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This study aimed to improve the protective immunity of a previously developed growth-deficient strain\u2014a double auxotroph for D-glutamate and D-alanine\u2014by engineering the inducible expression of type 1 fimbriae. Methods: PtetA-driven expression of the fim operon was achieved by \u03bb-Red mutagenesis. fimA expression was quantified by qRT-PCR, and fimbriation visualized by transmission electron microscopy. Adhesive properties were evaluated through FimH sequence analysis, yeast agglutination, mannose-binding\/inhibition assays, and HT-29 cell adherence. BALB\/c mice were immunized orogastrically with IRTA \u0394\u0394\u0394 or IRTA \u0394\u0394\u0394 PtetA::fim. Safety and immunogenicity were assessed by clinical monitoring, bacterial load, fecal shedding, ELISA tests, and adhesion\/blocking assays using fecal extracts. Protection was evaluated after challenging with wild-type and heterologous strains. Results: IRTA \u0394\u0394\u0394 PtetA::fim showed robust fimA expression, dense fimbrial coverage, a marked mannose-sensitive adhesive phenotype and enhanced HT-29 attachment. Fimbrial overexpression did not alter intestinal colonization or translocation to mesenteric lymph nodes (mLNs). Immunization elicited a mixed IgG1\/IgG2a, significantly increased IgA and IgG against type 1 fimbriae-expressing Salmonella, and enhanced the ability of fecal extracts to inhibit the adherence of wild-type strains. Upon challenge (IRTA wild-type\/20220258), IRTA \u0394\u0394\u0394 PtetA::fim reduced infection burden in the cecum (\u22121.46\/1.47-log), large intestine (\u22121.35\/2.17-log), mLNs (\u22121.32\/0.98-log) and systemic organs more effectively than IRTA \u0394\u0394\u0394. Conclusions: Inducible expression of type 1 fimbriae enhances mucosal immunity and protection, supporting their inclusion in next-generation Salmonella vaccines. Future work should assess cross-protection and optimize FimH-mediated targeting for mucosal delivery.<\/jats:p>","DOI":"10.3390\/vaccines13060659","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T09:57:48Z","timestamp":1750327068000},"page":"659","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Engineering and Evaluation of a Live-Attenuated Vaccine Candidate with Enhanced Type 1 Fimbriae Expression to Optimize Protection Against Salmonella Typhimurium"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0418-296X","authenticated-orcid":false,"given":"Patricia","family":"Garc\u00eda","sequence":"first","affiliation":[{"name":"Servicio de Microbiolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de A Coru\u00f1a (INIBIC), Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), Sergas, 15006 A Coru\u00f1a, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Rodr\u00edguez-Coello","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de A Coru\u00f1a (INIBIC), Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), Sergas, 15006 A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Garc\u00eda-Pose","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de A Coru\u00f1a (INIBIC), Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), Sergas, 15006 A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Del Carmen","family":"Fern\u00e1ndez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de A Coru\u00f1a (INIBIC), Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), Sergas, 15006 A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Muras","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de A Coru\u00f1a (INIBIC), Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), Sergas, 15006 A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8977-3269","authenticated-orcid":false,"given":"Miriam","family":"Moscoso","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de A Coru\u00f1a (INIBIC), Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), Sergas, 15006 A Coru\u00f1a, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Beceiro","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de A Coru\u00f1a (INIBIC), Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), Sergas, 15006 A Coru\u00f1a, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8837-0062","authenticated-orcid":false,"given":"Germ\u00e1n","family":"Bou","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda, Instituto de Investigaci\u00f3n Biom\u00e9dica de A Coru\u00f1a (INIBIC), Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), Sergas, 15006 A Coru\u00f1a, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Departamento de Fisioterapia, Medicina y Ciencias Biom\u00e9dicas, Universidad de A Coru\u00f1a, 15006 A Coru\u00f1a, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1086\/650733","article-title":"The global burden of nontyphoidal Salmonella gastroenteritis","volume":"50","author":"Majowicz","year":"2010","journal-title":"Clin. 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