{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T01:31:03Z","timestamp":1792373463387,"version":"4.4.0"},"reference-count":48,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2016,9,6]],"date-time":"2016-09-06T00:00:00Z","timestamp":1473120000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,11,2]],"date-time":"2016-11-02T00:00:00Z","timestamp":1478044800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2016,11,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Recombinant attenuated\n            <jats:named-content content-type=\"genus-species\">Salmonella enterica<\/jats:named-content>\n            serovar Typhimurium strains are believed to act as powerful live vaccine carriers that are able to elicit protection against various pathogens. Auxotrophic mutations, such as a deletion of\n            <jats:italic>aroA<\/jats:italic>\n            , are commonly introduced into such bacteria for attenuation without incapacitating immunostimulation. In this study, we describe the surprising finding that deletion of\n            <jats:italic>aroA<\/jats:italic>\n            dramatically increased the virulence of attenuated\n            <jats:italic>Salmonella<\/jats:italic>\n            in mouse models. Mutant bacteria lacking\n            <jats:italic>aroA<\/jats:italic>\n            elicited increased levels of the proinflammatory cytokine tumor necrosis factor alpha (TNF-\u03b1) after systemic application\n            <jats:italic>.<\/jats:italic>\n            A detailed genetic and phenotypic characterization in combination with transcriptomic and metabolic profiling demonstrated that \u0394\n            <jats:italic>aroA<\/jats:italic>\n            mutants display pleiotropic alterations in cellular physiology and lipid and amino acid metabolism, as well as increased sensitivity to penicillin, complement, and phagocytic uptake. In concert with other immunomodulating mutations, deletion of\n            <jats:italic>aroA<\/jats:italic>\n            affected flagellin phase variation and gene expression of the virulence-associated genes\n            <jats:italic>arnT<\/jats:italic>\n            and\n            <jats:italic>ansB<\/jats:italic>\n            . Finally,\n            <jats:italic>\u0394aroA<\/jats:italic>\n            strains displayed significantly improved tumor therapeutic activity. These results highlight the importance of a functional shikimate pathway to control homeostatic bacterial physiology. They further highlight the great potential of\n            <jats:italic>\u0394aroA<\/jats:italic>\n            -attenuated\n            <jats:italic>Salmonella<\/jats:italic>\n            for the development of vaccines and cancer therapies with important implications for host-pathogen interactions and translational medicine.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            Recombinant attenuated bacterial vector systems based on genetically engineered\n            <jats:italic>Salmonella<\/jats:italic>\n            have been developed as highly potent vaccines. Due to the pathogenic properties of\n            <jats:italic>Salmonella<\/jats:italic>\n            , efficient attenuation is required for clinical applications. Since the hallmark study by Hoiseth and Stocker in 1981 (S. K. Hoiseth and B. A. D. Stocker, Nature 291:238\u2013239, 1981, http:\/\/dx.doi.org\/10.1038\/291238a0), the auxotrophic \u0394\n            <jats:italic>aroA<\/jats:italic>\n            mutation has been generally considered safe and universally used to attenuate bacterial strains. Here, we are presenting the remarkable finding that a deletion of\n            <jats:italic>aroA<\/jats:italic>\n            leads to pronounced alterations of gene expression, metabolism, and cellular physiology, which resulted in increased immunogenicity, virulence, and adjuvant potential of\n            <jats:italic>Salmonella.<\/jats:italic>\n            These results suggest that the enhanced immunogenicity of\n            <jats:italic>aroA<\/jats:italic>\n            -deficient\n            <jats:italic>Salmonella<\/jats:italic>\n            strains might be advantageous for optimizing bacterial vaccine carriers and immunotherapy. Accordingly, we demonstrate a superior performance of \u0394\n            <jats:italic>aroA Salmonella<\/jats:italic>\n            in bacterium-mediated tumor therapy. In addition, the present study highlights the importance of a functional shikimate pathway to sustain bacterial physiology and metabolism.\n          <\/jats:p>","DOI":"10.1128\/mbio.01220-16","type":"journal-article","created":{"date-parts":[[2016,9,7]],"date-time":"2016-09-07T00:43:25Z","timestamp":1473209005000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":79,"title":["<i>aroA<\/i>\n            -Deficient Salmonella enterica Serovar Typhimurium Is More Than a Metabolically Attenuated Mutant"],"prefix":"10.1128","volume":"7","author":[{"given":"Sebastian","family":"Felgner","sequence":"first","affiliation":[{"name":"Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Frahm","sequence":"additional","affiliation":[{"name":"Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dino","family":"Kocijancic","sequence":"additional","affiliation":[{"name":"Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Rohde","sequence":"additional","affiliation":[{"name":"Central Facility for Microscopy, Helmholtz Centre for Infection Research, Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denitsa","family":"Eckweiler","sequence":"additional","affiliation":[{"name":"Department of Molecular Bacteriology, Helmholtz Centre for Infection Research, Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata","family":"Bielecka","sequence":"additional","affiliation":[{"name":"Department of Molecular Bacteriology, Helmholtz Centre for Infection Research, Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Bueno","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Ume\u00e5 University, Ume\u00e5, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Cava","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Ume\u00e5 University, Ume\u00e5, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolf-Rainer","family":"Abraham","sequence":"additional","affiliation":[{"name":"Department of Chemical Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Roy","family":"Curtiss","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Pathology, University of Florida, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"H\u00e4ussler","sequence":"additional","affiliation":[{"name":"Department of Molecular Bacteriology, Helmholtz Centre for Infection Research, Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Erhardt","sequence":"additional","affiliation":[{"name":"Junior Research Group Infection Biology of Salmonella, Helmholtz Centre for Infection Research, Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siegfried","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany"},{"name":"Institute of Immunology, Medical School Hannover, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"World health statistics 2014","author":"World Health Organization","year":"2013","unstructured":"World Health Organization. 2013. 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