{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T04:46:49Z","timestamp":1784090809681,"version":"3.55.0"},"reference-count":50,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2024,8,21]],"date-time":"2024-08-21T00:00:00Z","timestamp":1724198400000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82370244"],"award-info":[{"award-number":["82370244"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Severe bacterial infections can trigger acute lung injury (ALI) and acute respiratory distress syndrome, with bacterial pathogen\u2010associated molecular patterns (PAMPs) exacerbating the inflammatory response, particularly in COVID\u201019 patients. Cyclic\u2010di\u2010GMP (CDG), one of the PAMPs, is synthesized by various Gram\u2010positve and Gram\u2010negative bacteria. Previous studies mainly focused on the inflammatory responses triggered by intracellular bacteria\u2010released CDG. However, how extracellular CDG, which is released by bacterial autolysis or rupture, activates the inflammatory response remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The interaction between extracellular CDG and myeloid differentiation protein 2 (MD2) was investigated using in vivo and in vitro models. MD2 blockade was achieved using specific inhibitor and genetic knockout mice. Site\u2010directed mutagenesis, co\u2010immunoprecipitation, SPR and Bis\u2010ANS displacement assays were\u00a0used to identify the potential binding sites of MD2 on CDG.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our data show that extracellular CDG directly interacts with MD2,\u00a0leading to activation of the TLR4\u00a0signalling pathway and lung injury. Specific inhibitors or genetic knockout of MD2 in mice significantly alleviated CDG\u2010induced lung injury. Moreover, isoleucine residues at positions 80 and 94, along with phenylalanine at position 121, are essential for the binding of MD2 to CDG.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results reveal that extracellular CDG induces lung injury through direct interaction with MD2 and activation of the TLR4 signalling pathway, providing valuable insights into bacteria\u2010induced ALI mechanisms and new therapeutic approaches for the treatment of bacterial co\u2010infection in COVID\u201019 patients.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1744","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T02:40:06Z","timestamp":1724294406000},"source":"Crossref","is-referenced-by-count":9,"title":["Cyclic\u2010di\u2010GMP induces inflammation and acute lung injury through direct binding to MD2"],"prefix":"10.1002","volume":"14","author":[{"given":"Chenchen","family":"Qian","sequence":"first","affiliation":[{"name":"School 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