Interplay between antibacterial effectors:: A macrophage antimicrobial peptide impairs intracellular Salmonella replication
Interplay between antibacterial effectors:: A macrophage antimicrobial peptide impairs intracellular Salmonella replication
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DOI：
10.1073/pnas.0304455101
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发表时间：
2004-02-24
影响因子：
11.1
通讯作者：
Finlay, BB
中科院分区：
文献类型：
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作者：
Rosenberger, CM;Gallo, RL;Finlay, BB
抗菌肽在防御细胞外感染中起着重要作用，但阳离子多肽在巨噬细胞内的表达作为抗菌作用机制尚未得到证实。小鼠巨噬细胞被鼠伤寒沙门氏菌感染后，巨噬细胞中肠毒素相关抗菌肽(CRAMP)的表达增加，这需要活性氧中间体的参与。通过使用抽筋缺陷小鼠或合成的抽筋多肽，我们发现抽筋在体内和体外都会损害沙门氏菌的细胞分裂，导致长丝状细菌的产生。这种受损的细菌细胞分裂还依赖于细胞内弹性酶样丝氨酸蛋白酶的活性，该酶可以蛋白水解性激活空肠毒素。巨噬细胞丝氨酸蛋白酶活性在体外诱导丝状化，增强痉挛活性。一个多肽敏感的沙门氏菌突变体显示，在抽筋缺陷小鼠的巨噬细胞中，沙门氏菌的存活增加，表明沙门氏菌可以感知细胞内环境中的阳离子多肽并对其做出反应。虽然阳离子多肽被认为对巨噬细胞内的病原体具有活性，但这项工作提供了实验证据，表明巨噬细胞的抗菌库中包括杀菌素。这些结果表明，细胞内的活性氧中间体和蛋白水解酶调节巨噬细胞痉挛的表达和活性，从而削弱细胞内细菌病原体的复制，并且它们突出了巨噬细胞抗菌效应物之间的协同作用。
Antimicrobial peptides have established an important role in the defense against extracellular infections, but the expression of cationic peptides within macrophages as an antibacterial effector mechanism against intracellular pathogens has not been demonstrated. Macrophage expression of the murine cathelicidin-related antimicrobial peptide (CRAMP) was increased after infection by the intracellular pathogen Salmonella typhimurium, and this increase required reactive oxygen intermediates. By using CRAMP-deficient mice or synthetic CRAMP peptide, we found that CRAMP impaired Salmonella cell division in vivo and in vitro, resulting in long filamentous bacteria. This impaired bacterial cell division also depended on intracellular elastase-like serine protease activity, which can proteolytically activate cathelicidins. Macrophage serine protease activity induced filamentation and enhanced the activity of CRAMP in vitro. A peptide-sensitive Salmonella mutant showed enhanced survival within macrophages derived from CRAMP-deficient mice, indicating that Salmonella can sense and respond to cationic peptides in the intracellular environment. Although cationic peptides have been hypothesized to have activity against pathogens within macrophages, this work provides experimental evidence that the antimicrobial arsenal of macrophages includes cathelicidins. These results show that intracellular reactive oxygen intermediates and proteases regulate macrophage CRAMP expression and activity to impair the replication of an intracellular bacterial pathogen, and they highlight the cooperativity between macrophage antibacterial effectors.