Instituto Nacional para Pesquisa Translacional em Saude e Ambiente na Regiao Amazonica


Instituto Nacional para Pesquisa Translacional em Saude e Ambiente na Regiao Amazonica

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Silva-Filho J.L.,Federal University of Rio de Janeiro | Silva-Filho J.L.,University of Campinas | Caruso-Neves C.,Federal University of Rio de Janeiro | Caruso-Neves C.,Brazilian National Institute of Technology | And 2 more authors.
Frontiers in Cellular and Infection Microbiology | Year: 2017

CD8+ T-cell response is critical in the pathogenesis of cerebral malaria during blood-stage. Our group and other have been shown that angiotensin II (Ang II) and its receptor AT1 (AT1R), a key effector axis of renin-angiotensin system (RAS), have immune regulatory effects on T cells. Previously, we showed that inhibition of AT1R signaling protects mice against the lethal disease induced by Plasmodium berghei ANKA infection However, most of the Ang II/AT1R actions were characterized by using only pharmacological approaches, the effects of which may not always be due to a specific receptor blockade. In addition, the mechanisms of action of the AT1R in inducing the pathogenic activity of Plasmodium-specific CD8+ T cells during blood-stage were not determined. Here, we examined how angiotensin II/AT1R axis promotes the harmful response of Plasmodium-specific CD8+ T-cell during blood-stage by using genetic and pharmacological approaches. We evaluated the response of wild-type (WT) and AT1R-/- Plasmodium-specific CD8+ T cells in mice infected with a transgenic PbA lineage expressing ovalbumin; and in parallel infected mice receiving WT Plasmodium-specific CD8+ T cells were treated with losartan (AT1R antagonist) or captopril (ACE inhibitor). Both, AT1R-/- OT-I cells and WT OT-I cells from losartan- or captopril-treated mice showed lower expansion, reduced IL-2 production and IL-2Ra expression, lower activation (lower expression of CD69, CD44 and CD160) and lower exhaustion profiles. AT1R-/- OT-I cells also exhibit lower expression of the integrin LFA-1 and the chemokine receptors CCR5 and CXCR3, known to play a key role in the development of cerebral malaria. Moreover, AT1R-/- OT-I cells produce lower amounts of IFN-γ and TNF-α and show lower degranulation upon restimulation. In conclusion, our results show the pivotal mechanisms of AT1R-induced harmful phenotype of Plasmodium-specific CD8+ T cells during blood-stage malaria. © 2017 Silva-Filho, Caruso-Neves and Pinheiro.

Silva-Filho J.L.,Federal University of Rio de Janeiro | Souza M.C.,Institute Tecnologia em Farmacos | Ferreira-DaSilva C.T.,Federal University of Rio de Janeiro | Silva L.S.,Federal University of Rio de Janeiro | And 9 more authors.
PLoS ONE | Year: 2013

The contribution of T cells in severe malaria pathogenesis has been described. Here, we provide evidence for the potential role of angiotensin II (Ang II) in modulating splenic T cell responses in a rodent model of cerebral malaria. T cell activation induced by infection, determined by 3 to 4-fold enhancement in CD69 expression, was reduced to control levels when mice were treated with 20 mg/kg losartan (IC50 = 0.966 mg/kg/d), an AT1 receptor antagonist, or captopril (IC50 = 1.940 mg/kg/d), an inhibitor of angiotensin-converting enzyme (ACE). Moreover, the production of interferon-γ and interleukin-17 by CD4+ T cells diminished 67% and 70%, respectively, by both treatments. Losartan reduced perforin expression in CD8+ T cells by 33% while captopril completely blocked it. The upregulation in chemokine receptor expression (CCR2 and CCR5) observed during infection was abolished and CD11a expression was partially reduced when mice were treated with drugs. T cells activated by Plasmodium berghei ANKA antigens showed 6-fold enhance in AT1 levels in comparison with naive cells. The upregulation of AT1 expression was reduced by losartan (80%) but not by captopril. Our results suggest that the AT1/Ang II axis has a role in the establishment of an efficient T cell response in the spleen and therefore could participate in a misbalanced parasite-induced T cell immune response during P. berghei ANKA infection. © 2013 Silva-Filho et al.

Lemos M.,Federal University of Rio de Janeiro | Lemos M.,Brazilian National Institute of Technology | Fermino B.R.,University of Sao Paulo | Simas-Rodrigues C.,University of Sao Paulo | And 8 more authors.
Parasites and Vectors | Year: 2015

Background: Several Trypanosoma species transmitted by leeches infect marine and freshwater fish worldwide. To date, all South American fish trypanosome species identified have been based on unreliable morphological parameters. We recently isolated and cultured trypanosomes from the Brazilian armoured catfishes Hypostomus luetkeni and H. affinis. Here, we report the first phylogenetic analyses of South American (Brazilian) trypanosomes isolated from fish, and from leeches removed from these fish. We also analysed morphologically and morphometrically the different forms of fish, leech and cultured trypanosomes. Methods: V7V8 SSU rRNA and gGAPDH sequences were used for phylogenetic analysis of Brazilian fish and leech trypanosomes. Trypanosomes from cultures, fish blood and leech samples were also characterized morphologically and morphometrically by light and electron microscopy. Results: In blood smears from fish high trypanosome prevalence (90-100 %) and parasitemia (0.9-1.0x102) were observed. Phylogenetic relationships using SSU rRNA and gGAPDH showed that, despite relevant sequence divergence, all Brazilian fish (and derived cultures) and leech trypanosomes clustered together into a single clade. The Brazilian clade clustered with European, North American and African fish trypanosomes. Based on sequence analysis, we uncovered a new species of Brazilian fish trypanosome, Trypanosoma abeli n. sp. Trypanosoma abeli cultures contained pleomorphic epimastigotes, small trypomastigotes and rare sphaeromastigotes. Ultrastructural features of T. abeli included a cytostome-cytopharynx complex in epi- and trypomastigotes, a compact rod-like kinetoplast, lysosome-related organelles (LROs) and multivesicular bodies. Trypanosomes found in fish blood smears and leech samples were highly pleomorphic, in agreement with sequence data suggesting that catfishes and leeches often have mixed trypanosome infections. Conclusions: Trypanosoma abeli n. sp. is the first trypanosome from South American fishes isolated in culture, positioned in phylogenetic trees and characterized at the ultrastructural level. Trypanosoma abeli n. sp. is highly prevalent in H. luetkeni and H. affinis armoured catfish from the Atlantic Forest biome, and in other catfish species from the Amazon and the Pantanal. Sequencing data suggested that Brazilian catfish often have mixed trypanosome infections, highlighting the importance of molecular characterization to identify trypanosome species in fishes and leeches. © 2015 Lemos et al.

Vannier-Santos M.A.,Instituto Nacional Para Pesquisa Translacional em Saude e Ambiente Na Regiao Amazonica | Lenzi H.L.,Instituto Oswaldo Cruz
Journal of Parasitology Research | Year: 2011

This paper presents many types of interplays between parasites and the host, showing the history of parasites, the effects of parasites on the outcome of wars, invasions, migrations, and on the development of numerous regions of the globe, and the impact of parasitic diseases on the society and on the course of human evolution. It also emphasizes the pressing need to change the look at the parasitism phenomenon, proposing that the term cohabitant is more accurate than parasite, because every living being, from bacteria to mammals, is a consortium of living beings in the pangenome. Even the term parasitology should be replaced by cohabitology because there is no parasite alone and host alone: both together compose a new adaptive system: the parasitized-host or the cohabitant-cohabited being. It also suggests switching the old paradigm based on attrition and destruction, to a new one founded on adaptation and living together. Copyright 2011 Marcos A. Vannier-Santos and Henrique L. Lenzi.

Saraiva V.B.,Federal University of Fluminense | de Souza Silva L.,Federal University of Rio de Janeiro | Ferreira-DaSilva C.T.,Federal University of Rio de Janeiro | da Silva-Filho J.L.,Federal University of Rio de Janeiro | And 8 more authors.
PLoS ONE | Year: 2011

Plasmodium falciparum causes the most serious complications of malaria and is a public health problem worldwide with over 2 million deaths each year. The erythrocyte invasion mechanisms by Plasmodium sp. have been well described, however the physiological aspects involving host components in this process are still poorly understood. Here, we provide evidence for the role of renin-angiotensin system (RAS) components in reducing erythrocyte invasion by P. falciparum. Angiotensin II (Ang II) reduced erythrocyte invasion in an enriched schizont culture of P. falciparum in a dose-dependent manner. Using mass spectroscopy, we showed that Ang II was metabolized by erythrocytes to Ang IV and Ang-(1-7). Parasite infection decreased Ang-(1-7) and completely abolished Ang IV formation. Similar to Ang II, Ang-(1-7) decreased the level of infection in an A779 (specific antagonist of Ang-(1-7) receptor, MAS)-sensitive manner. 10-7 M PD123319, an AT2 receptor antagonist, partially reversed the effects of Ang-(1-7) and Ang II. However, 10-6 M losartan, an antagonist of the AT1 receptor, had no effect. Gs protein is a crucial player in the Plasmodium falciparum blood cycle and angiotensin peptides can modulate protein kinase A (PKA) activity; 10-8 M Ang II or 10-8 M Ang-(1-7) inhibited this activity in erythrocytes by 60% and this effect was reversed by 10-7 M A779. 10-6 M dibutyryl-cAMP increased the level of infection and 10-7 M PKA inhibitor decreased the level of infection by 30%. These results indicate that the effect of Ang-(1-7) on P. falciparum blood stage involves a MAS-mediated PKA inhibition. Our results indicate a crucial role for Ang II conversion into Ang-(1-7) in controlling the erythrocytic cycle of the malaria parasite, adding new functions to peptides initially described to be involved in the regulation of vascular tonus. © 2011 Saraiva et al.

Goncalves S.,University of Lisbon | Teixeira A.,University of Lisbon | Abade J.,University of Lisbon | De Medeiros L.N.,Federal University of Rio de Janeiro | And 4 more authors.
Biochimica et Biophysica Acta - Biomembranes | Year: 2012

Psd1, a 46 amino acid residues defensin isolated from the pea Pisum sativum seeds, exhibits anti-fungal activity by a poorly understood mechanism of action. In this work, the interaction of Psd1 with biomembrane model systems of different lipid compositions was assessed by fluorescence spectroscopy. Partition studies showed a marked lipid selectivity of this antimicrobial peptide (AMP) toward lipid membranes containing ergosterol (the main sterol in fungal membranes) or specific glycosphingolipid components, with partition coefficients (Kp) reaching uncommonly high values of 106. By the opposite, Psd1 does not partition to cholesterol-enriched lipid bilayers, such as mammalian cell membranes. The Psd1 mutants His36Lys and Gly12Glu present a membrane affinity loss relative to the wild type. Fluorescence quenching data obtained using acrylamide and membrane probes further clarify the mechanism of action of this peptide at the molecular level, pointing out the potential therapeutic use of Psd1 as a natural antimycotic agent. © 2012 Elsevier B.V. All rights reserved.

Andrade T.D.J.A.D.S.,Instituto Federal Of Educaao Tecnologia Do Piaui | Araujo B.Q.,Federal University of Piauí | Cito A.M.D.G.L.,Federal University of Piauí | Da Silva J.,Lutheran University of Brazil | And 4 more authors.
Food Chemistry | Year: 2011

The present study analysed the antioxidant activity of the technical Cashew Nut Shell Liquid (tCNSL) using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay and the xanthine oxidase assay, as well as in vivo evaluation by Saccharomyces cerevisiae assay. Also, the chemical composition of tCNSL was determined by gas chromatography-mass spectrometry (GC-MS), revealing the presence of cardanols (40.26%), cardols (29.95%), phytosterol (10.68%), triacontanes (4.66%) and anacardic acid (1.79%). The DPPH-based assay results showed that tCNSL 1000 μg/ml reduced the radical level by 88.9%, and the scavenging of hydroxyl radicals in the xanthine oxidase assay indicated significant antioxidant activity (IC 50 = 702 μg/ml). In addition, tCNSL exerts an important protective effect against oxidative stress in yeast when used in 100-500 μg/ml concentration range, when exposed to paraquat or H 2O 2, indicating an in vivo antioxidant effect. © 2010 Elsevier Ltd. All rights reserved.

Silva-Filho J.L.,Federal University of Rio de Janeiro | Souza M.C.,Institute Tecnologia em Farmacos | Henriques M.D.G.,Institute Tecnologia em Farmacos | Morrot A.,Federal University of Rio de Janeiro | And 6 more authors.
Molecular Immunology | Year: 2011

Angiotensin II (Ang II), a central renin-angiotensin system (RAS) effector molecule, and its receptors, AT1 and AT2, have been shown to be involved in the inflammatory aspects of different diseases, however the cellular mechanisms underlying the regulation of immunity are not fully understood. In this work, using spleen-derived CD4+ and CD8+ T lymphocytes activated in vitro, we tested the influence of Ang II on different aspects of the T cell function, such as activation and adhesion/transmigration through endothelial basal membrane proteins. The addition of 10-8M Ang II did not change any of the parameters evaluated. However, 10-6M losartan, an AT1 receptor antagonist: (i) reduced the percentage of CD25+ and CD69+ cells of both subsets; (ii) inhibited adhesion of these cells to fibronectin or laminin by 53% or 76%, respectively and (iii) significantly reduced transmigration through fibronectin or laminin by 57% or 43%, respectively. In addition, 10-6M captopril, an angiotensin-converting enzyme inhibitor had similar effects to Ang II, however its effects were reverted by exogenous Ang II (10-8M). None of these responses was modified by 10-7M PD123319, an AT2 antagonist. These data reinforce the notion of endogenous production of Ang II by T cells, which is important for T cell activation, and adhesion/transmigration induced on interaction with basal membrane proteins, possibly involving AT1 receptor activation. Moreover, AT1 receptor expression is 10-fold higher in activated T lymphocytes compared with naive cells, but AT2 receptor expression did not change after T cell receptor triggering. © 2011 Elsevier Ltd.

Oliveira S.D.S.,Federal University of Rio de Janeiro | Coutinho-Silva R.,Federal University of Rio de Janeiro | Coutinho-Silva R.,Instituto Nacional para Pesquisa Translacional em Saude e Ambiente na Regiao Amazonica | Silva C.L.M.,Federal University of Rio de Janeiro
Purinergic Signalling | Year: 2013

Endothelial cells control vascular tone, permeability and leukocyte transmigration and are modulated by pro-inflammatory mediators. Schistosomiasis is an intravascular disease associated with inflammation, therefore altering endothelial cells' phenotype. Purinergic P2X7 receptors (P2X7R) play an important role in inflammation; however, the impact of the disease upon endothelial P2X7R function or expression has not been explored. Using ethidium bromide uptake to investigate P2X7R function, we observed that the effects of ATP (3 mM) and the P2X7R agonist 3′-O-(4-benzoyl)-ATP (BzATP) were smaller in mesenteric endothelial cells from the Schistosoma mansoni-infected group than in the control group. In the control group, BzATP induced endothelial nitric oxide production, which was blocked by the P2X7R antagonists KN-62 and A740003. However, in the infected group, we observed a reduced effect of BzATP and no effect of both P2X7R antagonists, suggesting a downregulation of endothelial P2X7R in schistosomiasis. We observed similar results in both infected and P2X7R-/- groups, which were also comparable to data obtained with KN-62- or A740004-treated control cells. Data from Western blot and immunocytochemistry assays confirmed the reduced expression of P2X7R in the infected group. In conclusion, our data show a downregulation of P2X7R in schistosomiasis infection, which likely limits the infection-related endothelial damage. © 2012 Springer Science+Business Media B.V.

Neitzke-Montinelli V.,Federal University of Rio de Janeiro | Urmenyi T.P.,Federal University of Rio de Janeiro | Rondinelli E.,Federal University of Rio de Janeiro | Rondinelli E.,Instituto Nacional para Pesquisa Translacional em Saude e Ambiente na Regiao Amazonica | And 5 more authors.
American Journal of Human Biology | Year: 2012

Objective: We describe an association of two SNPs, rs3212345:C>T and rs3212346:G>A, located approximately 2.5 kb upstream of the melanocortin-1 receptor (MC1R) translation initiation codon, with pigmentation phenotype variation in a Southeast Brazilian miscegenated population. Methods: One hundred thirty-eight genetically unrelated subjects, with multicolor phenotype, were selected from the southeast region of Brazil. Skin, hair and eye color, and tanning ability were rated. Genotypes for each SNP (rs3212345:C>T and rs3212346:G>A) were determined. A logistic regression analysis was performed with the additive model to determine which of the polymorphisms contributed to a specific phenotype. Results: We found that the rs3212345:C>T is associated with light skin, red hair, and poor tanning ability, while the rs3212346:G>A is associated with dark skin, black hair, and strong tanning ability. The presence of rs3212345-C and rs3212346-A alleles in human, chimpanzee, gorilla, orangutan, and marmoset genomes suggests that they are the ancestral alleles. Conclusion: These data suggest that the rs3212345-T and rs3212346-G alleles may have contributed to lighter pigmentation phenotypes in modern humans. Genotyping for these SNPs may prove useful to the fields of molecular anthropology and forensic genetics. © 2012 Wiley Periodicals, Inc.

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