Bacterial pneumonia-induced shedding of epithelial heparan sulfate inhibits the bactericidal activity of cathelicidin in a murine model.

Autor:	Zehr EP; Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States., Erzen CL; Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States., Oshima K; Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States., Langouet-Astrie CJ; Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States., LaRiviere WB; Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States., Shi D; Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York, United States., Zhang F; Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York, United States., McCollister BD; Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States., Windham SL; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States., Rizzo AN; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States., Bastarache JA; Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States., Horswill AR; Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States.; Department of Medicine, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado, United States., Schmidt EP; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States., Kwiecinski JM; Department of Microbiology, Jagiellonian University, Krakow, Poland., Colbert JF; Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States.; Department of Medicine, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado, United States.
Jazyk:	angličtina
Zdroj:	American journal of physiology. Lung cellular and molecular physiology [Am J Physiol Lung Cell Mol Physiol] 2024 Feb 01; Vol. 326 (2), pp. L206-L212. Date of Electronic Publication: 2023 Dec 19.
DOI:	10.1152/ajplung.00178.2023
Abstrakt:	Bacterial pneumonia is a common clinical syndrome leading to significant morbidity and mortality worldwide. In the current study, we investigate a novel, multidirectional relationship between the pulmonary epithelial glycocalyx and antimicrobial peptides in the setting of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Using an in vivo pneumonia model, we demonstrate that highly sulfated heparan sulfate (HS) oligosaccharides are shed into the airspaces in response to MRSA pneumonia. In vitro, these HS oligosaccharides do not directly alter MRSA growth or gene transcription. However, in the presence of an antimicrobial peptide (cathelicidin), increasing concentrations of HS inhibit the bactericidal activity of cathelicidin against MRSA as well as other nosocomial pneumonia pathogens ( Klebsiella pneumoniae and Pseudomonas aeruginosa ) in a dose-dependent manner. Surface plasmon resonance shows avid binding between HS and cathelicidin with a dissociation constant of 0.13 μM. These findings highlight a complex relationship in which shedding of airspace HS may hamper host defenses against nosocomial infection via neutralization of antimicrobial peptides. These findings may inform future investigation into novel therapeutic targets designed to restore local innate immune function in patients suffering from primary bacterial pneumonia. NEW & NOTEWORTHY Primary Staphylococcus aureus pneumonia causes pulmonary epithelial heparan sulfate (HS) shedding into the airspace. These highly sulfated HS fragments do not alter bacterial growth or transcription, but directly bind with host antimicrobial peptides and inhibit the bactericidal activity of these cationic polypeptides. These findings highlight a complex local interaction between the pulmonary epithelial glycocalyx and antimicrobial peptides in the setting of bacterial pneumonia.
Databáze:	MEDLINE
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