Cathelicidin host defence peptide augments clearance of pulmonary Pseudomonas aeruginosa infection by its influence on neutrophil function in vivo.
Cathelicidin host defence peptide augments clearance of pulmonary Pseudomonas aeruginosa infection by its influence on neutrophil function in vivo.
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DOI：
10.1371/journal.pone.0099029
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Davidson DJ
中科院分区：
文献类型：
--
作者：
Beaumont PE;McHugh B;Gwyer Findlay E;Mackellar A;Mackenzie KJ;Gallo RL;Govan JR;Simpson AJ;Davidson DJ
Cathelicidin是多功能阳离子宿主防御肽（CHDP;也称为抗微生物肽），并且是宿主抵抗感染的先天防御的重要组分。除了杀微生物的潜力，这些肽具有调节炎症和免疫力的能力。然而，这些特性在体内感染过程中发挥重要作用的程度仍不清楚。使用急性铜绿假单胞菌肺部感染的鼠模型，证明了凯萨林菌素介导的体内细菌清除的增强。发现外源性合成人凯萨林菌素LL-37的递送增强了对感染的保护性促炎反应，在没有直接杀微生物活性的情况下有效地促进了细菌从肺中的清除，具有增强的早期嗜中性粒细胞反应，其需要感染和肽暴露两者并且独立于天然凯萨林菌素产生。此外，尽管cathelicidin缺陷小鼠具有完整的早期细胞炎症反应，但这些动物中不存在对感染的晚期中性粒细胞反应，铜绿假单胞菌的清除显著受损。这些研究结果表明，在体内肺部感染的cathelicidins的调节特性的重要性，并强调了cathelicidins在诱导保护性肺中性粒细胞反应，特定的感染环境中的关键作用。除了其生理作用外，CHDP已被提议作为未来的抗菌治疗剂。阐明和利用cathelicidins的调节特性有可能为开发合成肽类似物和新的治疗方法提供信息，这些方法基于增强先天宿主对感染的防御，有或没有病原体的直接杀微生物靶向。
Cathelicidins are multifunctional cationic host-defence peptides (CHDP; also known as antimicrobial peptides) and an important component of innate host defence against infection. In addition to microbicidal potential, these peptides have properties with the capacity to modulate inflammation and immunity. However, the extent to which such properties play a significant role during infection in vivo has remained unclear. A murine model of acute P. aeruginosa lung infection was utilised, demonstrating cathelicidin-mediated enhancement of bacterial clearance in vivo. The delivery of exogenous synthetic human cathelicidin LL-37 was found to enhance a protective pro-inflammatory response to infection, effectively promoting bacterial clearance from the lung in the absence of direct microbicidal activity, with an enhanced early neutrophil response that required both infection and peptide exposure and was independent of native cathelicidin production. Furthermore, although cathelicidin-deficient mice had an intact early cellular inflammatory response, later phase neutrophil response to infection was absent in these animals, with significantly impaired clearance of P. aeruginosa. These findings demonstrate the importance of the modulatory properties of cathelicidins in pulmonary infection in vivo and highlight a key role for cathelicidins in the induction of protective pulmonary neutrophil responses, specific to the infectious milieu. In additional to their physiological roles, CHDP have been proposed as future antimicrobial therapeutics. Elucidating and utilising the modulatory properties of cathelicidins has the potential to inform the development of synthetic peptide analogues and novel therapeutic approaches based on enhancing innate host defence against infection with or without direct microbicidal targeting of pathogens.
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