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We describe a vaccine platform that leverages a peptide epitope derived from the T. cruzi trans-sialidase group II (Tc85pep), displayed on the virus-like particle derived from the PP7 bacteriophage, to stimulate both innate and adaptive immunity. In silico analyses revealed that Tc85pep contains threonine residues predicted to undergo post-translational phosphorylation at conserved PKA and PKG sites and bind with high affinity to murine and human MHC class I and II alleles. Structural modeling and molecular docking suggested a potential interaction between Tc85pep and the TLR4\/MD2 complex, supporting the hypothesis that the peptide may engage TLR4-associated signaling pathways. Functional analyses in TLR-deficient macrophages revealed that a multivalent conjugate of the peptide on the particle (PP7-Tc85pep) triggers nitric oxide production in a TLR4-dependent manner. In vivo, C57BL\/6 mice immunized with PP7-Tc85pep exhibited a greater than 60% reduction in parasitemia and significant protection against cardiac inflammation and amastigote burden following a lethal T. cruzi challenge. The vaccine elicited a balanced Th1\/Th2\/Th17 immune response, marked by elevated detection of IL-10, IL-6, TNF-\u03b1, IFN-\u03b3, and IL-17A, and provided tissue-level protection in the absence of chemotherapy. These findings identify PP7-Tc85pep as a potent, multifunctional epitope capable of engaging innate and adaptive immune pathways. The data support further development of Tc85pep-based epitope vaccines as a next-generation strategy for Chagas disease prevention.<\/jats:p>","DOI":"10.1021\/acsomega.6c04457","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T03:01:44Z","timestamp":1786503704000},"page":"49775-49784","source":"Crossref","is-referenced-by-count":0,"title":["Immunization with\nthe Tc85-Derived Peptide Displayed\non Virus-like Particles Confers Protection against\n                    <i>Trypanosoma cruzi<\/i>\n                    Infection"],"prefix":"10.1021","volume":"11","author":[{"given":"Ugochukwu","family":"Oduwe","sequence":"first","affiliation":[{"name":"University of Southern Mississippi , , , ,","place":["Hattiesburg, Mississippi, United States, 39406"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgi","family":"Kenkebashvili","sequence":"additional","affiliation":[{"name":"University of Southern Mississippi , , , ,","place":["Hattiesburg, Mississippi, United States, 39406"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1979-0642","authenticated-orcid":true,"given":"Syed","family":"Uddin","sequence":"additional","affiliation":[{"name":"University of Southern Mississippi , , , ,","place":["Hattiesburg, Mississippi, United States, 39406"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward Valencia","family":"Ayala","sequence":"additional","affiliation":[{"name":"Universidad Nacional Mayor de San Marcos , , ,","place":["Lima, Peru, 15081"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisele Macedo","family":"Rodrigues da Cunha","sequence":"additional","affiliation":[{"name":"Universidade Federal de Minas Gerais , , ,","place":["Belo Horizonte, Brazil, 31270-901"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery","family":"Noble","sequence":"additional","affiliation":[{"name":"Georgia Institute of Technology , , , ,","place":["Atlanta, Georgia, United States, 30332"]},{"name":"Georgia Institute of Technology , , , ,","place":["Atlanta, Georgia, United States, 30332"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Jimenez","family":"Chunga","sequence":"additional","affiliation":[{"name":"Universidad Nacional Mayor de San Marcos , , ,","place":["Lima, Peru, 15081"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8247-3108","authenticated-orcid":true,"given":"M. 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