The role of antimicrobial peptides in animal defenses
The role of antimicrobial peptides in animal defenses
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DOI：
10.1073/pnas.97.16.8856
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发表时间：
2000-08-01
影响因子：
11.1
通讯作者：
Scott, MG
中科院分区：
文献类型：
--
作者：
Hancock, REW;Scott, MG
越来越清楚的是，阳离子抗菌肽是所有生命物种先天防御的重要组成部分。这些肽可以由细菌或其产物组成型表达或诱导。最好的肽对广泛的细菌菌株具有良好的活性，包括耐药性分离株。它们杀死非常迅速，不容易选择耐药突变体，与常规抗生素，其他肽和溶菌酶具有协同作用，并且能够在动物模型中杀死细菌。已知细菌感染，特别是当用抗生素治疗时，可导致细菌产物如脂多糖（LPS）和脂磷壁酸的释放，从而导致潜在致命的败血症。与抗生素相反，这些肽实际上阻止了组织培养物和人血液中细菌产物引起的细胞因子诱导，并且它们阻断了内毒素血症小鼠模型中脓毒症的发作。与此一致，使用巨噬细胞系的转录基因阵列实验证明，模型肽CEMA阻断了许多基因的表达，这些基因的转录是由LPS诱导的。这些肽部分地通过阻断LPS与血清蛋白LBP的相互作用来实现这一点。此外，CEMA本身对巨噬细胞基因表达有直接影响。因为阳离子抗菌肽是由LPS诱导的，能够抑制动物细胞对LPS的脓毒症反应。我们提出，除了它们在直接和溶菌酶辅助杀死微生物中的作用外，它们还在细胞因子应答的反馈调节中起作用。我们目前正在开发变异肽作为治疗药物对抗生素耐药感染。
It is becoming clear that the cationic antimicrobial peptides are an important component of the innate defenses of all species of life. Such peptides can be constitutively expressed or induced by bacteria or their products. The best peptides have good activities vs. a broad range of bacterial strains, including antibiotic-resistant isolates. They kill very rapidly, do not easily select resistant mutants, are synergistic with conventional antibiotics, other peptides, and lysozyme, and are able to kill bacteria in animal models. It is known that bacterial infections, especially when treated with antibiotics, can lead to the release of bacterial products such as lipopolysaccharide (LPS) and lipoteichoic acid, resulting in potentially lethal sepsis. In contrast to antibiotics, the peptides actually prevent cytokine induction by bacterial products in tissue culture and human blood, and they block the onset of sepsis in mouse models of endotoxemia. Consistent with this, transcriptional gene array experiments using a macrophage cell line demonstrated that a model peptide, CEMA, blocks the expression of many genes whose transcription was induced by LPS. The peptides do this in part by blocking LPS interaction with the serum protein LBP. In addition, CEMA itself has a direct effect on macrophage gene expression. Because cationic antimicrobial peptides are induced by LPS and are able to dampen the septic response of animal cells to LPS. we propose that, in addition to their role in direct and lysozyme-assisted killing of microbes, they have a role in feedback regulation of cytokine responses. We are currently developing variant peptides as therapeutics against antibiotic-resistant infections.