Bacterial pneumonia-induced shedding of epithelial heparan sulfate inhibits the bactericidal activity of cathelicidin in a murine model.
Bacterial pneumonia-induced shedding of epithelial heparan sulfate inhibits the bactericidal activity of cathelicidin in a murine model.
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在小鼠模型中，细菌性肺炎诱导的上皮硫酸乙酰肝素脱落抑制了抗菌素的杀菌活性。
DOI：
10.1152/ajplung.00178.2023
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Kwieci
中科院分区：
文献类型：
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作者：
Zehr,EvanP;Erzen,ChristopherL;Oshima,Kaori;Langouet-Astrie,ChristopheJ;LaRiviere,WellsB;Shi,Deling;Zhang,Fuming;McCollister,BruceD;Windham,SamuelL;Rizzo,AliciaN;Bastarache,JulieA;Horswill,AlexanderR;Schmidt,EricP;Kwieci
细菌性肺炎是一种常见的临床综合征，在全世界范围内导致显着的发病率和死亡率。在当前的研究中，我们研究了耐甲氧西林金黄色葡萄球菌（MRSA）肺炎中肺上皮糖萼和抗菌肽之间的新型多向关系。使用体内肺炎模型，我们证明高度硫酸化的硫酸乙酰肝素 (HS) 寡糖会因 MRSA 肺炎而脱落到空气空间中。在体外，这些 HS 寡糖不会直接改变 MRSA 的生长或基因转录。然而，在抗菌肽（cathelicidin）存在的情况下，HS浓度的增加会以剂量依赖性方式抑制cathelicidin对MRSA以及其他院内肺炎病原体（肺炎克雷伯菌和铜绿假单胞菌）的杀菌活性。表面等离振子共振显示 HS 和抗菌肽之间存在强烈结合，解离常数为 0.13 μM。这些发现强调了一种复杂的关系，其中空域HS的脱落可能会通过中和抗菌肽来阻碍宿主对医院感染的防御。这些发现可能为未来研究旨在恢复原发性细菌性肺炎患者局部先天免疫功能的新治疗靶点的研究提供信息。新的和值得注意的原发性金黄色葡萄球菌肺炎会导致肺上皮硫酸乙酰肝素 (HS) 脱落到空气空间中。这些高度硫酸化的HS片段不会改变细菌的生长或转录，而是直接与宿主抗菌肽结合并抑制这些阳离子多肽的杀菌活性。这些发现强调了细菌性肺炎中肺上皮糖萼和抗菌肽之间复杂的局部相互作用。
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-resistantStaphylococcus 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 pneumoniaeandPseudomonas 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 & NOTEWORTHYPrimaryStaphylococcus aureuspneumonia 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.