{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T08:29:46Z","timestamp":1792571386331,"version":"4.5.0"},"reference-count":38,"publisher":"National Academy of Sciences","issue":"31","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,8,4]]},"abstract":"<jats:p>\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    is a major cause of community-acquired and nosocomial infections including the life-threatening conditions endocarditis, necrotizing pneumonia, necrotizing fasciitis, and septicemia. Toll-like receptor (TLR)-2, a membrane-bound microbial sensor, detects staphylococcal components, but macrophages lacking TLR2 or both TLR2 and TLR4 remain\n                    <jats:italic>S. aureus<\/jats:italic>\n                    responsive, suggesting that an alternative microbial recognition receptor might be involved. The cytoplasmic sensor nucleotide-binding oligomerization domain containing (NOD) 2\/caspase recruitment domain (CARD) 15 detects muramyl dipeptide from bacterial peptidoglycans and mediates cytokine responses to\n                    <jats:italic>S. aureus<\/jats:italic>\n                    in vitro, but the physiological significance of these observations is not well defined. Here we show that NOD2-deficient mice exhibit a delayed but ultimately exacerbated ulcerative response and impaired bacterial clearance after s.c. infection with\n                    <jats:italic>S. aureus<\/jats:italic>\n                    . NOD2-dependent recognition of\n                    <jats:italic>S. aureus<\/jats:italic>\n                    and muramyl dipeptide is facilitated by \u03b1-toxin (\u03b1-hemolysin), a pore-forming toxin and virulence factor of the pathogen. The action of NOD2 is dependent on IL-1\u03b2-amplified production of IL-6, which promotes rapid bacterial killing by neutrophils. These results significantly broaden the physiological importance of NOD2 in innate immunity from the recognition of bacteria that primarily enter the cytoplasm to the detection of bacteria that typically reside extracellularly and demonstrate that this microbial sensor contributes to the discrimination between commensal bacteria and bacterial pathogens that elaborate pore-forming toxins.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0904958106","type":"journal-article","created":{"date-parts":[[2009,6,16]],"date-time":"2009-06-16T21:50:13Z","timestamp":1245189013000},"page":"12873-12878","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":174,"title":["NOD2 contributes to cutaneous defense against\n                    <i>Staphylococcus aureus<\/i>\n                    through \u03b1-toxin-dependent innate immune activation"],"prefix":"10.1073","volume":"106","author":[{"given":"Petr","family":"Hruz","sequence":"first","affiliation":[{"name":"Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelies S.","family":"Zinkernagel","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Jenikova","sequence":"additional","affiliation":[{"name":"Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory J.","family":"Botwin","sequence":"additional","affiliation":[{"name":"Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Hugot","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, U843, Universit\u00e9 Paris 7, H\u00f4pital Robert Debr\u00e9, 75019 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Karin","sequence":"additional","affiliation":[{"name":"Laboratory of Gene Expression and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Nizet","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, and"},{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Eckmann","sequence":"additional","affiliation":[{"name":"Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,8,4]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199808203390806"},{"key":"e_1_3_3_2_2","first-page":"1","article-title":"TLR signaling","volume":"311","author":"Akira S","year":"2006","unstructured":"S Akira, TLR signaling. 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