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This study investigates the role of LINE-1 (L1) activation in inflammation and loss of self-tolerance during Tc infection. In vitro assays evaluated the expression of genes involved in L1 regulation and interferon signaling under basal conditions and following L1 suppression via CRISPR\/dCas9. In vivo analyses in a murine model included L1 and IFN expression profiling, autoantibody quantification, and histopathological assessments of liver, spleen, intestine, and heart. Tc infection induced L1 upregulation, correlating with an increased expression of its inhibitors, MOV-10 and APOBEC-3, suggesting host-driven regulatory mechanisms. L1 activation was also associated with the upregulation of DNA repair pathways (MMR and NHEJ) and RNA-sensing pathways (MDA-5 and RIG-I), leading to type I interferon responses. In the murine model, L1 expression was highest in the intestine and heart, independent of parasite burden, and correlated with increased interferon gene expression and autoantibody production. Our findings suggest that CD pathogenesis involves L1-induced chronic inflammation, which may contribute to late-stage symptoms. This highlights self-recognition mechanisms in disease severity and reveals potential therapeutic targets for novel treatments.<\/jats:p>","DOI":"10.3390\/ijms26104466","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T04:06:21Z","timestamp":1746677181000},"page":"4466","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Beyond Trypanosoma cruzi: LINE-1 Activation as a Driver of Chronic Inflammation in Chagas Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5587-9462","authenticated-orcid":false,"given":"Marina","family":"Dias","sequence":"first","affiliation":[{"name":"Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline","family":"Moraes","sequence":"additional","affiliation":[{"name":"Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3079-6869","authenticated-orcid":false,"given":"Tatiana","family":"Shiroma","sequence":"additional","affiliation":[{"name":"Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5616-1585","authenticated-orcid":false,"given":"Vit\u00f3ria","family":"Pessoa","sequence":"additional","affiliation":[{"name":"Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Ermoges","sequence":"additional","affiliation":[{"name":"Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3512-7696","authenticated-orcid":false,"given":"Tamires","family":"Vital","sequence":"additional","affiliation":[{"name":"Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Hagstr\u00f6m","sequence":"additional","affiliation":[{"name":"Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1237-0693","authenticated-orcid":false,"given":"Davi","family":"de Sousa","sequence":"additional","affiliation":[{"name":"Veterinary Pathology and Forensics, Faculty of Veterinary Medicine, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3996-0856","authenticated-orcid":false,"given":"M\u00e1rcio","family":"de Castro","sequence":"additional","affiliation":[{"name":"Veterinary Pathology and Forensics, Faculty of Veterinary Medicine, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4883-1076","authenticated-orcid":false,"given":"Bruno","family":"Dallago","sequence":"additional","affiliation":[{"name":"Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2785-4255","authenticated-orcid":false,"given":"Izabela Marques Dourado","family":"Bastos","sequence":"additional","affiliation":[{"name":"Laboratory of Pathogen-Host Interaction, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadjar","family":"Nitz","sequence":"additional","affiliation":[{"name":"Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Hecht","sequence":"additional","affiliation":[{"name":"Interdisciplinary Laboratory of Biosciences, Faculty of Medicine, University of Bras\u00edlia, Bras\u00edlia 70910-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,8]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (WHO) (2024). 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