Epithelial Genes in Allergic Inflammation

特应性皮炎（AD）是一种慢性、复发性炎症性皮肤病，影响全世界15-20%的儿童。除了伴有强烈瘙痒的特征性病变外，AD还增加了微生物定植和过敏反应的风险，包括食物过敏、过敏性鼻炎和哮喘，这一过程被称为特应性进行。40多年前，人们就注意到AD病变经常被金黄色葡萄球菌定植。最近，人们发现AD患者的病变被金黄色葡萄球菌和表皮葡萄球菌菌株定植，它们形成生物膜，这些生物膜是表面附着的粘附菌落，对抗生素和免疫反应具有高度耐药性。表皮葡萄球菌是一种正常的皮肤共生菌，在某些情况下可以拮抗金黄色葡萄球菌生物膜的生长。然而，我们发现金黄色葡萄球菌和表皮葡萄球菌在共培养时能够形成协同的混合生物膜，这与最近的皮肤微生物组调查显示金黄色葡萄球菌和表皮葡萄球菌在AD病变皮肤上的患病率增加一致。我们和其他实验室的数据表明，葡萄球菌生物膜的生长依赖于表皮葡萄球菌和金黄色葡萄球菌表面分别表达的Aap和SasG蛋白介导的细胞间粘附事件。最近有研究表明，Aap和SasG可以介导表皮葡萄球菌和金黄色葡萄球菌细胞之间的嗜异性粘附事件。我们的主要假设是，这种嗜异性蛋白粘附事件促进了AD病变皮肤上强混合种葡萄球菌生物膜的生长，从而促进炎症，损害皮肤屏障功能，导致更严重的AD和进展为哮喘。

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder that affects 15-20% of children worldwide. In addition to the characteristic lesions accompanied by intense itching, AD increases the risk of microbial colonization and allergic responses including food allergy, allergic rhinitis, and asthma, in a process referred to as the atopic march. It was noted over 40 years ago that AD lesions were frequently colonized by Staphylococcus aureus. Recently, lesions from AD patients were discovered to be colonized by both S. aureus and S. epidermidis strains that formed biofilms, which are adhesive surface-attached colonies that become highly resistant to antibiotics and immune responses. S. epidermidis is a normal skin commensal that in some contexts can antagonize S. aureus biofilm growth. However, we have found that S. aureus and S. epidermidis are capable of forming synergistic mixed biofilms when co-cultured, which is consistent with recent skin microbiome surveys showing increased prevalence of both S. aureus and S. epidermidis on AD lesional skin. Data from our lab and others has shown that staphylococcal biofilm growth is dependent on intercellular adhesion events mediated by the Aap and SasG proteins expressed on the surfaces of S. epidermidis and S. aureus, respectively. It has recently been shown that Aap and SasG can mediate heterophilic adhesion events between S. epidermidis and S. aureus cells. Our central hypothesis is that such heterophilic protein adhesion events facilitate the growth of strong mixed-species staphylococcal biofilms on AD lesional skin, which promote inflammation, compromise skin barrier function, and result in more severe AD and progression to asthma. Through the proposed aims, we will 1) test whether heterophilic protein interactions between Aap and SasG allow synergistic growth of mixed-species biofilms between Staphylococcus spp colonizing AD but not normal skin; 2) delineate the mechanistic basis by which mixed biofilms promote disease; and 3) test whether synergistic staphylococcal strains that make the strongest mixed biofilms are associated with AD severity, barrier dysfunction, and progression to asthma in M-PAACH children.