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Macrophages are a key component of the innate immune response to\n                      <jats:italic>S. aureus<\/jats:italic>\n                      infection and play a major role in disease outcomes. To investigate the adaptive evolution of\n                      <jats:italic>S. aureus<\/jats:italic>\n                      in response to macrophages, we developed an experimental infection assay.\n                      <jats:italic>S. aureus<\/jats:italic>\n                      strains representing major human epidemic clones were passaged many times in a macrophage cell line, accumulating mutations in an array of genomic loci. Phenotypic analysis revealed the emergence of a lineage exhibiting increased survival in macrophages and human blood, and resistance to vancomycin. The evolved lineage exhibited a previously undescribed small colony variant (SCV) phenotype characterized by hyper-pigmentation, which resulted from a missense mutation in\n                      <jats:italic>rsbW<\/jats:italic>\n                      . Notably, the novel SCV was a conditional adaptive trait that was unstable in nutrient-replete conditions\n                      <jats:italic>in vitro<\/jats:italic>\n                      , rapidly converting from hyper-pigmented SCV to a non-pigmented large colony variant via spontaneous\n                      <jats:italic>sigB<\/jats:italic>\n                      deletion events. Importantly, we identified similar deletions in the genome sequences of a limited number of clinical\n                      <jats:italic>S. aureus<\/jats:italic>\n                      isolates from public databases, indicating that related events may occur during clinical infection. Experimental infection of zebrafish did not reveal a difference in virulence between parent and novel SCV but demonstrated an\n                      <jats:italic>in vivo<\/jats:italic>\n                      fitness cost for the compensatory\n                      <jats:italic>sigB<\/jats:italic>\n                      deletion events. Taken together, we report an experimental evolutionary approach for investigating bacterial innate immune cell interactions, revealing a conditional adaptation that promotes\n                      <jats:italic>S. aureus<\/jats:italic>\n                      survival in macrophages and resistance to vancomycin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Staphylococcus aureus<\/jats:italic>\n                      is an important human bacterial pathogen. The host response to\n                      <jats:italic>S. aureus<\/jats:italic>\n                      involves the production of innate immune cells such as macrophages which are important for fighting infection. Here we report a new model of experimental evolution for studying how\n                      <jats:italic>S. aureus<\/jats:italic>\n                      can evade killing by macrophages. We identified a novel adaptive phenotype that promotes survival in macrophages and blood and resistance to antibiotics. The phenotype is lost rapidly upon growth in nutrient-rich conditions via disruption of the alternative sigma factor sigB, revealing a conditional niche-specific fitness advantage. Genomic analysis of clinical isolates suggests similar adaptations may occur during human infections. Our model may be used broadly to identify adaptations of\n                      <jats:italic>S. aureus<\/jats:italic>\n                      to the innate immune response.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00346-24","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T09:00:39Z","timestamp":1714381239000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":24,"title":["Experimental evolution of\n                    <i>Staphylococcus aureus<\/i>\n                    in macrophages: dissection of a conditional adaptive trait promoting intracellular survival"],"prefix":"10.1128","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3131-9834","authenticated-orcid":false,"given":"Joana","family":"Alves","sequence":"first","affiliation":[{"name":"The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manouk","family":"Vrieling","sequence":"additional","affiliation":[{"name":"The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Ring","sequence":"additional","affiliation":[{"name":"The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"Yebra","sequence":"additional","affiliation":[{"name":"The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2154-224X","authenticated-orcid":true,"given":"Amy","family":"Pickering","sequence":"additional","affiliation":[{"name":"The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz K.","family":"Prajsnar","sequence":"additional","affiliation":[{"name":"Florey Institute, Bateson Centre and Division of Clinical Medicine, School of Medicine and Population Health, Sheffield, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen A.","family":"Renshaw","sequence":"additional","affiliation":[{"name":"Florey Institute, Bateson Centre and Division of Clinical Medicine, School of Medicine and Population Health, Sheffield, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9233-8468","authenticated-orcid":true,"given":"J. 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