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Expression of the LLO-encoding gene (\n            <jats:italic>hly<\/jats:italic>\n            ) requires the transcriptional activator PrfA, and both\n            <jats:italic>hly<\/jats:italic>\n            and\n            <jats:italic>prfA<\/jats:italic>\n            genes are essential for\n            <jats:named-content content-type=\"genus-species\">L. monocytogenes<\/jats:named-content>\n            virulence. Here, we used the hemolytic activity of LLO as a phenotypic marker to screen for spontaneous virulence-attenuating mutations in\n            <jats:named-content content-type=\"genus-species\">L. monocytogenes<\/jats:named-content>\n            . Sixty nonhemolytic isolates were identified among a collection of 57,820 confirmed\n            <jats:named-content content-type=\"genus-species\">L. monocytogenes<\/jats:named-content>\n            strains isolated from a variety of sources (0.1%). In most cases (56\/60; 93.3%), the nonhemolytic phenotype resulted from nonsense, missense, or frameshift mutations in\n            <jats:italic>prfA<\/jats:italic>\n            . Five strains carried\n            <jats:italic>hly<\/jats:italic>\n            mutations leading to a single amino acid substitution (G299V) or a premature stop codon causing strong virulence attenuation in mice. In one strain, both\n            <jats:italic>hly<\/jats:italic>\n            and\n            <jats:italic>gshF<\/jats:italic>\n            (encoding a glutathione synthase required for full PrfA activity) were missing due to genomic rearrangements likely caused by a transposable element. The PrfA\/LLO loss-of-function (PrfA\n            <jats:sup>\u2212<\/jats:sup>\n            \/LLO\n            <jats:sup>\u2212<\/jats:sup>\n            ) mutants belonged to phylogenetically diverse clades of\n            <jats:named-content content-type=\"genus-species\">L. monocytogenes<\/jats:named-content>\n            , and most were identified among nonclinical strains (57\/60). Consistent with the rare occurrence of loss-of-virulence mutations, we show that\n            <jats:italic>prfA<\/jats:italic>\n            and\n            <jats:italic>hly<\/jats:italic>\n            are under purifying selection. Although occurring at a low frequency, PrfA\n            <jats:sup>\u2212<\/jats:sup>\n            \/LLO\n            <jats:sup>\u2212<\/jats:sup>\n            mutational events in\n            <jats:named-content content-type=\"genus-species\">L. monocytogenes<\/jats:named-content>\n            lead to niche restriction and open an evolutionary path for obligate saprophytism in this facultative intracellular pathogen.\n          <\/jats:p>","DOI":"10.1128\/iai.00541-17","type":"journal-article","created":{"date-parts":[[2017,8,22]],"date-time":"2017-08-22T00:30:24Z","timestamp":1503361824000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":84,"title":["Spontaneous Loss of Virulence in Natural Populations of Listeria monocytogenes"],"prefix":"10.1128","volume":"85","author":[{"given":"Myl\u00e8ne M.","family":"Maury","sequence":"first","affiliation":[{"name":"Institut Pasteur, National Reference Centre and WHO Collaborating Centre for Listeria, Paris, France"},{"name":"Institut Pasteur, Biology of Infection Unit, Paris, France"}]},{"given":"Viviane","family":"Chenal-Francisque","sequence":"additional","affiliation":[{"name":"Institut Pasteur, National Reference Centre and WHO Collaborating Centre for Listeria, Paris, France"},{"name":"Institut Pasteur, Biology of Infection Unit, Paris, France"}]},{"given":"H\u00e9l\u00e8ne","family":"Bracq-Dieye","sequence":"additional","affiliation":[{"name":"Institut Pasteur, National Reference Centre and WHO Collaborating Centre for Listeria, Paris, France"},{"name":"Institut Pasteur, Biology of Infection Unit, Paris, France"}]},{"given":"Lei","family":"Han","sequence":"additional","affiliation":[{"name":"Microbial Pathogenesis Unit, Medical School (Biomedical Sciences), University of Edinburgh, Edinburgh, United Kingdom"}]},{"given":"Alexandre","family":"Leclercq","sequence":"additional","affiliation":[{"name":"Institut Pasteur, National Reference Centre and WHO Collaborating Centre for Listeria, Paris, France"},{"name":"Institut Pasteur, Biology of Infection Unit, Paris, France"}]},{"given":"Guillaume","family":"Vales","sequence":"additional","affiliation":[{"name":"Institut Pasteur, National Reference Centre and WHO Collaborating Centre for Listeria, Paris, France"},{"name":"Institut Pasteur, Biology of Infection Unit, Paris, France"}]},{"given":"Alexandra","family":"Moura","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Biology of Infection Unit, Paris, France"},{"name":"Inserm U1117, Paris, France"}]},{"given":"Edith","family":"Gouin","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Bacteria-Cell Interactions Unit, Paris, France"}]},{"given":"Mariela","family":"Scortti","sequence":"additional","affiliation":[{"name":"Microbial Pathogenesis Unit, Medical School (Biomedical Sciences), University of Edinburgh, Edinburgh, United Kingdom"},{"name":"Division of Infection and Immunity, The Roslin 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