{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:26:16Z","timestamp":1790126776870,"version":"4.0.1"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,24]],"date-time":"2021-08-24T00:00:00Z","timestamp":1629763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Chronic Chagasic cardiomyopathy (CCC) is a severe clinical manifestation that develops in 30%\u201340% of individuals chronically infected with the protozoal parasite <jats:italic>Trypanosoma cruzi<\/jats:italic> and is thus an important public health problem. Parasite persistence during chronic infection drives pathologic changes in the heart, including myocardial inflammation and progressive fibrosis, that contribute to clinical disease. Clinical manifestations of CCC span a range of symptoms, including cardiac arrhythmias, thromboembolic disease, dilated cardiomyopathy, and heart failure. This study aimed to investigate the role of signal transducer and activator of transcription-3 (STAT3) in cardiac pathology in a mouse model of CCC. STAT3 is a known cellular mediator of collagen deposition and fibrosis. Mice were infected with <jats:italic>T. cruzi<\/jats:italic> and then treated daily from 70 to 91 days post infection (DPI) with TTI-101, a small molecule inhibitor of STAT3; benznidazole; a combination of benznidazole and TTI-101; or vehicle alone. Cardiac function was evaluated at the beginning and end of treatment by echocardiography. By the end of treatment, STAT3 inhibition with TTI-101 eliminated cardiac fibrosis and fibrosis biomarkers but increased cardiac inflammation; serum levels of interleukin-6 (IL-6), and IFN\u2212<jats:italic>\u03b3<\/jats:italic>; cardiac gene expression of STAT1 and nuclear factor-\u03baB (NF-\u03baB); and upregulation of IL-6 and Type I and Type II IFN responses. Concurrently, decreased heart function was measured by echocardiography and myocardial strain. These results indicate that STAT3 plays a critical role in the cardiac inflammatory\u2013fibrotic axis during CCC.<\/jats:p>","DOI":"10.3389\/fcimb.2021.708325","type":"journal-article","created":{"date-parts":[[2021,8,24]],"date-time":"2021-08-24T12:47:06Z","timestamp":1629809226000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Signal Transducer and Activator of Transcription-3 Modulation of Cardiac Pathology in Chronic Chagasic Cardiomyopathy"],"prefix":"10.3389","volume":"11","author":[{"given":"Kristyn A.","family":"Hoffman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Jose","family":"Villar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Poveda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Elena","family":"Bottazzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Hotez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Tweardy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn M.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,24]]},"reference":[{"key":"B1","first-page":"1237","article-title":"Transcription Factors NF-IL6 and STAT3 Involved in Cytokine Signal Transductions","volume":"41","author":"Akira","year":"1996","journal-title":"Tanpakushitsu Kakusan Koso"},{"key":"B2","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1590\/s0074-02761999000700007","article-title":"Immunopathology of Chagas Disease","author":"Andrade","year":"1999","journal-title":"Memorias do Instituto Oswaldo Cruz"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.1086\/345882","article-title":"Implication of Transforming Growth Factor-Beta1 in Chagas Disease Myocardiopathy","volume":"186","author":"Araujo-Jorge","year":"2002","journal-title":"J. Infect. Dis."},{"key":"B4","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1016\/j.cytogfr.2008.08.002","article-title":"Pivotal Role for TGF-Beta in Infectious Heart Disease: The Case of Trypanosoma Cruzi Infection and Consequent Chagasic Myocardiopathy","volume":"19","author":"Araujo-Jorge","year":"2008","journal-title":"Cytokine Growth Factor Rev."},{"key":"B5","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1080\/21645515.2015.1119346","article-title":"A Therapeutic Nanoparticle Vaccine Against Trypanosoma Cruzi in a BALB\/c Mouse Model of Chagas Disease","volume":"12","author":"Barry","year":"2016","journal-title":"Hum. Vaccines immunotherapeutics"},{"key":"B6","doi-asserted-by":"publisher","first-page":"147","DOI":"10.2174\/1573403X11309020007","article-title":"Heart Failure in South America","volume":"9","author":"Bocchi","year":"2013","journal-title":"Curr. Cardiol. Rev."},{"key":"B7","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1146\/annurev-pathol-020117-043711","article-title":"Pathology and Pathogenesis of Chagas Heart Disease","volume":"14","author":"Bonney","year":"2019","journal-title":"Annu. Rev. Pathol."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01267","article-title":"IL-10\/STAT3\/SOCS3 Axis Is Involved in the Anti-Inflammatory Effect of Benznidazole","volume":"10","author":"Cevey","year":"2019","journal-title":"Front. Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"8043","DOI":"10.1073\/pnas.122236099","article-title":"Mutational Switch of an IL-6 Response to an Interferon-Gamma-Like Response","volume":"99","author":"Costa-Pereira","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B10","volume-title":"Guide for the Care and Use of Laboratory Animals","author":"Council","year":"2011"},{"key":"B11","doi-asserted-by":"publisher","first-page":"3222","DOI":"10.1038\/s41598-021-82930-w","article-title":"Vaccine-Linked Chemotherapy Induces IL-17 Production and Reduces Cardiac Pathology During Acute Trypanosoma Cruzi Infection","volume":"11","author":"Cruz-Chan","year":"2021","journal-title":"Sci. Rep."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/683230","article-title":"Chagas Disease Cardiomyopathy: Immunopathology and Genetics","volume":"2014","author":"Cunha-Neto","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"B13","doi-asserted-by":"publisher","first-page":"133","DOI":"10.2174\/157340309788166642","article-title":"Strain and Strain Rate Imaging by Echocardiography - Basic Concepts and Clinical Applicability","volume":"5","author":"Dandel","year":"2009","journal-title":"Curr. Cardiol. Rev."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1161\/01.cir.14.6.1035","article-title":"Chagas\u2019 Disease; a Clinical, Epidemiologic, and Pathologic Study","volume":"14","author":"Dias","year":"1956","journal-title":"Circulation"},{"key":"B15","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/j.imbio.2016.01.009","article-title":"Proteins Involved on TGF-Beta Pathway are Up-Regulated During the Acute Phase of Experimental Chagas Disease","volume":"221","author":"Ferreira","year":"2016","journal-title":"Immunobiology"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0007602","article-title":"TGF-Beta Inhibitor Therapy Decreases Fibrosis and Stimulates Cardiac Improvement in a Pre-Clinical Study of Chronic Chagas\u2019 Heart Disease","volume":"13","author":"Ferreira","year":"2019","journal-title":"PloS Negl. Trop. Dis."},{"key":"B17","doi-asserted-by":"publisher","first-page":"S414","DOI":"10.1038\/bjp.2008.1","article-title":"Role of Gp130-Mediated Signalling Pathways in the Heart and its Impact on Potential Therapeutic Aspects","author":"Fischer","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e00832","DOI":"10.1128\/aac.00832-18","article-title":"Assessing the Effectiveness of Curative Benznidazole Treatment in Preventing Chronic Cardiac Pathology in Experimental Models of Chagas Disease","volume":"62","author":"Fortes Francisco","year":"2018","journal-title":"Antimicr Agents chemother."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1002\/1521-4141(200105)31:5<1503::Aid-immu1503>3.0.Co;2-w","article-title":"Trypanosoma Cruzi Trans-Sialidase Potentiates T Cell Activation Through Antigen-Presenting Cells: Role of IL-6 and Bruton\u2019s Tyrosine Kinase","volume":"31","author":"Gao","year":"2001","journal-title":"Eur. J. Immunol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1161\/circulationaha.109.933127","article-title":"Continuous Glycoprotein-130-Mediated Signal Transducer and Activator of Transcription-3 Activation Promotes Inflammation, Left Ventricular Rupture, and Adverse Outcome in Subacute Myocardial Infarction","volume":"122","author":"Hilfiker-Kleiner","year":"2010","journal-title":"Circulation"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1161\/jaha.119.013365","article-title":"Improved Biomarker and Imaging Analysis for Characterizing Progressive Cardiac Fibrosis in a Mouse Model of Chronic Chagasic Cardiomyopathy","volume":"8","author":"Hoffman","year":"2019","journal-title":"J. Am. Heart Assoc."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0079445","article-title":"IL-10 Inhibits the NF-kappaB and ERK\/MAPK-Mediated Production of Pro-Inflammatory Mediators by Up-Regulation of SOCS-3 in Trypanosoma Cruzi-Infected Cardiomyocytes","volume":"8","author":"Hovsepian","year":"2013","journal-title":"PloS One"},{"key":"B23","doi-asserted-by":"publisher","first-page":"3641","DOI":"10.1128\/iai.00423-07","article-title":"Modulation of Autoimmunity by Treatment of an Infectious Disease","volume":"75","author":"Hyland","year":"2007","journal-title":"Infect Immun."},{"key":"B24","doi-asserted-by":"publisher","first-page":"12929","DOI":"10.1073\/pnas.2134694100","article-title":"Cardiomyocyte-Restricted Knockout of STAT3 Results in Higher Sensitivity to Inflammation, Cardiac Fibrosis, and Heart Failure With Advanced Age","volume":"100","author":"Jacoby","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B25","doi-asserted-by":"publisher","first-page":"22145","DOI":"10.18632\/oncotarget.13530","article-title":"Involvement of Inflammation and its Related microRNAs in Hepatocellular Carcinoma","volume":"8","author":"Jin","year":"2017","journal-title":"Oncotarget"},{"key":"B26","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1038\/nrclinonc.2018.8","article-title":"Targeting the IL-6\/JAK\/STAT3 Signalling Axis in Cancer","volume":"15","author":"Johnson","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00876-17","article-title":"Vaccine-Linked Chemotherapy Improves Benznidazole Efficacy for Acute Chagas Disease","volume":"86","author":"Jones","year":"2018","journal-title":"Infect Immun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2299","DOI":"10.3390\/ijms19082299","article-title":"Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment","volume":"19","author":"Kasembeli","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1016\/j.micinf.2010.03.005","article-title":"The Innate Immune Response to Trypanosoma Cruzi Infection","volume":"12","author":"Kayama","year":"2010","journal-title":"Microbes Infect \/ Institut Pasteur"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004431","article-title":"Coordinating Role of Rxr\u03b1 in Downregulating Hepatic Detoxification During Inflammation Revealed by Fuzzy-Logic Modeling","volume":"12","author":"Keller","year":"2016","journal-title":"PloS Comput. Biol."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.03029","article-title":"Recent Developments on the Crosstalk Between STAT3 and Inflammation in Heart Function and Disease","volume":"9","author":"Kurdi","year":"2018","journal-title":"Front. Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.taap.2016.11.015","article-title":"Benznidazole, the Trypanocidal Drug Used for Chagas Disease, Induces Hepatic NRF2 Activation and Attenuates the Inflammatory Response in a Murine Model of Sepsis","volume":"315","author":"Lambertucci","year":"2017","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/437623","article-title":"Protective Function of STAT3 in CVB3-Induced Myocarditis","volume":"2012","author":"Lindner","year":"2012","journal-title":"Cardiol. Res. Pract."},{"key":"B34","doi-asserted-by":"publisher","first-page":"30708","DOI":"10.1074\/jbc.M113.478685","article-title":"Transforming Growth Factor-\u03b2 (TGF-\u03b2)-Mediated Connective Tissue Growth Factor (CTGF) Expression in Hepatic Stellate Cells Requires Stat3 Signaling Activation","volume":"288","author":"Liu","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B35","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1590\/s0074-02762009000900042","article-title":"The BENEFIT Trial: Testing the Hypothesis That Trypanocidal Therapy is Beneficial for Patients With Chronic Chagas Heart Disease","author":"Marin-Neto","year":"2009","journal-title":"Memorias do Instituto Oswaldo Cruz"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1056\/NEJMoa1507574","article-title":"Randomized Trial of Benznidazole for Chronic Chagas\u2019 Cardiomyopathy","volume":"373","author":"Morillo","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/s0008-6363(00)00138-3","article-title":"Activation of JAK\/STAT Pathway Transduces Cytoprotective Signal in Rat Acute Myocardial Infarction","volume":"47","author":"Negoro","year":"2000","journal-title":"Cardiovasc. Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e169","DOI":"10.1161\/cir.0000000000000599","article-title":"Chagas Cardiomyopathy: An Update of Current Clinical Knowledge and Management: A Scientific Statement From the American Heart Association","volume":"138","author":"Nunes","year":"2018","journal-title":"Circulation"},{"key":"B39","doi-asserted-by":"publisher","first-page":"e4","DOI":"10.1038\/cti.2013.2","article-title":"Interleukin-6: A New Therapeutic Target in Systemic Sclerosis","volume":"2","author":"O\u2019Reilly","year":"2013","journal-title":"Clin. Trans. Immunol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"9952","DOI":"10.1074\/jbc.M113.545822","article-title":"Interleukin-6 (IL-6) Trans Signaling Drives a STAT3-Dependent Pathway That Leads to Hyperactive Transforming Growth Factor-\u03b2 (TGF-\u03b2) Signaling Promoting SMAD3 Activation and Fibrosis via Gremlin Protein","volume":"289","author":"O\u2019Reilly","year":"2014","journal-title":"J. Biol. Chem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.immuni.2008.03.002","article-title":"Cytokine Signaling Modules in Inflammatory Responses","volume":"28","author":"O\u2019Shea","year":"2008","journal-title":"Immunity"},{"key":"B42","doi-asserted-by":"publisher","first-page":"2520","DOI":"10.1038\/sj.onc.1209281","article-title":"Loss of SOCS3 in the Liver Promotes Fibrosis by Enhancing STAT3-Mediated TGF-Beta1 Production","volume":"25","author":"Ogata","year":"2006","journal-title":"Oncogene"},{"key":"B43","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1091\/mbc.E17-06-0342","article-title":"STAT3 Controls COL1A2 Enhancer Activation Cooperatively With JunB, Regulates Type I Collagen Synthesis Posttranscriptionally, and is Essential for Lung Myofibroblast Differentiation","volume":"29","author":"Papaioannou","year":"2018","journal-title":"Mol. Biol. Cell"},{"key":"B44","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1096\/fj.15-273953","article-title":"STAT-3 Contributes to Pulmonary Fibrosis Through Epithelial Injury and Fibroblast-Myofibroblast Differentiation","volume":"30","author":"Pedroza","year":"2016","journal-title":"FASEB J. Off. Publ. Fed. Am. Societies Exp. Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1838","DOI":"10.1093\/rheumatology\/kex347","article-title":"Role of STAT3 in Skin Fibrosis and Transforming Growth Factor Beta Signalling","volume":"57","author":"Pedroza","year":"2018","journal-title":"Rheumatol. (Oxford England)"},{"key":"B46","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1016\/j.bbadis.2012.12.003","article-title":"Trypanosoma Cruzi, the Causative Agent of Chagas Disease, Modulates Interleukin-6-Induced STAT3 Phosphorylation via Gp130 Cleavage in Different Host Cells","volume":"1832","author":"Ponce","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0091154","article-title":"Cytokine Profiling in Chagas Disease: Towards Understanding the Association With Infecting Trypanosoma Cruzi Discrete Typing Units (a BENEFIT TRIAL Sub-Study)","volume":"9","author":"Poveda","year":"2014","journal-title":"PloS One"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1388","DOI":"10.1016\/S0140-6736(10)60061-X","article-title":"Chagas Disease","volume":"375","author":"Rassi","year":"2010","journal-title":"Lancet"},{"key":"B49","doi-asserted-by":"publisher","first-page":"637","DOI":"10.4269\/ajtmh.1993.48.637","article-title":"Characterization of Inflammatory Infiltrates in Chronic Chagasic Myocardial Lesions: Presence of Tumor Necrosis Factor-Alpha+ Cells and Dominance of Granzyme A+, CD8+ Lymphocytes","volume":"48","author":"Reis","year":"1993","journal-title":"Am. J. Trop. Med. Hygiene"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1906","DOI":"10.1093\/jac\/dkaa101","article-title":"Efficacy of Continuous Versus Intermittent Administration of Nanoformulated Benznidazole During the Chronic Phase of Trypanosoma Cruzi Nicaragua Infection in Mice","volume":"75","author":"Rial","year":"2020","journal-title":"J. Antimicr. Chemother."},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.actatropica.2019.105168","article-title":"Immunity and Vaccine Development Efforts Against Trypanosoma Cruzi","volume":"200","author":"Rios","year":"2019","journal-title":"Acta tropica"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006839","article-title":"Viral Manipulation of STAT3: Evade, Exploit, and Injure","volume":"14","author":"Roca Suarez","year":"2018","journal-title":"PloS Pathog."},{"key":"B53","doi-asserted-by":"publisher","first-page":"3855","DOI":"10.1128\/iai.67.8.3855-3863.1999","article-title":"Predominance of CD4 Th1 and CD8 Tc1 Cells Revealed by Characterization of the Cellular Immune Response Generated by Immunization With a DNA Vaccine Containing a Trypanosoma Cruzi Gene","volume":"67","author":"Rodrigues","year":"1999","journal-title":"Infect Immun."},{"key":"B54","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1016\/j.molimm.2010.12.021","article-title":"Benznidazole Treatment Attenuates Liver NF-kappaB Activity and MAPK in a Cecal Ligation and Puncture Model of Sepsis","volume":"48","author":"Ronco","year":"2011","journal-title":"Mol. Immunol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1590\/S0074-02762005000300012","article-title":"Trypanosoma Cruzi Isolates From Mexican and Guatemalan Acute and Chronic Chagasic Cardiopathy Patients Belong to Trypanosoma Cruzi I","volume":"100","author":"Ruiz-Sanchez","year":"2005","journal-title":"Memorias do Instituto Oswaldo Cruz"},{"key":"B56","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1161\/CIRCULATIONAHA.112.123612","article-title":"Ten-Year Incidence of Chagas Cardiomyopathy Among Asymptomatic Trypanosoma Cruzi-Seropositive Former Blood Donors","volume":"127","author":"Sabino","year":"2013","journal-title":"Circulation"},{"key":"B57","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.jim.2018.08.005","article-title":"Aging and the Immune System: An Overview","volume":"463","author":"Sadighi Akha","year":"2018","journal-title":"J.\u00a0Immunol. Methods"},{"key":"B58","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1016\/j.bbadis.2017.01.006","article-title":"IL-6 Promotes M2 Macrophage Polarization by Modulating Purinergic Signaling and Regulates the Lethal Release of Nitric Oxide During Trypanosoma Cruzi Infection","volume":"1863","author":"Sanmarco","year":"2017","journal-title":"Biochim. Biophys. Acta"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002645","article-title":"CD8+ T-Cells Expressing Interferon Gamma or Perforin Play Antagonistic Roles in Heart Injury in Experimental Trypanosoma Cruzi-Elicited Cardiomyopathy","volume":"8","author":"Silverio","year":"2012","journal-title":"PloS Pathog."},{"key":"B60","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1007\/s10495-013-0822-x","article-title":"Trypomastigotes and Amastigotes of Trypanosoma Cruzi Induce Apoptosis and STAT3 Activation in Cardiomyocytes In Vitro","volume":"18","author":"Stahl","year":"2013","journal-title":"Apoptosis"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0110512","article-title":"Trypanosoma Cruzi Evades the Protective Role of Interferon-Gamma-Signaling in Parasite-Infected Cells","volume":"9","author":"Stahl","year":"2014","journal-title":"PloS One"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0006742","article-title":"Amiodarone for Arrhythmia in Patients With Chagas Disease: A Systematic Review and Individual Patient Data Meta-Analysis","volume":"12","author":"Stein","year":"2018","journal-title":"PloS Negl. Trop. Dis."},{"key":"B63","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1161\/circresaha.117.311045","article-title":"EphrinB2 Regulates Cardiac Fibrosis Through Modulating the Interaction of Stat3 and TGF-\u03b2\/Smad3 Signaling","volume":"121","author":"Su","year":"2017","journal-title":"Circ. Res."},{"key":"B64","doi-asserted-by":"publisher","first-page":"4302","DOI":"10.1074\/jbc.M116.773085","article-title":"Transforming Growth Factor-\u03b2 (TGF-\u03b2) Directly Activates the JAK1-STAT3 Axis to Induce Hepatic Fibrosis in Coordination With the SMAD Pathway","volume":"292","author":"Tang","year":"2017","journal-title":"J. Biol. Chem."},{"key":"B65","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1586\/14779072.2015.1103648","article-title":"Developments in the Management of Chagas Cardiomyopathy","volume":"13","author":"Tanowitz","year":"2015","journal-title":"Expert Rev. Cardiovasc. Ther."},{"key":"B66","doi-asserted-by":"publisher","first-page":"456","DOI":"10.5935\/abc.20140052","article-title":"Relationship Between Fibrosis and Ventricular Arrhythmias in Chagas Heart Disease Without Ventricular Dysfunction","volume":"102","author":"Tassi","year":"2014","journal-title":"Arquivos Brasileiros Cardiologia"},{"key":"B67","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1016\/S1471-4922(02)02283-3","article-title":"Chemokines, Inflammation and Trypanosoma Cruzi Infection","volume":"18","author":"Teixeira","year":"2002","journal-title":"Trends Parasitol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1097\/01.JAA.0000547749.92933.6a","article-title":"Chagas Disease: An Underrecognized Diagnosis","volume":"31","author":"Tzizik","year":"2018","journal-title":"JAAPA"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0003747","article-title":"Early Regulation of Profibrotic Genes in Primary Human Cardiac Myocytes by Trypanosoma Cruzi","volume":"10","author":"Udoko","year":"2016","journal-title":"PloS Negl. Trop. Dis."},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1111\/pim.12769","article-title":"TLR4 Agonist Protects Against Trypanosoma Cruzi Acute Lethal Infection by Decreasing Cardiac Parasite Burdens","author":"Villanueva-Lizama","year":"2020","journal-title":"Parasite Immunol."},{"key":"B71","doi-asserted-by":"publisher","first-page":"5115","DOI":"10.1128\/iai.70.9.5115-5123.2002","article-title":"Increased Trypanosoma Cruzi Invasion and Heart Fibrosis Associated With High Transforming Growth Factor Beta Levels in Mice Deficient in Alpha(2)-Macroglobulin","volume":"70","author":"Waghabi","year":"2002","journal-title":"Infect Immun."},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0004783","article-title":"Chemical Probes That Competitively and Selectively Inhibit Stat3 Activation","volume":"4","author":"Xu","year":"2009","journal-title":"PloS One"},{"key":"B73","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1101\/gad.1553707","article-title":"Unphosphorylated STAT3 Accumulates in Response to IL-6 and Activates Transcription by Binding to NFkappaB","volume":"21","author":"Yang","year":"2007","journal-title":"Genes Dev."},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/359674","article-title":"STAT3 Regulates Proliferation and Survival of CD8+ T Cells: Enhances Effector Responses to HSV-1 Infection, and Inhibits IL-10+ Regulatory CD8+ T Cells in Autoimmune Uveitis","volume":"2013","author":"Yu","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"B75","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1093\/jmcb\/mjw042","article-title":"SENP1 Regulates IFN-\u03b3-STAT1 Signaling Through STAT3-SOCS3 Negative Feedback Loop","volume":"9","author":"Yu","year":"2017","journal-title":"J. Mol. Cell Biol."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2021.708325\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,24]],"date-time":"2021-08-24T12:47:13Z","timestamp":1629809233000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2021.708325\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,24]]},"references-count":75,"alternative-id":["10.3389\/fcimb.2021.708325"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2021.708325","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,24]]},"article-number":"708325"}}