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

金黄色葡萄球菌定植 AD 患者的生物标志物鉴定、病毒敏感性和管理

• 批准号: 10374846
• 负责人: Lisa Ann Beck
• 金额: $ 46.2万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-06 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374846
• 关键词: Acne; Affect; Applications Grants; Atopic Dermatitis; Bacteria; Biological; Biological Markers; Biology; Blood Circulation; Cells; Child; Clinical; Coupled; Data; Eczema Herpeticum; Eczema Vaccinatum; Enrollment; Epithelial; Exposure to; Fatality rate; Functional disorder; Genome; Growth; Human; Immune Targeting; Immunity; Individual; Infectious Skin Diseases; Inflammatory; Lesion; Measures; Mediating; Microbe; Pathogenesis; Patients; Phenotype; Play; Predisposition; Production; Publications; Registries; Ribosomal RNA; Role; Serum; Severities; Severity of illness; Simplexvirus; Site; Skin; Skin colonization; Smallpox; Smallpox Vaccine; Staphylococcus aureus; Surface; Systemic Therapy; Testing; Vaccination; Vaccinia virus; Viral; Virulence Factors; Virulent; Virus Diseases; biomarker identification; biomarker panel; clinical predictors; commensal bacteria; design; enhancing factor; experience; experimental study; gene product; host microbiome; pathogen; permissiveness; prospective; recruit; response; skin barrier; skin disorder; skin microbiome; skin microbiota; systemic inflammatory response; treatment response

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).

项目总结/摘要 金黄色葡萄球菌(S.金黄色葡萄球菌）已被强烈暗示为特应性角膜炎发病机制中的一个致病因素 皮炎（AD），并且进一步得到了证明S.金黄色葡萄球菌皮肤 定植先于AD发作。ADRN研究发现，50%的AD受试者定植，且该AD 表型与更大的表皮屏障功能障碍、2型免疫、疾病严重性和 皮肤微生物组的显著变化（增加的S.金黄色葡萄球菌相对丰度和还原 结果表明，在1000 ~ 10000 mg/L的浓度范围内，共生细菌的丰度分别为：痤疮）。此外，S.金色定殖 AD受试者更有可能出现严重的病毒性疾病，称为疱疹性湿疹。一个更 严重的情况是牛痘湿疹，由接触牛痘病毒（天花疫苗接种）引起， 死亡率高达30%。为了解释这一点，我们发现表皮暴露 一个高毒力的S.金黄色葡萄球菌菌株（USA 300），常见于AD受试者，可显著增强其 对痘苗病毒易感性。这些观察结果共同支持了我们的假设，即S.金黄色可 是疾病严重程度和对全身治疗反应的关键驱动因素（目标1）以及严重的病毒性 并发症（目标2）。C.确定什么角色痤疮，最丰富的共生皮肤细菌，发挥 在抑制S.金黄色葡萄球菌将是目标3中概述的研究重点。这些研究将充分利用 深度表型AD受试者及其来自先前ADRN研究（ADRN 02-登记处， ADRN 06-ADEH和ADRN 09-Dupilumab）和入组URMC纵向“真实世界”AD的患者 Study.目的表明如何首先关注S.金黄色葡萄球菌定植（例如 宏观水平;目标1），并转移到“表皮（宿主）-微生物组”相互作用（目标2），最终 皮肤表面的微生物-微生物相互作用（例如，微观水平;目标3）。