Expression of an additional cathelicidin antimicrobial peptide protects against bacterial skin infection
Expression of an additional cathelicidin antimicrobial peptide protects against bacterial skin infection
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DOI：
10.1073/pnas.0500268102
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发表时间：
2005-03-08
影响因子：
11.1
通讯作者：
Gallo, RL
中科院分区：
文献类型：
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作者：
Lee, PHA;Ohtake, T;Gallo, RL
抗菌肽是哺乳动物先天免疫防御的效应器。人类和老鼠只有一个抗菌肽基因，而驯化的哺乳动物如猪、牛和马有多个抗菌肽基因。我们假设多种抗菌肽基因的进化为这些动物提供了增强的抗感染能力。为了验证这一点，我们通过在体外结合合成的抗菌肽，在培养物中产生过表达抗菌肽的人角质形成细胞，或在体内产生组成性过表达抗菌肽的转基因小鼠，来研究添加抗菌肽的影响。猪抗菌肽PR-39与人抗菌肽LL-37联合杀灭A组链球菌（GAS）。慢病毒递送PR-39增强人角质形成细胞对GAS的杀伤作用。最后，在K14启动子的影响下，表达PR-39的转基因小鼠对GAS皮肤感染的抵抗力增强（坏死溃疡缩小50%，存活细菌减少60%）。设计过表达其天然抗菌肽的类似构建的转基因小鼠没有显示出增加的耐药性。这些发现表明，外源抗菌肽的靶向基因转移赋予抗感染能力，并表明在抗菌肽的进化中复制和分化的好处。
Cathelicidin antimicrobial peptides are effectors of innate immune defense in mammals. Humans and mice have only one cathelicidin gene, whereas domesticated mammals such as the pig, cow, and horse have multiple cathelicidin genes. We hypothesized that the evolution of multiple cathelicidin genes provides these animals with enhanced resistance to infection. To test this, we investigated the effects of the addition of cathelicidins by combining synthetic cathelicidin peptides in vitro, by producing human keratinocytes that overexpress cathelicidins in culture, or by producing transgenic mice that constitutively overexpress cathelicidins in vivo. The porcine cathelicidin peptide PR-39 acted additively with human cathelicidin LL-37 to kill group A Streptococcus (GAS). Lentiviral delivery of PR-39 enhanced killing of GAS by human keratinocytes. Finally, transgenic mice expressing PR-39 under the influence of a K14 promoter showed increased resistance to GAS skin infection (50% smaller necrotic ulcers and 60% fewer surviving bacteria). Similarly constructed transgenic mice designed to overexpress their native cathelicidin did not show increased resistance. These findings demonstrate that targeted gene transfer of a xenobiotic cathelicidin confers resistance against infection and suggests the benefit of duplication and divergence in the evolution of antimicrobial peptides.