ADAM10 polymorphism in susceptibility to S. aureus disease

项目总结 在其他健康的成人和儿童中，金黄色葡萄球菌感染是发病率的重要原因， 死亡率和经济损失。感染的复发很常见，这突显了金黄色葡萄球菌颠覆 保护性免疫的发展。一种预防金黄色葡萄球菌感染的疫苗的开发已经完成 这是该领域二十多年来的首要目标，但多个候选人类疫苗在临床上都失败了 审判。了解调节金黄色葡萄球菌感染易感性的病原体和宿主特异性因素 期望为推进疫苗设计和实施提供洞察力，但也提供了一个机会 开发可在床边使用的特定工具，以客观评估个别患者的风险。这类工具是必需的 推动该领域朝着个性化和精准医疗的目标迈进。广泛的研究，包括我们的 自己的研究，支持靶向金黄色葡萄球菌α毒素(Hla)作为一种毒力因子，以保护免受感染。 人类白细胞抗原与其真核受体ADAM10的相互作用提供了一个额外的机会之窗 评估改变ADAM10表达或细胞活动的宿主特异性因素是否影响易感性 到金黄色葡萄球菌病。我们成功地利用了人类对感染金黄色葡萄球菌的儿童的临床研究，并 在小鼠模型系统中检测ADAM10的实验扰动是否为单核苷酸 ADAM10启动子(Rs653765)的SNP改变金黄色葡萄球菌感染的易感性。二 互补的数据提供了这种SNP具有功能相关性的初步见解：1)患有 Rs653765 GG基因型显示侵袭性金黄色葡萄球菌感染的优势比显著降低；2)基因工程 新的小鼠品系中ADAM10的SNP变异反映了在人类中观察到的初步临床结果 Rs653765 GG基因型，提示SNP类型影响皮肤和软组织的易感性 感染。在这个项目中，我们建议利用现有的人类基因组dna生物样本 全面研究ADAM10 rs653765 SNP对儿童金黄色葡萄球菌感染免疫的影响 金黄色葡萄球菌感染易感性的变异。我们将把这一分析与假设驱动的研究配对，以确定 Rs653765单核苷酸改变宿主对疾病易感性的分子和细胞机制。这些 处于人类遗传流行病学和机械学研究交汇处的研究提供了一种罕见的 有机会定义一个聚焦的生物标记物，以帮助了解金黄色葡萄球菌病的风险。这个 成功完成这些研究将提供一个无与伦比的机会，利用SNP打字来 在传染病的背景下推进个性化护理。

PROJECT SUMMARY Staphylococcus aureus infection in otherwise healthy adults and children is a significant cause of morbidity, mortality, and economic loss. Recurrence of infection is common, highlighting the fact that S. aureus subverts the development of protective immunity. The development of a vaccine to prevent S. aureus infection has been a premier goal in the field for over two decades, yet multiple human vaccine candidates have failed in clinical trials. Understanding the pathogen and host-specific factors that modulate susceptibility to S. aureus infection is expected to provide insight to advance vaccine design and implementation, but also affords an opportunity to develop specific bedside-accessible tools for objectively assessing individual patient risk. Such tools are required to advance the field toward the goals of personalized and precision medicine. Extensive research, including our own studies, supports the targeting of S. aureus α-toxin (Hla) as a virulence factor to protect against infection. The interaction of Hla with its eukaryotic receptor ADAM10 provides an additional window of opportunity to evaluate whether host-specific factors that modify ADAM10 expression or cellular activity impact susceptibility to S. aureus disease. We have successfully leveraged human clinical studies of S. aureus-infected children and experimental perturbation of ADAM10 in a mouse model system to examine whether a single nucleotide polymorphism (SNP) in the ADAM10 promoter (rs653765) alters susceptibility to S. aureus infection. Two complementary lines of data provide initial insight that this SNP is of functional relevance: 1) children with the rs653765 GG genotype display a significant reduction in odds ratio of invasive S. aureus infection; 2) engineered SNP variants of ADAM10 in novel mouse lines reflect the initial clinical findings observed in humans harboring the rs653765 GG genotype, and suggest that the SNP type influences susceptibility to skin and soft tissue infection. In this project, we propose to leverage existing human genomic DNA biospecimens from an ongoing study of pediatric immunity to S. aureus infection to fully characterize the impact of ADAM10 rs653765 SNP variation in susceptibility to S. aureus infection. We will pair this analysis with hypothesis-driven studies to define the molecular and cellular mechanisms by which the rs653765 SNP alters host susceptibility to disease. These studies which sit at the intersection of human genetic epidemiology and mechanistic research afford a rare opportunity to define a focused biomarker that can inform an understanding of risk for S. aureus disease. The successful completion of these studies would provide an unparalleled opportunity to utilize SNP typing to advance personalized care in the context of infectious disease.