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In 2017, the CDC designated methicillin-resistant S. aureus (MRSA) as a serious threat, reporting \u223c300\u2009000 cases of MRSA-associated hospitalizations annually, resulting in over 19\u2009000 deaths, surpassing that of HIV in the USA. S. aureus is a proficient biofilm-forming organism that rapidly acquires resistance to antibiotics, most commonly methicillin (MRSA). This review focuses on a large group of (&amp;gt;30) S. aureus adhesins, either surface-associated or secreted that are designed to specifically bind to 15 or more of the proteins that form key components of the human extracellular matrix (hECM). Importantly, this includes hECM proteins that are pivotal to the homeostasis of almost every tissue environment [collagen (skin), proteoglycans (lung), hemoglobin (blood), elastin, laminin, fibrinogen, fibronectin, and fibrin (multiple organs)]. These adhesins offer S. aureus the potential to establish an infection in every sterile tissue niche. These infections often endure repeated immune onslaught, developing into chronic, biofilm-associated conditions that are tolerant to \u223c1000 times the clinically prescribed dose of antibiotics. Depending on the infection and the immune response, this allows S. aureus to seamlessly transition from colonizer to pathogen by subtly manipulating the host against itself while providing the time and stealth that it requires to establish and persist as a biofilm. This is a comprehensive discussion of the interaction between S. aureus biofilms and the hECM. We provide particular focus on the role of these interactions in pathogenesis and, consequently, the clinical implications for the prevention and treatment of S. aureus biofilm infections.<\/jats:p>","DOI":"10.1093\/femsre\/fuae002","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T00:01:23Z","timestamp":1707350483000},"source":"Crossref","is-referenced-by-count":77,"title":["The role of human extracellular matrix proteins in defining\n                    <i>Staphylococcus aureus<\/i>\n                    biofilm infections"],"prefix":"10.1093","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0268-6379","authenticated-orcid":false,"given":"Mohini","family":"Bhattacharya","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine , Aurora, CO 80045 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander R","family":"Horswill","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine , Aurora, CO 80045 , United States"},{"name":"Department of Veterans Affairs, Eastern Colorado Health Care System , Aurora, CO 80045 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,2,9]]},"reference":[{"key":"2024021704273270800_bib1","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1099\/mic.0.057018-0","article-title":"Staphylococcus aureus clumping factor B mediates biofilm formation in the absence of calcium","volume":"158","author":"Abraham","year":"2012","journal-title":"Microbiology (Reading)"},{"key":"2024021704273270800_bib2","doi-asserted-by":"crossref","first-page":"344","DOI":"10.4049\/jimmunol.1601178","article-title":"Platelets mediate host-defense against S. aureus through direct bactericidal activity and by enhancing macrophage 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