2026-04-29T12:24:05Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/160292025-05-07T11:00:51Zcom_20.500.12105_2052com_20.500.12105_2051com_20.500.12105_15322col_20.500.12105_19609col_20.500.12105_16985col_20.500.12105_16990
Repisalud
author
García, Patricia
author
Moscoso, Miriam
author
Fuentes-Valverde, Víctor
author
Rodicio, M Rosario
author
Herrera-León, Silvia
author
Bou, Germán
funder
Xunta de Galicia (España)
funder
Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas)
funder
Instituto de Salud Carlos III
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
2023-05-09T09:35:31Z
2023-05-09T09:35:31Z
2023-04
Journal of Microbiology, Immunology and Infection. 2023,56:324-336.
10.1016/j.jmii.2022.10.002
1684-1182
Journal of Microbiology, Immunology and Infection
http://hdl.handle.net/20.500.12105/16029
Background: Salmonella enterica serovar Typhimurium (S. Typhimurium) has become an important intestinal pathogen worldwide and is responsible for lethal invasive infections in populations at risk. There is at present an unmet need for preventive vaccines. Methods: IRTA GN-3728 genome was sequenced by Illumina and D-glutamate and D-glutamate/D-alanine knockout-auxotrophs were constructed. They were characterized using electron microscopy, growth/viability curves, reversion analysis, and motility/agglutination assays. Their potential as vaccine candidates were explored using two BALB/c mouse models for Salmonella infections: a systemic and an intestinal inflammation. Clinical signs/body weight and survival were monitored, mucosal lactoferrin and specific/cross-reactive IgA/IgG were quantified by enzyme-linked-immunosorbent assays and bacterial shedding/burden in fecal/tissues were evaluated. Results: The D-glutamate auxotroph, IRTA DmurI, is highly attenuated, immunogenic and fully protective against systemic infection. The IRTA DmurI Dalr DdadX double auxotroph, constructed to reinforce vaccine safety, showed a higher level of attenuation and was 100% effective against systemic disease. In the intestinal model, it proved to be safe, yielding a lowdegree of mucosal inflammation, short-term shedding and undetectable invasiveness in the long-term, while eliciting cross-reactive fecal IgA/serum IgG against clinically relevant multidrug-resistant (MDR) S. Typhimurium strains. It also conferred protection against homologous oral challenge, and protected mice from local and extra-intestinal dissemination caused by one MDR strain responsible for an international outbreak of highly severe human infections. Additionally, oral vaccination promoted extended survival after lethal heterologous infection. Conclusion: This study yielded a very safe S. Typhimurium vaccine candidate that could be further refined for mucosal application against disease in humans.
eng
D-glutamate
D-alanine
Intestinal infection model
Live auxotrophic vaccines
Mucosal vaccine
Non-typhoidal Salmonella
Non-typhoidal Typhimurium
A highly-safe live auxotrophic vaccine protecting against disease caused by non-typhoidal Salmonella Typhimurium in mice
research article
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