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Microbiol."],"abstract":"<jats:p>\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    invasion of the osteocyte lacuno-canalicular network (OLCN) is a novel mechanism of bacterial persistence and immune evasion in chronic osteomyelitis. Previous work highlighted\n                    <jats:italic>S. aureus<\/jats:italic>\n                    cell wall transpeptidase, penicillin binding protein 4 (PBP4), and surface adhesin,\n                    <jats:italic>S. aureus<\/jats:italic>\n                    surface protein C (SasC), as critical factors for bacterial deformation and propagation through nanopores\n                    <jats:italic>in vitro<\/jats:italic>\n                    , representative of the confined canaliculi\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Given these findings, we hypothesized that cell wall synthesis machinery and surface adhesins enable durotaxis- and haptotaxis-guided invasion of the OLCN, respectively. Here, we investigated select\n                    <jats:italic>S. aureus<\/jats:italic>\n                    cell wall synthesis mutants (\u0394pbp3, \u0394atl, and \u0394mreC) and surface adhesin mutants (\u0394clfA and \u0394sasC) for nanopore propagation\n                    <jats:italic>in vitro<\/jats:italic>\n                    and osteomyelitis pathogenesis\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                    <jats:italic>In vitro<\/jats:italic>\n                    evaluation in the microfluidic silicon membrane-canalicular array (\u03bcSiM-CA) showed\n                    <jats:italic>pbp3<\/jats:italic>\n                    ,\n                    <jats:italic>atl<\/jats:italic>\n                    ,\n                    <jats:italic>clfA<\/jats:italic>\n                    , and\n                    <jats:italic>sasC<\/jats:italic>\n                    deletion reduced nanopore propagation. Using a murine model for implant-associated osteomyelitis,\n                    <jats:italic>S. aureus<\/jats:italic>\n                    cell wall synthesis proteins were found to be key modulators of\n                    <jats:italic>S. aureus<\/jats:italic>\n                    osteomyelitis pathogenesis, while surface adhesins had minimal effects. Specifically, deletion of\n                    <jats:italic>pbp3<\/jats:italic>\n                    and\n                    <jats:italic>atl<\/jats:italic>\n                    decreased septic implant loosening and\n                    <jats:italic>S. aureus<\/jats:italic>\n                    abscess formation in the medullary cavity, while deletion of surface adhesins showed no significant differences. Further, peri-implant osteolysis, osteoclast activity, and receptor activator of nuclear factor kappa-B ligand (RANKL) production were decreased following\n                    <jats:italic>pbp3<\/jats:italic>\n                    deletion. Most notably, transmission electron microscopy (TEM) imaging of infected bone showed that\n                    <jats:italic>pbp3<\/jats:italic>\n                    was the only gene herein associated with decreased submicron invasion of canaliculi\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Together, these results demonstrate that\n                    <jats:italic>S. aureus<\/jats:italic>\n                    cell wall synthesis enzymes are critical for OLCN invasion and osteomyelitis pathogenesis\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.3389\/fmicb.2021.723498","type":"journal-article","created":{"date-parts":[[2021,8,16]],"date-time":"2021-08-16T05:44:41Z","timestamp":1629092681000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":49,"title":["Staphylococcus aureus Cell Wall Biosynthesis Modulates Bone Invasion and Osteomyelitis Pathogenesis"],"prefix":"10.3389","volume":"12","author":[{"given":"Elysia A.","family":"Masters","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gowrishankar","family":"Muthukrishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lananh","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann Lindley","family":"Gill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L.","family":"de Mesy Bentley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad A.","family":"Galloway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James L.","family":"McGrath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hani A.","family":"Awad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven R.","family":"Gill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward M.","family":"Schwarz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2020.115568","article-title":"Intracellular Staphylococcus aureus in bone and joint infections: a mechanism of disease recurrence, inflammation, and bone and cartilage destruction.","volume":"141","author":"Alder","year":"2020","journal-title":"Bone"},{"key":"B2","doi-asserted-by":"crossref","DOI":"10.1155\/2015\/832127","article-title":"Bone loss triggered by the cytokine network in inflammatory autoimmune diseases.","volume":"2015","author":"Amarasekara","year":"2015","journal-title":"J. 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