The role of bacterial toxins in human skin disease.

细菌毒素在人类皮肤病中的作用。

• 批准号: 7884902
• 负责人: Elena Goleva
• 金额: $ 32.1万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-17 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884902
• 关键词: Adult; Affect; Allergens; Allergic; Applications Grants; Atopic Dermatitis; Bacterial Toxins; Binding; CCL27 gene; Cells; Chemicals; Chemosensitization; Child; Chronic; Co-Immunoprecipitations; Data; Environment; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Gene Expression; Gene Expression Profiling; Gene Proteins; Genes; Genus staphylococcus; Goals; Grant; Homing; Human; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Integrin alpha5beta1; Lead; Mass Spectrum Analysis; Matrix Metalloproteinases; Molecular Profiling; Mononuclear; Morbidity - disease rate; Mus; Necrosis; Occupational; Pathway interactions; Patients; Peptide Hydrolases; Peptidoglycan; Prevalence; Production; Public Health; Role; STAT6 gene; Sampling; Severities; Signal Pathway; Skin; Staphylococcal Enterotoxin B; Staphylococcus alpha toxin; Staphylococcus aureus; Superantigens; T-Lymphocyte; Techniques; Th2 Cells; Therapeutic; Time; Toll-Like Receptor 2; Toxic Shock Syndrome Toxin-1; Toxin; Transgenic Mice; Validation; Western Blotting; absorption; alpha Toxin; atopy; cell motility; chemokine; cytokine; disability; effective therapy; in vivo; keratinocyte; lipoteichoic acid; mRNA Expression; novel; pathogen; protein expression; public health relevance; receptor; response; skin disorder; skin lesion; staphylococcal enterotoxin; synergism; treatment strategy

DESCRIPTION (provided by applicant): Atopic dermatitis (AD) is a pruritic chronic inflammatory skin disease associated with significant morbidity and occupational disability affecting 17% of children and nearly 2% of adults in the U.S. Studies have highlighted the importance of S. aureus infection, colonization and toxin production in AD severity/exacerbation. The overall goal of this competing renewal R01 grant application (5 R01 AR41256-18) will be to determine how colonization with toxin producing S. aureus in AD patients alters inflammatory response in the skin. As well, we wish to investigate novel mechanisms by which Th2 environment in combination with toxin production by S. aureus enhance skin inflammation. Our previous studies of staphylococcal superantigens primarily focused on mononuclear cell activation by these toxins in the skin. New preliminary data show that staphylococcal superantigens (staphylococcal enterotoxin B, SEB) also exert effects directly on keratinocytes and contribute to the skin inflammation by inducing proinflammatory and Th2 cell skin homing chemokines. Global gene expression profiling of SEB stimulated human keratinocytes demonstrates protease activation by SEB and suggests that SEB may enhance allergic skin sensitization due to changes in extracellular matrix that can affect allergen absorption and inflammation, which we will explore in this proposal. We present evidence for Th2 cytokine potentiation of keratinocyte responses to SEB and propose that this occurs either through synergism with SEB induced pathways and/or increased expression of a specific receptor to SEB, therefore amplifying inflammatory responses in atopic skin. Finally, we demonstrate that staphylococcal pore forming alpha-toxin, that often coincides with superantigen production by S. aureus, can potentiate responses to staphylococcal products by facilitating their intracellular entry via toxin-induced pores, thereby allowing the engagement of intracellular receptors. Th2 cytokines may increase alpha-toxin binding to keratinocytes, affecting pore formation and intensifying keratinocyte responses to staphylococcal products. The specific aims of this proposal will be: first, to determine the effects of staphylococcal superantigens on inflammatory responses of keratinocytes, focusing on gene and protein expression profiling in superantigen activated human keratinocytes and skin samples from AD patients colonized with superantigen producing S. aureus, in vivo inflammatory responses and allergen absorption in murine skin following epicutaneous application of SEB; second, to explore the modulatory role of Th2 cytokines in responses to staphylococcal superantigens in the skin by analyzing changes in gene and protein expression in keratinocytes, assessing inflammatory responses to SEB in STAT6 transgenic mice, exploring signaling pathways engaged by SEB and Th2 cytokines, and defining the specific SEB receptor; finally, to investigate the immunomodulatory role of staphylococcal alpha-toxin in keratinocyte responses to SEB/other staphylococcal products. Studies will likely identify therapeutic approaches in the control of skin inflammation initiated by staphylococcal toxins and atopy. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus has emerged as a worldwide pathogen that is rapidly increasing in prevalence and causing serious illness. The specific objectives of this study will be to determine the mechanisms by which staphylococcal toxins cause human skin disease particularly atopic dermatitis which is the most common cause of chronic skin disease in children and often persist into adulthood. Data from this grant may lead to more effective treatment strategies for this serious public health issue.

描述(申请人提供)：特应性皮炎(AD)是一种瘙痒性慢性炎症性皮肤病，与严重的发病率和职业残疾有关，影响美国17%的儿童和近2%的成年人。研究强调了金黄色葡萄球菌感染、定植和毒素产生在AD严重/恶化中的重要性。这项竞争性的R01续期拨款申请(5 R01 AR41256-18)的总体目标将是确定在AD患者中产毒金黄色葡萄球菌的定植如何改变皮肤的炎症反应。此外，我们还希望研究Th2环境与金黄色葡萄球菌产生的毒素结合起来增强皮肤炎症的新机制。我们之前对葡萄球菌超抗原的研究主要集中在皮肤中这些毒素对单核细胞的激活。新的初步数据表明，葡萄球菌超抗原(葡萄球菌肠毒素B，SEB)也直接作用于角质形成细胞，并通过诱导促炎和Th2细胞皮肤归巢趋化因子而促进皮肤炎症。SEB刺激的人角质形成细胞的全球基因表达谱显示SEB激活了蛋白水解酶，提示SEB可能由于细胞外基质的变化而增强过敏性皮肤敏化，这可能会影响过敏原的吸收和炎症，我们将在本提案中进行探索。我们提出了Th2细胞因子增强角质形成细胞对SEB的反应的证据，并提出这可能是通过与SEB诱导的通路协同作用和/或SEB的特定受体表达增加而发生的，从而放大了特应性皮肤的炎症反应。最后，我们证明，金黄色葡萄球菌产生超抗原时形成的α-毒素，可以通过毒素诱导的毛孔促进葡萄球菌产物进入细胞内，从而允许细胞内受体的参与，从而增强对葡萄球菌产品的反应。Th2细胞因子可增加α-毒素与角质形成细胞的结合，影响毛孔形成，增强角质形成细胞对葡萄球菌产物的反应。这项建议的具体目的将是：第一，确定葡萄球菌超抗原对角质形成细胞炎症反应的影响，重点研究超抗原激活的人角质形成细胞和AD患者皮肤标本中基因和蛋白质的表达谱，体内炎症反应和皮肤表面应用SEB后的变应原吸收；第二，通过分析角质形成细胞基因和蛋白表达的变化，评估STAT6转基因小鼠对SEB的炎症反应，探索SEB和Th2细胞因子参与的信号通路，并确定特异性SEB受体，探讨Th2细胞因子在皮肤对葡萄球菌超抗原反应中的调节作用；最后，研究葡萄球菌α-毒素在角质形成细胞对SEB/其他葡萄球菌产物反应中的免疫调节作用。研究可能会确定控制葡萄球菌毒素和特应性皮肤炎的治疗方法。 公共卫生相关性：金黄色葡萄球菌已经成为一种世界性的病原体，它的流行率正在迅速增加，并导致严重的疾病。这项研究的具体目标将是确定葡萄球菌毒素引起人类皮肤病的机制，特别是特应性皮炎，这是儿童慢性皮肤病的最常见原因，通常持续到成年。这笔赠款的数据可能会为这一严重的公共卫生问题带来更有效的治疗策略。