytokine produced after TLR8 activation) was higher in digestive and cardiodigestive patients when compared to indeterminate. Moreover, there was a positive correlation between TLR8 and IFN-β mRNA expression with sigmoid and rectum size. Cardiac and cardiodigestive patients presented higher TLR2, IL-12 and TNF-α mRNA expression than indeterminate and digestive patients. Moreover, cardiac patients also expressed higher levels of NLRP3, ASC and IL-1β mRNAs than indeterminate patients. In addition, we showed a negative correlation among TLR2, IL-1β, IL-12 and TNF-α levels with left ventricular ejection fraction, and positive correlation between NLRP3 with cardiothoracic index, and TLR2, IL-1β and IL-12 with left ventricular mass index. Together, our data suggest that high expression of innate immune receptors in cardiac and digestive patients may induce an enhancement of cytokine expression and participate of cardiac and digestive dysfunction

Innate immune receptors over expression correlate with chronic chagasic cardiomyopathy and digestive damage in patients

Submitted by Sandra Infurna ([email protected]) on 2019-01-30T10:27:25Z No. of bitstreams: 1 adelaideV_Motta_etal_IOC_2018.pdf: 4348852 bytes, checksum: 2a6663ea033f9812085adebf92dec5ce (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2019-01-30T10:46:20Z (GMT) No. of bitstreams: 1 adelaideV_Motta_etal_IOC_2018.pdf: 4348852 bytes, checksum: 2a6663ea033f9812085adebf92dec5ce (MD5)Made available in DSpace on 2019-01-30T10:46:20Z (GMT). No. of bitstreams: 1 adelaideV_Motta_etal_IOC_2018.pdf: 4348852 bytes, checksum: 2a6663ea033f9812085adebf92dec5ce (MD5) Previous issue date: 2018Universidade Federal de Minas Gerais. Departamento de Parasitologia. Belo Horizonte, MG, Brasil / Universidade Federal do Rio Grande do Norte. Departamento de Microbiologia e Parasitologia. Natal, RN, Brasil / Universidade Potiguar. Escola de Saúde. Natal, RN, Brasil.Universidade Federal do Rio Grande do Norte. Departamento de Microbiologia e Parasitologia. Natal, RN, Brasil.Universidade Federal de Minas Gerais. Departamento de Parasitologia. Belo Horizonte, MG, Brasil.Universidade do Estado do Rio Grande do Norte. Departamento de Ciências Biomédicas. Mossoró, RN, Brasil.Instituto Internacional de Neurociências Edmond e Lilly Safra. Macaíba, RN, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ. Brasil.Universidade Federal do Rio Grande do Norte. Departamento de Análises Clínicas e Toxicológicas. Natal, RN, Brasil.Universidade Federal de Minas Gerais. Departamento de Parasitologia. Belo Horizonte, MG, Brasil.Universidade Federal do Rio Grande do Norte. Departamento de Microbiologia e Parasitologia. Natal, RN, Brasil.Universidade Federal de Minas Gerais. Departamento de Parasitologia. Belo Horizonte, MG, BrasilChronic chagasic cardiomyopathy (CCC) is observed in 30% to 50% of the individuals infected by Trypanosoma cruzi and heart failure is the important cause of death among patients in the chronic phase of Chagas disease. Although some studies have elucidated the role of adaptive immune responses involving T and B lymphocytes in cardiac pathogenesis, the role of innate immunity receptors such as Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in CCC pathophysiology has not yet been determined. In this study, we evaluated the association among innate immune receptors (TLR1-9 and nucleotide-binding domain-like receptor protein 3/NLRP3), its adapter molecules (Myd88, TRIF, ASC and caspase- 1) and cytokines (IL-1β, IL-6, IL-12, IL-18, IL-23, TNF-α, and IFN-β) with clinical manifestation, digestive and cardiac function in patients with different clinical forms of chronic Chagas disease. The TLR8 mRNA expression levels were enhanced in the peripheral blood mononuclear cells (PBMC) from digestive and cardiodigestive patients compared to indeterminate and cardiac patients. Furthermore, mRNA expression of IFN-β (cytokine produced after TLR8 activation) was higher in digestive and cardiodigestive patients when compared to indeterminate. Moreover, there was a positive correlation between TLR8 and IFN-β mRNA expression with sigmoid and rectum size. Cardiac and cardiodigestive patients presented higher TLR2, IL-12 and TNF-α mRNA expression than indeterminate and digestive patients. Moreover, cardiac patients also expressed higher levels of NLRP3, ASC and IL-1β mRNAs than indeterminate patients. In addition, we showed a negative correlation among TLR2, IL-1β, IL-12 and TNF-α levels with left ventricular ejection fraction, and positive correlation between NLRP3 with cardiothoracic index, and TLR2, IL-1β and IL-12 with left ventricular mass index. Together, our data suggest that high expression of innate immune.receptors in cardiac and digestive patients may induce an enhancement of cytokine expression and participate of cardiac and digestive dysfunction

Inflammation Enhances the Risks of Stroke and Death in Chronic Chagas Disease Patients

Submitted by sandra infurna ([email protected]) on 2016-06-19T18:59:10Z No. of bitstreams: 1 mariaadelaide_matta_etal_IOC_2016.pdf: 749988 bytes, checksum: 989d8777a371bcd276efecde9a5d4214 (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-06-19T19:21:52Z (GMT) No. of bitstreams: 1 mariaadelaide_matta_etal_IOC_2016.pdf: 749988 bytes, checksum: 989d8777a371bcd276efecde9a5d4214 (MD5)Made available in DSpace on 2016-06-19T19:21:52Z (GMT). No. of bitstreams: 1 mariaadelaide_matta_etal_IOC_2016.pdf: 749988 bytes, checksum: 989d8777a371bcd276efecde9a5d4214 (MD5) Previous issue date: 2016Made available in DSpace on 2016-07-08T12:21:49Z (GMT). No. of bitstreams: 3 mariaadelaide_matta_etal_IOC_2016.pdf.txt: 58546 bytes, checksum: d1a8f1e931ab9591fce414aa980fdaa1 (MD5) mariaadelaide_matta_etal_IOC_2016.pdf: 749988 bytes, checksum: 989d8777a371bcd276efecde9a5d4214 (MD5) license.txt: 2991 bytes, checksum: 5a560609d32a3863062d77ff32785d58 (MD5) Previous issue date: 2016Universidade Federal do Rio Grande do Norte. Departamento de Microbiologia e Parasiologia. Natal, RN, BrasilUniversidade do Estado do Rio Grande do Norte. Departamento de Ciências Biomédicas. Mossoró, RN, Brasil.Universidade Federal de Minas Gerais. Departamento de Parasitologia. Belo Horizonte, MG, Brasil.Universidade Federal do Rio Grande do Norte. Departamento de Microbiologia e Parasiologia. Natal, RN, Brasil / Universidade Federal de Minas Gerais. Departamento de Parasitologia. Belo Horizonte, MG, Brasil.Universidade Federal do Rio Grande do Norte. Departamento de Microbiologia e Parasiologia. Natal, RN, BrasilUniversidade Federal de Ouro Preto. Escola de Medicina. Ouro Preto, MG, Brasil.Univrsidade de São Paulo. Escola de Medicina de Ribeirão Preto. Ribeirão Preto, SP, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório deUltraestrutura Celular. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio Grande do Norte. Departmaneto de Análises Clínicas e Toxicológicas. Natal, RN, Brasil.Universidade Federal de Minas Gerais. Departamento de Parasitologia. Belo Horizonte, MG, Brasil.Ischemic strokes have been implicated as a cause of death in Chagas disease patients. Inflammation has been recognized as a key component in all ischemic processes, including the intravascular events triggered by vessel interruption, brain damage and repair. In this study, we evaluated the association between inflammatory markers and the death risk (DR) and stroke risk (SR) of patients with different clinical forms of chronic Chagas disease. The mRNA expression levels of cytokines, transcription factors expressed in the adaptive immune response (Th1, Th2, Th9, Th17, Th22 and regulatory T cell), and iNOS were analyzed by realtime PCR in peripheral blood mononuclear cells of chagasic patients who exhibited the indeterminate, cardiac, digestive and cardiodigestive clinical forms of the disease, and the levels of these transcripts were correlated with the DR and SR. Cardiac patients exhibited lowermRNA expression levels of GATA-3, FoxP3, AHR, IL-4, IL-9, IL-10 and IL-22 but exhibited higher expression of IFN-γ and TNF-α compared with indeterminate patients. Digestive patients showed similar levels of GATA-3, IL-4 and IL-10 than indeterminate patients. Cardiodigestive patients exhibited higher levels of TNF-α compared with indeterminate and digestive patients. Furthermore, we demonstrated that patients with high DR and SR exhibited lower GATA-3, FoxP3, and IL-10 expression and higher IFN-γ, TNF-α and iNOS mRNA expression than patients with low DR and SR. A negative correlation was observed between Foxp3 and IL-10 mRNA expression and the DR and SR. Moreover, TNF-α and iNOS expression was positively correlated with DR and SR. Our data suggest that an inflammatory imbalance in chronic Chagas disease patients is associated with a high DR and SR. This study provides a better understanding of the stroke pathobiology in the general population and might aid the development of therapeutic strategies for controlling the morbidity and mortality of Chagas disease

Clinical data of chronic chagasic patients from the Northeast of Brazil included in this investigation.

<p>Clinical data of chronic chagasic patients from the Northeast of Brazil included in this investigation.</p

Chronic chagasic cardiomyopathy is correlated with high TLR2 mRNA expression and digestive form is correlated with high TLR8 expression.

<p>The mRNA expression levels of TLR1 (A), TLR2 (B), TLR3 (C), TLR4 (D), TLR5 (E), TLR6 (F), TLR7 (G), TLR8 (H) and TLR9 (I) were determined by real-time PCR in peripheral blood mononuclear cells of patients with the indeterminate (n = 18), cardiac (n = 17), cardiodigestive (n = 15) and digestive (n = 15) clinical forms of Chagas disease. The expression levels were normalized to the expression level of β-actin. The results are expressed as the means ± standard errors. *p < 0.05. UCI: Uninfected control individuals (n = 15).</p

High NLRP3 expression is correlated with high cardiothoracic index (CI).

<p>The mRNA expression levels of NLRP3 (A), TLR2 (B), IL-1β (C) and IL-12 (D) were determined by real-time PCR in peripheral blood mononuclear cells of patients with the indeterminate (n = 18), cardiac (n = 17), digestive (n = 15) and cardiodigestive (n = 15) clinical forms of Chagas disease and correlated with cardiothoracic index (CI). The expression levels were normalized to the expression level of β-actin. Spearman test was used.</p

Sequences of the primers used for RT-PCR reactions.

<p>Sequences of the primers used for RT-PCR reactions.</p

High left ventricle mass index (LVMI) is correlated with high TLR-2, IL-1β and TNF-α mRNA expression.

<p>The mRNA expression levels of NLRP3 (A), TLR2 (B), IL-1β (C) and IL-12 (D) were determined by real-time PCR in PBMC of indeterminate (n = 18), cardiac (n = 17), digestive (n = 15) and cardiodigestive (n = 15) patients and correlated with LVMI. Spearman test was used.</p

Chronic chagasic cardiomyopathy is correlated with high IL-12 and TNF-α levels in sera.

<p>Levels of the cytokines IL-12 (A), TNF-α (B) and IL-1β (C) was analyzed by ELISA in the sera of indeterminate/IND (n = 18), cardiac/CARD (n = 17), digestive/DIG (n = 15) and cardiodigestive/CARDIG (n = 15) patients. The results are expressed as means ± standard errors. *p < 0.05. UCI: Uninfected control individuals (n = 15).</p

Cardiac patients exhibited higher NLRP3, ASC and IL-1β mRNA expression than indeterminate patients.

<p>The mRNA expression levels of NLRP3 (A), ASC (B), Caspase-1 (C), IL-1β (D) and IL-18 (E) were determined by real-time PCR in peripheral blood mononuclear cells of patients with the indeterminate (n = 18), cardiac (n = 17), digestive (n = 15) and cardiodigestive (n = 15) clinical forms of Chagas disease. The expression levels were normalized to the expression level of β-actin. The results are expressed as the means ± standard errors. *p < 0.05. UC: Uninfected control individuals (n = 15).</p