{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:30:08Z","timestamp":1768509008541,"version":"3.49.0"},"posted":{"date-parts":[[2023,10,5]]},"group-title":"Immunology","reference-count":73,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,10,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Chagas disease, caused by the protozoan parasite\n                  <jats:italic>Trypanosoma cruzi<\/jats:italic>\n                  , is a neglected parasitic disease that affects approximately 6 million individuals worldwide. Of those infected, 20-30% will go on to develop chronic Chagas cardiomyopathy (CCC), and ultimately many of these individuals will progress to advanced heart failure. The mechanism by which this progression occurs is poorly understood, as few studies have focused on early CCC. In this study, we sought to understand the physiologic changes associated with\n                  <jats:italic>T. cruzi<\/jats:italic>\n                  infection and the development of CCC. We analyzed gene expression in the peripheral blood of asymptomatic Chagas patients with early structural heart disease, Chagas patients without any signs or symptoms of disease, and Chagas-negative patients with and without early structural heart disease. Our analysis shows that early CCC was associated with a downregulation of various peripheral immune response genes, with gene expression changes suggestive of reduced antigen presentation and T cell activation. Notably, these genes and processes were distinct from those of early cardiomyopathy in Chagas-negative patients, suggesting that the processes mediating CCC may be unique from those mediating progression to other cardiomyopathies. This work highlights the importance of the immune response in early CCC, providing insight into the early pathogenesis of this disease. The changes we have identified may serve as biomarkers of progression and could inform strategies for the treatment of CCC in its early stages, before significant cardiac damage has occurred.\n                <\/jats:p>","DOI":"10.1101\/2023.10.03.560680","type":"posted-content","created":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T20:35:15Z","timestamp":1696538115000},"source":"Crossref","is-referenced-by-count":1,"title":["Immunologic changes are detectable in the peripheral blood transcriptome of clinically asymptomatic Chagas cardiomyopathy patients"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3737-3858","authenticated-orcid":false,"given":"Carolina","family":"Duque","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2775-2811","authenticated-orcid":false,"given":"Jaime","family":"So","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6824-9206","authenticated-orcid":false,"given":"Yagahira E.","family":"Castro-Sesquen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly","family":"DeToy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9329-0067","authenticated-orcid":false,"given":"Sneider A. Gutierrez","family":"Guarnizo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatemeh","family":"Jahanbakhsh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0075-6655","authenticated-orcid":false,"given":"Edith Malaga","family":"Machaca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Miranda-Schaeubinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7914-3500","authenticated-orcid":false,"given":"Indira","family":"Chakravarti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia","family":"Cooper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary E.","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2704-978X","authenticated-orcid":false,"given":"Luigi","family":"Adamo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Marcus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kawsar R.","family":"Talaat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9037-0712","authenticated-orcid":false,"given":"Robert H.","family":"Gilman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1535-2530","authenticated-orcid":false,"given":"Monica R.","family":"Mugnier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"the Chagas Working Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023101100351607000_2023.10.03.560680v1.1","unstructured":"PAHO\/WHO Chagas Disease in the Americas for General Public; 2020. 2020."},{"issue":"11","key":"2023101100351607000_2023.10.03.560680v1.2","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1016\/j.amjmed.2020.05.022","article-title":"Chagas Disease: Epidemiology and Barriers to Treatment","volume":"133","year":"2020","journal-title":"Am J Med"},{"key":"2023101100351607000_2023.10.03.560680v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(01)00065-2"},{"key":"2023101100351607000_2023.10.03.560680v1.4","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000599"},{"issue":"12","key":"2023101100351607000_2023.10.03.560680v1.5","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.3390\/pathogens11121402","article-title":"The Characterization of Cardiac Explants Reveals Unique Fibrosis Patterns and a Predominance of CD8+ T Cell Subpopulations in Patients with Chronic Chagas Cardiomyopathy","volume":"11","year":"2022","journal-title":"Pathogens"},{"key":"2023101100351607000_2023.10.03.560680v1.6","doi-asserted-by":"publisher","DOI":"10.1093\/ajcp\/aqw098"},{"key":"2023101100351607000_2023.10.03.560680v1.7","doi-asserted-by":"publisher","DOI":"10.1159\/000175035"},{"key":"2023101100351607000_2023.10.03.560680v1.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1507574"},{"key":"2023101100351607000_2023.10.03.560680v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60061-X"},{"key":"2023101100351607000_2023.10.03.560680v1.10","first-page":"681635","article-title":"Clinical and Epidemiological Characterization of Acute Chagas Disease in Casanare, Eastern Colombia, 2012-2020","volume":"8","year":"2021","journal-title":"Front Med (Lausanne)"},{"key":"2023101100351607000_2023.10.03.560680v1.11","doi-asserted-by":"publisher","DOI":"10.1080\/14656566.2019.1650915"},{"issue":"6","key":"2023101100351607000_2023.10.03.560680v1.12","doi-asserted-by":"crossref","first-page":"e0006567","DOI":"10.1371\/journal.pntd.0006567","article-title":"Electrocardiographic abnormalities in Chagas disease in the general population: A systematic review and meta-analysis","volume":"12","year":"2018","journal-title":"PLoS Negl Trop Dis"},{"key":"2023101100351607000_2023.10.03.560680v1.13","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.113.000632"},{"key":"2023101100351607000_2023.10.03.560680v1.14","doi-asserted-by":"crossref","unstructured":"Kapa, S. , et al., Fascicular Ventricular Arrhythmias: Pathophysiologic Mechanisms, Anatomical Constructs, and Advances in Approaches to Management. Circ Arrhythm Electrophysiol, 2017. 10(1).","DOI":"10.1161\/CIRCEP.116.002476"},{"key":"2023101100351607000_2023.10.03.560680v1.15","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.019893"},{"issue":"4","key":"2023101100351607000_2023.10.03.560680v1.16","doi-asserted-by":"crossref","first-page":"e1009502","DOI":"10.1371\/journal.ppat.1009502","article-title":"DNA damage and oxidative stress in human cells infected by Trypanosoma cruzi","volume":"17","year":"2021","journal-title":"PLoS Pathog"},{"key":"2023101100351607000_2023.10.03.560680v1.17","doi-asserted-by":"publisher","DOI":"10.1086\/342510"},{"key":"2023101100351607000_2023.10.03.560680v1.18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0208133"},{"key":"2023101100351607000_2023.10.03.560680v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.actatropica.2012.08.020"},{"key":"2023101100351607000_2023.10.03.560680v1.20","doi-asserted-by":"publisher","DOI":"10.1093\/ajcp\/aqw098"},{"key":"2023101100351607000_2023.10.03.560680v1.21","doi-asserted-by":"crossref","unstructured":"Diaz, M.L. , et al., The Characterization of Cardiac Explants Reveals Unique Fibrosis Patterns and a Predominance of CD8+ T Cell Subpopulations in Patients with Chronic Chagas Cardiomyopathy. Pathogens, 2022. 11(12).","DOI":"10.3390\/pathogens11121402"},{"key":"2023101100351607000_2023.10.03.560680v1.22","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.3389\/fimmu.2018.01929","article-title":"The Unsolved Jigsaw Puzzle of the Immune Response in Chagas Disease","volume":"9","year":"2018","journal-title":"Front Immunol"},{"key":"2023101100351607000_2023.10.03.560680v1.23","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.ijcard.2014.10.133","article-title":"Infectious agents and inflammation in donated hearts and dilated cardiomyopathies related to cardiovascular diseases, Chagas\u2019 heart disease, primary and secondary dilated cardiomyopathies","volume":"178","year":"2015","journal-title":"Int J Cardiol"},{"key":"2023101100351607000_2023.10.03.560680v1.24","doi-asserted-by":"crossref","first-page":"105079","DOI":"10.1016\/j.meegid.2021.105079","article-title":"Detecting imperative genes and infiltrating immune cells in chronic Chagas cardiomyopathy by bioinformatics analysis","volume":"95","year":"2021","journal-title":"Infect Genet Evol"},{"key":"2023101100351607000_2023.10.03.560680v1.25","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.2007.01987.x"},{"key":"2023101100351607000_2023.10.03.560680v1.26","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.2005.01668.x"},{"key":"2023101100351607000_2023.10.03.560680v1.27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001294"},{"key":"2023101100351607000_2023.10.03.560680v1.28","doi-asserted-by":"crossref","first-page":"800","DOI":"10.3389\/fimmu.2019.00800","article-title":"Evidence of Different IL-1beta Activation Pathways in Innate Immune Cells From Indeterminate and Cardiac Patients With Chronic Chagas Disease","volume":"10","year":"2019","journal-title":"Front Immunol"},{"key":"2023101100351607000_2023.10.03.560680v1.29","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.624296"},{"issue":"3","key":"2023101100351607000_2023.10.03.560680v1.30","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1093\/infdis\/jiw540","article-title":"Blood Gene Signatures of Chagas Cardiomyopathy With or Without Ventricular Dysfunction","volume":"215","year":"2017","journal-title":"J Infect Dis"},{"issue":"5","key":"2023101100351607000_2023.10.03.560680v1.31","doi-asserted-by":"crossref","first-page":"e0010386","DOI":"10.1371\/journal.pntd.0010386","article-title":"Use of benznidazole to treat chronic Chagas disease: An updated systematic review with a meta-analysis","volume":"16","year":"2022","journal-title":"PLoS Negl Trop Dis"},{"issue":"9","key":"2023101100351607000_2023.10.03.560680v1.32","doi-asserted-by":"crossref","first-page":"e303","DOI":"10.1093\/cid\/ciaa1101","article-title":"Use of a Latent Class Analysis in the Diagnosis of Chronic Chagas Disease in the Washington Metropolitan Area","volume":"72","year":"2021","journal-title":"Clin Infect Dis"},{"issue":"4","key":"2023101100351607000_2023.10.03.560680v1.33","doi-asserted-by":"crossref","first-page":"ofab096","DOI":"10.1093\/ofid\/ofab096","article-title":"Evaluation of 2 Lateral Flow Rapid Tests in the Diagnosis of Chagas Disease in the Washington Metropolitan Area","volume":"8","year":"2021","journal-title":"Open Forum Infect Dis"},{"issue":"1","key":"2023101100351607000_2023.10.03.560680v1.34","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1186\/s13071-016-1918-2","article-title":"Geographical, landscape and host Associations of Trypanosoma cruzi DTUs and lineages","volume":"9","year":"2016","journal-title":"Parasit Vectors"},{"issue":"1","key":"2023101100351607000_2023.10.03.560680v1.35","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/s41597-022-01452-w","article-title":"Discrete typing units of Trypanosoma cruzi: Geographical and biological distribution in the Americas","volume":"9","year":"2022","journal-title":"Sci Data"},{"key":"2023101100351607000_2023.10.03.560680v1.36","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cix277"},{"issue":"9","key":"2023101100351607000_2023.10.03.560680v1.37","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1128\/jcm.34.9.2143-2147.1996","article-title":"Immunoblot assay using excreted-secreted antigens of Trypanosoma cruzi in serodiagnosis of congenital, acute, and chronic Chagas\u2019 disease","volume":"34","year":"1996","journal-title":"J Clin Microbiol"},{"key":"2023101100351607000_2023.10.03.560680v1.38","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"issue":"3","key":"2023101100351607000_2023.10.03.560680v1.39","first-page":"100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","year":"2021","journal-title":"Innovation (Camb)"},{"key":"2023101100351607000_2023.10.03.560680v1.40","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"2023101100351607000_2023.10.03.560680v1.41","unstructured":"Korotkevich, G. , et al., Fast gene set enrichment analysis. bioRxiv, 2021: p. 060012."},{"issue":"6","key":"2023101100351607000_2023.10.03.560680v1.42","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1016\/j.celrep.2019.01.041","article-title":"RNA-Seq Signatures Normalized by mRNA Abundance Allow Absolute Deconvolution of Human Immune Cell Types","volume":"26","year":"2019","journal-title":"Cell Rep"},{"issue":"7","key":"2023101100351607000_2023.10.03.560680v1.43","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41587-019-0114-2","article-title":"Determining cell type abundance and expression from bulk tissues with digital cytometry","volume":"37","year":"2019","journal-title":"Nat Biotechnol"},{"key":"2023101100351607000_2023.10.03.560680v1.44"},{"key":"2023101100351607000_2023.10.03.560680v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80148-X"},{"issue":"1","key":"2023101100351607000_2023.10.03.560680v1.46","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/j.1365-2567.2009.03155.x","article-title":"Efficiency of T-cell costimulation by CD80 and CD86 cross-linking correlates with calcium entry","volume":"129","year":"2010","journal-title":"Immunology"},{"key":"2023101100351607000_2023.10.03.560680v1.47","doi-asserted-by":"publisher","DOI":"10.1159\/000350523"},{"key":"2023101100351607000_2023.10.03.560680v1.48","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1782"},{"key":"2023101100351607000_2023.10.03.560680v1.49","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00486"},{"key":"2023101100351607000_2023.10.03.560680v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.09.045"},{"key":"2023101100351607000_2023.10.03.560680v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10018-1"},{"key":"2023101100351607000_2023.10.03.560680v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80574-9"},{"key":"2023101100351607000_2023.10.03.560680v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-018-0196-9"},{"key":"2023101100351607000_2023.10.03.560680v1.54","doi-asserted-by":"publisher","DOI":"10.1038\/nri979"},{"key":"2023101100351607000_2023.10.03.560680v1.55","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.41.26923"},{"key":"2023101100351607000_2023.10.03.560680v1.56","doi-asserted-by":"crossref","first-page":"103974","DOI":"10.1016\/j.cellimm.2019.103974","article-title":"Diminished mitogen-induced T cell proliferation by Trypanosoma cruzi antigens associated with antigen-presenting cell modulation and CD3 signaling","volume":"348","year":"2020","journal-title":"Cell Immunol"},{"key":"2023101100351607000_2023.10.03.560680v1.57","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0095977"},{"key":"2023101100351607000_2023.10.03.560680v1.58","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxf077"},{"key":"2023101100351607000_2023.10.03.560680v1.59","doi-asserted-by":"crossref","first-page":"584538","DOI":"10.3389\/fimmu.2021.584538","article-title":"Terminally Differentiated CD4(+) T Cells Promote Myocardial Inflammaging","volume":"12","year":"2021","journal-title":"Front Immunol"},{"issue":"5","key":"2023101100351607000_2023.10.03.560680v1.60","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1128\/iai.62.5.1820-1829.1994","article-title":"Depletion of T-cell Subpopulations results in exacerbation of myocarditis and parasitism in experimental Chagas\u2019 disease","volume":"62","year":"1994","journal-title":"Infect Immun"},{"key":"2023101100351607000_2023.10.03.560680v1.61","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/8.1.13"},{"issue":"12","key":"2023101100351607000_2023.10.03.560680v1.62","doi-asserted-by":"crossref","first-page":"5129","DOI":"10.1128\/iai.61.12.5129-5133.1993","article-title":"Differential susceptibilities of mice genomically deleted of CD4 and CD8 to infections with Trypanosoma cruzi or Trypanosoma brucei","volume":"61","year":"1993","journal-title":"Infect Immun"},{"key":"2023101100351607000_2023.10.03.560680v1.63","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.308030"},{"key":"2023101100351607000_2023.10.03.560680v1.64","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035966"},{"key":"2023101100351607000_2023.10.03.560680v1.65","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0057181"},{"key":"2023101100351607000_2023.10.03.560680v1.66","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2012.04.008"},{"issue":"2","key":"2023101100351607000_2023.10.03.560680v1.67","doi-asserted-by":"crossref","first-page":"e0009059","DOI":"10.1371\/journal.pntd.0009059","article-title":"A proportion of CD4+ T cells from Patients with chronic Chagas disease undergo a dysfunctional process, which is partially reversed by benznidazole treatment","volume":"15","year":"2021","journal-title":"PLoS Negl Trop Dis"},{"key":"2023101100351607000_2023.10.03.560680v1.68","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2200924"},{"key":"2023101100351607000_2023.10.03.560680v1.69","doi-asserted-by":"crossref","unstructured":"Kumar, V. , et al., Cardiomyocyte-specific adenylyl cyclase type-8 overexpression induces cell-autonomous activation of RelA and non-cell-autonomous myocardial and systemic inflammation. bioRxiv, 2023: p. 2023.07.15.549173.","DOI":"10.1101\/2023.07.15.549173"},{"key":"2023101100351607000_2023.10.03.560680v1.70","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2007.08.003"},{"key":"2023101100351607000_2023.10.03.560680v1.71","doi-asserted-by":"publisher","DOI":"10.1016\/j.trim.2007.08.001"},{"issue":"6","key":"2023101100351607000_2023.10.03.560680v1.72","first-page":"e20230269","article-title":"SBC Guideline on the Diagnosis and Treatment of Patients with Cardiomyopathy of Chagas Disease - 2023","volume":"120","year":"2023","journal-title":"Arq Bras Cardiol"},{"issue":"3","key":"2023101100351607000_2023.10.03.560680v1.73","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1093\/jac\/dkz473","article-title":"Tolerance to nifurtimox and benznidazole in adult Patients with chronic Chagas\u2019 disease","volume":"75","year":"2020","journal-title":"J Antimicrob Chemother"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.10.03.560680","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:19:55Z","timestamp":1768454395000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.10.03.560680"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,5]]},"references-count":73,"URL":"https:\/\/doi.org\/10.1101\/2023.10.03.560680","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1016\/j.lana.2025.101090","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2023,10,5]]},"subtype":"preprint"}}