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      Trypanosoma cruzi Infection and Endothelin-1 Cooperatively Activate Pathogenic Inflammatory Pathways in Cardiomyocytes

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          Abstract

          Trypanosoma cruzi, the causative agent of Chagas' disease, induces multiple responses in the heart, a critical organ of infection and pathology in the host. Among diverse factors, eicosanoids and the vasoactive peptide endothelin-1 (ET-1) have been implicated in the pathogenesis of chronic chagasic cardiomyopathy. In the present study, we found that T. cruzi infection in mice induces myocardial gene expression of cyclooxygenase-2 ( Cox2) and thromboxane synthase ( Tbxas1) as well as endothelin-1 ( Edn1) and atrial natriuretic peptide ( Nppa). T. cruzi infection and ET-1 cooperatively activated the Ca 2+/calcineurin (Cn)/nuclear factor of activated T cells (NFAT) signaling pathway in atrial myocytes, leading to COX-2 protein expression and increased eicosanoid (prostaglandins E 2 and F , thromboxane A 2) release. Moreover, T. cruzi infection of ET-1-stimulated cardiomyocytes resulted in significantly enhanced production of atrial natriuretic peptide (ANP), a prognostic marker for impairment in cardiac function of chagasic patients. Our findings support an important role for the Ca 2+/Cn/NFAT cascade in T. cruzi-mediated myocardial production of inflammatory mediators and may help define novel therapeutic targets.

          Author Summary

          Chronic cardiomyopathy is the most common and severe manifestation of human Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi. Among diverse inflammation-promoting moieties, eicosanoids and the vasoactive peptide endothelin-1 (ET-1) have been implicated in its pathogenesis. Nevertheless, the link between these two factors has not yet been identified. In the present study, we found that T. cruzi infection induces gene expression of ET-1 and eicosanoid-forming enzymes in the heart of infected mice. We also demonstrated that HL-1 atrial myocytes respond to ET-1 stimulus and T. cruzi infection by induction of cyclooxygenase-2 through activation of the Ca 2+/calcineurin/NFAT intracellular signaling pathway. Moreover, the cooperation between T. cruzi and ET-1 leads to overproduction of eicosanoids (prostaglandins E 2 and F , thromboxane A 2) and the pro-hypertrophic atrial natriuretic peptide. Our results support an important role for NFAT in T. cruzi plus ET-1-dependent induction of key agents of pathogenesis in chronic chagasic cardiomyopathy. Identification of the Ca 2+/calcineurin/NFAT cascade as mediator of cardiovascular pathology in Chagas' disease advances our understanding of host-parasite interrelationship and may help define novel potential targets for therapeutic interventions to ameliorate or prevent cardiomyopathy during chronic T. cruzi infection.

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          Most cited references59

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          HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte.

          We have derived a cardiac muscle cell line, designated HL-1, from the AT-1 mouse atrial cardiomyocyte tumor lineage. HL-1 cells can be serially passaged, yet they maintain the ability to contract and retain differentiated cardiac morphological, biochemical, and electrophysiological properties. Ultrastructural characteristics typical of embryonic atrial cardiac muscle cells were found consistently in the cultured HL-1 cells. Reverse transcriptase-PCR-based analyses confirmed a pattern of gene expression similar to that of adult atrial myocytes, including expression of alpha-cardiac myosin heavy chain, alpha-cardiac actin, and connexin43. They also express the gene for atrial natriuretic factor. Immunohistochemical staining of the HL-1 cells indicated that the distribution of the cardiac-specific markers desmin, sarcomeric myosin, and atrial natriuretic factor was similar to that of cultured atrial cardiomyocytes. A delayed rectifier potassium current (IKr) was the most prominent outward current in HL-1 cells. The activating currents displayed inward rectification and deactivating current tails were voltage-dependent, saturated at >+20 mV, and were highly sensitive to dofetilide (IC50 of 46.9 nM). Specific binding of [3H]dofetilide was saturable and fit a one-site binding isotherm with a Kd of 140 +/- 60 nM and a Bmax of 118 fmol per 10(5) cells. HL-1 cells represent a cardiac myocyte cell line that can be repeatedly passaged and yet maintain a cardiac-specific phenotype.
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            Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages.

            After apoptosis, phagocytes prevent inflammation and tissue damage by the uptake and removal of dead cells. In addition, apoptotic cells evoke an anti-inflammatory response through macrophages. We have previously shown that there is intense lymphocyte apoptosis in an experimental model of Chagas' disease, a debilitating cardiac illness caused by the protozoan Trypanosoma cruzi. Here we show that the interaction of apoptotic, but not necrotic T lymphocytes with macrophages infected with T. cruzi fuels parasite growth in a manner dependent on prostaglandins, transforming growth factor-beta (TGF-beta) and polyamine biosynthesis. We show that the vitronectin receptor is critical, in both apoptotic-cell cytoadherence and the induction of prostaglandin E2/TGF-beta release and ornithine decarboxylase activity in macrophages. A single injection of apoptotic cells in infected mice increases parasitaemia, whereas treatment with cyclooxygenase inhibitors almost completely ablates it in vivo. These results suggest that continual lymphocyte apoptosis and phagocytosis of apoptotic cells by macrophages have a role in parasite persistence in the host, and that cyclooxygenase inhibitors have potential therapeutic application in the control of parasite replication and spread in Chagas' disease.
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              NF-AT components define a family of transcription factors targeted in T-cell activation.

              The NF-AT transcription complex is required for the expression of a group of proteins that collectively coordinate the immune response. Here we purify two proteins encoded by separate genes that represent the pre-existing (p) and cytosolic (c) components of NF-AT. Expression of the full-length complementary DNA encoding NF-ATc activates the interleukin (IL-2) promoter in non-T lymphocytes, whereas a dominant negative of NF-ATc specifically blocks activation of the IL-2 promoter in T lymphocytes, indicating that NF-ATc is required for IL-2 gene expression. NF-ATc RNA expression is largely restricted to lymphoid tissues and is induced upon T-cell activation. The other protein, NF-ATp, is highly homologous to NF-ATc over a limited domain which shows similarity to the Dorsal/Rel family, but has a wider tissue distribution. Agents that increase intracellular Ca2+ or activate protein kinase C independently modify NF-ATc, indicating that distinct signalling pathways converge on NF-ATc to regulate its function.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                1935-2727
                1935-2735
                February 2013
                7 February 2013
                : 7
                : 2
                : e2034
                Affiliations
                [1 ]Servicio de Parasitología-Chagas, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
                [2 ]Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain
                [3 ]Instituto de Investigación Sanitaria Princesa, Hospital Universitario de La Princesa, Madrid, Spain
                National Institutes of Health, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RSC MF NG. Performed the experiments: RSC NAG HC. Analyzed the data: RSC MF NG NAG HC. Contributed reagents/materials/analysis tools: RSC MF. Wrote the paper: RSC MF NG.

                [¤]

                Current address: Laboratory for Accelerated Vascular Research, Division of Vascular Surgery, Department of Surgery, University of California, San Francisco, San Francisco, California, United States of America

                Article
                PNTD-D-12-01028
                10.1371/journal.pntd.0002034
                3566987
                23409199
                895909c4-8aca-4d08-a6f7-ebc8fd159e87
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 17 August 2012
                : 12 December 2012
                Page count
                Pages: 12
                Funding
                This work was supported by grants to M.F. from Ministerio de Ciencia y Tecnología, Spain (SAF2007-61716; SAF2005-02220); Red Temática de Investigación en Enfermedades Cardiovasculares (RECAVA RD06/0014/1013); Red de Investigación de Centros de Enfermedades Tropicales (RICET RD06/0021/0016); European Union (HEALTH-FE-2008-22303, ChagasEpiNet); Universidad Autónoma de Madrid and Comunidad de Madrid (CC08-UAM/SAL-4440/08); Fundación Ramón Areces and Agencia Española de Cooperación Internacional para el Desarrollo (AECID, A/9418/07 and A/017500/08 to M.F. and R.S.C.); and Fondo de Investigaciones Sanitarias (PS09/00538 to N.G.). R.S.C. is a Member of Research Career from Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina. M.F. and N.G. are professors at the “Biología Molecular” Department, Universidad Autónoma de Madrid. N.G. is a holder of a fellowship from Red de Investigación Cooperativa en Enfermedades Tropicales (RICET). N.A.G. was a recipient of a contract from RICET. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Immunology
                Immunopathology
                Microbiology
                Host-Pathogen Interaction
                Parasitology
                Pathogenesis
                Molecular Cell Biology
                Signal Transduction
                Signaling Cascades
                Arachidonic Acid Signaling Cascades
                Calcium Signaling Cascade
                Signaling in Cellular Processes
                Calcium Signaling
                Signaling Pathways
                Calcium-Mediated Signal Transduction
                Medicine
                Cardiovascular
                Infectious Diseases
                Neglected Tropical Diseases
                Chagas Disease
                Parasitic Diseases
                Chagas Disease

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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