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Cengiz Goekeri, Kerstin A.K. Linke, Karen Hoffmann, Elena Lopez-Rodriguez, Vladimir Gluhovic, Anne Voß, Sandra Kunder, Andreas Zappe, Sara Timm, Alina Nettesheim, Sebastian M.K. Schickinger, Christian M. Zobel, Kevin Pagel, Achim D Gruber, Matthias Ochs, Martin Witzenrath, Geraldine Nouailles. Am J Res Cell Mol Biol 2024: in press
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The pulmonary epithelial glycocalyx is rich in glycosaminoglycans such as hyaluronan andheparan sulfate. Despite their presence, the importance of these glycosaminoglycans inbacterial lung infections remains elusive. To address this, we intranasally inoculated mice withStreptococcus pneumoniae in the presence or absence of enzymes targeting pulmonaryhyaluronan and heparan sulfate, followed by characterization of subsequent disease pathology,pulmonary inflammation, and lung barrier dysfunction. Enzymatic degradation of hyaluronanand heparan sulfate exacerbated pneumonia in mice, as evidenced by increased disease scoresand alveolar neutrophil recruitment. However, targeting epithelial hyaluronan in combinationwith Streptococcus pneumoniae infection further exacerbated systemic disease, indicated byelevated splenic bacterial load and plasma levels of pro-inflammatory cytokines. In contrast,enzymatic cleavage of heparan sulfate resulted in increased bronchoalveolar bacterial burden,lung damage and pulmonary inflammation in mice infected with Streptococcus pneumoniae.Accordingly, heparinase-treated mice also exhibited disrupted lung barrier integrity asevidenced by higher alveolar edema scores and vascular protein leakage into the airways. Thisfinding was corroborated in a human alveolus-on-a-chip platform, confirming that heparinasetreatment also disrupts the human lung barrier during Streptococcus pneumoniae infection.Notably, enzymatic pre-treatment with either hyaluronidase or heparinase also rendered humanepithelial cells more sensitive to pneumococcal-induced barrier disruption, as determined bytransepithelial electrical resistance measurements, consistent with our findings in murinepneumonia. Taken together, these findings demonstrate the importance of intact hyaluronanand heparan sulfate in limiting pneumococci-induced damage, pulmonary inflammation, andepithelial barrier function and integrity.