Biomarker Identification, Viral Susceptibility and Management in S. aureus Colonized AD Patients

项目摘要/摘要 金黄色葡萄球菌(S.aureus)被认为是特应性疾病的致病因素之一。 自20世纪70年代以来，皮炎(AD)，并得到进一步支持的出版物显示金黄色葡萄球菌皮肤 殖民先于AD发病。ADRN研究发现，50%的AD受试者是定植的，而这是AD 表型与更大的表皮屏障功能障碍、2型免疫、疾病严重程度和 皮肤微生物群显著变化(金黄色葡萄球菌相对丰度增加，而金黄色葡萄球菌相对丰度减少 共生细菌痤疮皮肤杆菌(C.acnes)的丰度。此外，金黄色葡萄球菌-殖民 AD患者更有可能患上一种严重的病毒疾病，称为疱疹湿疹。一个更多的 病情严重的是牛痘湿疹，因接触牛痘病毒(天花疫苗接种)而引起 致死率高达30%。为了解释这一点，我们发现，暴露在皮肤上的 对于一种在AD患者中常见的高毒力金黄色葡萄球菌菌株(USA300)，显著增强其 对牛痘病毒的易感性。总的来说，这些观察结果支持了我们的假设，即金黄色葡萄球菌可能是 疾病严重程度和对系统治疗(目标1)以及严重病毒反应的关键驱动因素 并发症(目标2)。确定痤疮假单胞菌--最丰富的共生皮肤细菌--所扮演的角色 抑制金黄色葡萄球菌将是目标3中概述的研究的重点。这些研究将利用 来自先前ADRN研究的表型较深的AD受试者和他们的生物样本(ADRN02-注册， ADRN06-ADEH和ADRN09-Dupilumab)，以及那些注册参加城市居民和社区发展中心的纵向“真实世界”AD的人 学习。这些目标表明，如何首先将重点放在金黄色葡萄球菌定植的系统性特征上(例如： 宏观层面；目标1)，并转移到“表皮(宿主)-微生物群”相互作用(目标2)，最终 微生物与微生物在皮肤表面的相互作用(例如，微观层面；目标3)。

Project Summary/Abstract Staphylococcus aureus (S. aureus) has been strongly implicated as a causal factor in pathogenesis of atopic dermatitis (AD) since the 1970s, and is further supported by publications demonstrating S. aureus skin colonization precedes AD onset. ADRN studies found that 50% of AD subjects are colonized and this AD phenotype is associated with greater epidermal barrier dysfunction, type 2 immunity, disease severity and remarkable alterations in the skin microbiome (increased S. aureus relative abundance and reduced abundance of the commensal bacteria, Cutibacterium acnes (C. acnes). Additionally, S. aureus-colonized AD subjects are more likely to develop a severe viral condition, called eczema herpeticum. An even more serious condition is eczema vaccinatum, caused by exposure to vaccinia virus (smallpox vaccination), which has a fatality rate as high as 30%. In an effort to explain this, we found discovered that epidermal exposure to a highly virulent S. aureus strain (USA300), commonly found on AD subjects, markedly enhances its susceptibility to vaccinia virus. Collectively, these observations support our hypothesis that S. aureus may be a key driver of disease severity and response to systemic treatments (Aim 1) as well as serious viral complications (Aim 2). Determining what role C. acnes, the most abundant commensal skin bacteria, plays in suppressing S. aureus will be the focus of studies outlined in Aim 3. These studies will leverage the wealth of deeply-phenotyped AD subjects and their biospecimens from previous ADRN studies (ADRN02-Registry, ADRN06-ADEH and ADRN09-Dupilumab) and those enrolled into URMCs Longitudinal ‘Real-World’ AD Study. The Aims demonstrate how the focus is first on the systemic features of S. aureus colonization (e.g. macro level; Aim 1) and moves to the “epidermal (host) – microbiome” interaction (Aim 2) and ultimately to the microbe-microbe interaction at the skin surface (e.g. micro level; Aim 3).