{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T19:13:35Z","timestamp":1784229215591,"version":"3.55.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Diabetic foot ulcers (DFUs) are serious complications of type 2 diabetes and are frequently infected with\n                      <jats:italic>Staphylococcus aureus<\/jats:italic>\n                      . However, the virulence mechanisms that enable\n                      <jats:italic>S. aureus<\/jats:italic>\n                      to adapt to diabetic conditions and drive disease progression remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To investigate the relationship between\n                      <jats:italic>S. aureus<\/jats:italic>\n                      virulence and DFU severity, we freshly isolated\n                      <jats:italic>S. aureus<\/jats:italic>\n                      from DFU patients with clinical severities ranging from Grade 2 (mild) and Grade 4 (severe). We evaluated their virulence characteristics using in vitro assays and an\n                      <jats:italic>in vivo<\/jats:italic>\n                      diabetic pressure wound infection model in diabetic TALLYHO\/JngJ mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>S. aureus<\/jats:italic>\n                      isolates from Grade 4 DFUs exhibited significantly greater biofilm formation, hemolytic activity, and resistance to oxidative stress compared to Grade 2 isolates. In the in vivo diabetic pressure wound infection model, Grade 4 isolates induced significantly greater tissue necrosis and delayed wound healing, accompanied by sustained expression of pro-inflammatory M1 macrophage-associated genes (\n                      <jats:italic>NOS2, IL1B<\/jats:italic>\n                      , and\n                      <jats:italic>IFNG<\/jats:italic>\n                      ). In contrast, Grade 2 isolates caused minimal tissue necrosis and promoted rapid wound healing with expression of anti-inflammatory M2 macrophage-associated genes (\n                      <jats:italic>ARG1, IL4<\/jats:italic>\n                      , and\n                      <jats:italic>IL10<\/jats:italic>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Collectively, these findings demonstrate that highly virulent\n                      <jats:italic>S. aureus<\/jats:italic>\n                      strains associated with severe DFUs exhibit enhanced virulence traits that promote host colonization and immune responses skewing macrophage polarization toward a sustained pro-inflammatory M1 phenotype, thereby exacerbating tissue damage and impairing wound healing. These virulence characteristics may serve as functional biomarkers to distinguish pathogenic\n                      <jats:italic>S. aureus<\/jats:italic>\n                      from less pathogenic or opportunistic\n                      <jats:italic>S. aureus<\/jats:italic>\n                      strains in DFUs.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2026.1805111","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T05:38:35Z","timestamp":1780637915000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical severity-dependent virulence of Staphylococcus aureus from human diabetic foot ulcers drives impaired wound healing in a diabetic murine model"],"prefix":"10.3389","volume":"16","author":[{"given":"Keun Seok","family":"Seo","sequence":"first","affiliation":[{"name":"Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University","place":["Mississippi State, MS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee M.","family":"Nicols","sequence":"additional","affiliation":[{"name":"Central Surgical Associates","place":["Jackson, MS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cara Dale","family":"Palmer","sequence":"additional","affiliation":[{"name":"Central Surgical Associates","place":["Jackson, MS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. Taylor","family":"Hellmann","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center","place":["Jackson, MS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Ashley","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center","place":["Jackson, MS, United States"]},{"name":"Center for Immunology and Microbial Research, University of Mississippi Medical Center","place":["Jackson, MS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia K.","family":"Olivier","sequence":"additional","affiliation":[{"name":"Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University","place":["Mississippi State, MS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin A.","family":"Thornton","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Arts and Sciences, Mississippi State University","place":["Mississippi State, MS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khadija","family":"Ferdous","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University","place":["Mississippi State, MS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilson\u00a0Cooper","family":"Brookshire","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University","place":["Mississippi State, MS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joo Youn","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University","place":["Mississippi State, MS, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"11447","DOI":"10.1038\/s41598-019-47836-8","article-title":"High glucose environments interfere with bone marrow-derived macrophage inflammatory mediator release, the TLR4 pathway and glucose metabolism","volume":"9","author":"Ayala","year":"2019","journal-title":"Sci. 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