权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Pathogen and host-derived lipid membranes governing Staphylococcus aureus-mediated skin inflammation

病原体和宿主来源的脂质膜控制金黄色葡萄球菌介导的皮肤炎症

基本信息

批准号：
234105777
负责人：
Professor Dr. Andreas Peschel
金额：
--
依托单位：
Lehrstuhl für Infektionsbiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/234105777?language=en
关键词：
Pathogen host derived lipid membranes

项目摘要

Human skin is colonized by a complex microbiome constantly releasing pro-inflammatory microbe-associated molecular pattern (MAMP) molecules. It has remained largely unclear how permanent skin inflammation is avoided while invading pathogens still lead to rapid pro-inflammatory responses. The keratinized, dead corneocytes forming the upper skin layers are embedded in a protective layer of lipid lamellar membranes, which may prevent bacterial molecules from reaching MAMP-responsive live keratinocytes. Atopic dermatitis (AD) patients exhibit major defects in skin barrier function, in particular in the integrity of lipid lamellar membranes. The bacterial pathogen Staphylococcus aureus is a frequent cause of skin inflammation in AD patients. It activates live keratinocytes by releasing bacterial lipoproteins, potent agonists of the Toll-like receptor (TLR) 2. We analysed in the first phase of the project how bioactive bacterial and host peptides contribute to activation and inflammation. We found that lipoproteins can only be efficiently released by S. aureus with the help of surfactant-like phenol-soluble modulin (PSM) peptides, which mobilize the hydrophobic lipoproteins in an unclear fashion. Preliminary data suggest that PSMs promote the release of membrane vesicles (MVs) containing the membrane-embedded lipoproteins from S. aureus. Based on these findings we propose that (i) S. aureus activates keratinocytes in AD largely by lipoprotein-containing MVs and that (ii) such MVs are retained by skin lamellar membranes in healthy skin while they can easily reach TLR2-expressing keratinocytes in AD patients with compromised skin lamellar membrane integrity to cause inflammation.We propose to investigate these hypotheses by elucidating how and when S. aureus releases MVs, if most bacterial lipoproteins are associated with MVs, and how they can leave MVs to activate TLR2 in keratinocytes. In vitro and in vivo experiments are envisaged to elucidate if and how lamellar membrane dysfunction impacts on TLR2-dependent skin inflammation and if supplementation of AD skin with lipid cocktails can help to prevent the access of S. aureus lipoproteins to MAMP-responsive keratinocytes. Our project will help to elucidate key processes of bacterial MAMP releases and of skin barrier function and it should inspire better clinical interventions against skin inflammation in AD patients and other chronic inflammatory skin diseases.

人类皮肤被复杂的微生物群落定殖，不断释放促炎微生物相关分子模式（MAMP）分子。目前还不清楚如何避免永久性皮肤炎症，而入侵的病原体仍然导致快速的促炎反应。形成上皮肤层的角质化的死角质细胞包埋在脂质层状膜的保护层中，这可以防止细菌分子到达MAMP响应性活角质形成细胞。特应性皮炎（AD）患者表现出皮肤屏障功能的主要缺陷，特别是脂质板层膜的完整性。细菌病原体金黄色葡萄球菌是AD患者皮肤炎症的常见原因。它通过释放细菌脂蛋白（Toll样受体（TLR）2的有效激动剂）来激活活的角质形成细胞。我们在项目的第一阶段分析了生物活性细菌和宿主肽如何促进激活和炎症。我们发现脂蛋白只能通过S.金黄色葡萄球菌在表面活性剂样酚可溶性调节蛋白（PSM）肽的帮助下，以一种不清楚的方式动员疏水性脂蛋白。初步的数据表明，PSM促进释放膜囊泡（MV）含有膜包埋脂蛋白从S。金黄色。基于这些发现，我们提出（i）S.金黄色葡萄球菌在AD中主要通过含脂蛋白的MV激活角质形成细胞，并且（ii）这种MV被健康皮肤中的皮肤板层膜保留，而在具有受损皮肤板层膜完整性的AD患者中，它们可以容易地到达表达TLR 2的角质形成细胞以引起炎症。金黄色葡萄球菌释放MV，如果大多数细菌脂蛋白与MV相关，以及它们如何离开MV以激活角质形成细胞中的TLR2。体外和体内实验旨在阐明板层膜功能障碍是否以及如何影响TLR2依赖性皮肤炎症，以及补充AD皮肤脂质混合物是否有助于防止S.金黄色葡萄球菌脂蛋白对MAMP反应性角质形成细胞的影响。我们的项目将有助于阐明细菌MAMP释放和皮肤屏障功能的关键过程，它应该激发更好的临床干预措施，以对抗AD患者和其他慢性炎症性皮肤病的皮肤炎症。