Methicillin-resistant Staphylococcus aureus adaptation to human keratinocytes.
Methicillin-resistant Staphylococcus aureus adaptation to human keratinocytes.
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DOI：
10.1128/mbio.00289-15
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发表时间：
2015-04-21
期刊：
影响因子：
6.4
通讯作者：
Prince A
中科院分区：
文献类型：
--
作者：
Soong G;Paulino F;Wachtel S;Parker D;Wickersham M;Zhang D;Brown A;Lauren C;Dowd M;West E;Horst B;Planet P;Prince A
皮肤是金黄色葡萄球菌最常见的感染部位。虽然大多数这些感染是自限性的，但复发性感染很常见。角质形成细胞和募集的免疫细胞参与皮肤对感染的防御。我们假设金黄色葡萄球菌能够适应人角质形成细胞内的环境，以避免角质形成细胞介导的清除。从一组从慢性感染的特应性皮炎患者中分离的金黄色葡萄球菌中，我们注意到22%的金黄色葡萄球菌具有agr mu样表型。使用几种人类皮肤感染模型，我们证明了毒素缺乏，耐甲氧西林金黄色葡萄球菌（MRSA）USA 300的agr突变体能够通过刺激自噬和逃避caspase-1和炎性小体激活而在角质形成细胞内持续存在。MRSA感染诱导角质形成细胞自噬，如半乳糖凝集素-8和LC 3积累所证明。自噬促进炎性小体成分的降解，促进葡萄球菌的存活。与对照角质形成细胞相比，从渥曼青霉素处理的角质形成细胞内野生型（WT）MRSA接种物的agr或RNAIII突变体（P < 0.0001）的回收率超过58%，反映了不再表达agr依赖性毒素的突变体的存活优势。我们的研究结果说明了金黄色葡萄球菌和角质形成细胞之间的动态相互作用，这可能导致选择突变体，这些突变体专门适应逃避角质形成细胞介导的清除机制。人类皮肤是葡萄球菌感染的主要部位，角质形成细胞积极参与这些病原体的根除。我们证明，耐甲氧西林金黄色葡萄球菌（MRSA）摄入的角质形成细胞和激活caspase-1介导的清除通过焦亡。在角质形成细胞中选择毒素缺陷型MRSA突变体，这些突变体无法诱导半胱氨酸蛋白酶-1活性和角质形成细胞介导的清除。这些细胞内葡萄球菌诱导自噬，通过减少炎性体成分来增强其细胞内存活。这些发现表明，金黄色葡萄球菌突变体，通过利用自噬，可以在人类角质形成细胞内持续存在。
Skin is the most common site of Staphylococcus aureus infection. While most of these infections are self-limited, recurrent infections are common. Keratinocytes and recruited immune cells participate in skin defense against infection. We postulated that S. aureus is able to adapt to the milieu within human keratinocytes to avoid keratinocyte-mediated clearance. From a collection of S. aureus isolated from chronically infected patients with atopic dermatitis, we noted 22% had an agr mutant-like phenotype. Using several models of human skin infection, we demonstrate that toxin-deficient, agr mutants of methicillin-resistant S. aureus (MRSA) USA300 are able to persist within keratinocytes by stimulating autophagy and evading caspase-1 and inflammasome activation. MRSA infection induced keratinocyte autophagy, as evidenced by galectin-8 and LC3 accumulation. Autophagy promoted the degradation of inflammasome components and facilitated staphylococcal survival. The recovery of more than 58% agr or RNAIII mutants (P < 0.0001) of an inoculum of wild-type (WT) MRSA from within wortmannin-treated keratinocytes compared to control keratinocytes reflected the survival advantage for mutants no longer expressing agr-dependent toxins. Our results illustrate the dynamic interplay between S. aureus and keratinocytes that can result in the selection of mutants that have adapted specifically to evade keratinocyte-mediated clearance mechanisms. Human skin is a major site of staphylococcal infection, and keratinocytes actively participate in eradication of these pathogens. We demonstrate that methicillin-resistant Staphylococcus aureus (MRSA) is ingested by keratinocytes and activates caspase-1-mediated clearance through pyroptosis. Toxin-deficient MRSA mutants are selected within keratinocytes that fail to induce caspase-1 activity and keratinocyte-mediated clearance. These intracellular staphylococci induce autophagy that enhances their intracellular survival by diminishing inflammasome components. These findings suggest that S. aureus mutants, by exploiting autophagy, can persist within human keratinocytes.