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ADAM10 polymorphism in susceptibility to S. aureus disease

ADAM10 多态性对金黄色葡萄球菌病的易感性

基本信息

批准号：
10649082
负责人：
Juliane Bubeck Wardenburg
金额：
$ 23.4万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649082
关键词：
Adult Antibody titer measurement Antimicrobial Resistance Bacteremia Binding Binding Sites Biological Biological Markers Biological Models Bypass Caring Cells Cessation of life Child Childhood Clinical Clinical Medicine Clinical Research Clinical Trials Communicable Diseases Complex Cytotoxin Data Development Disease Disease susceptibility Disintegrins Economics Engineering Exhibits Financial Hardship Generations Genetic Genetic Markers Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genomic DNA Genotype Genus staphylococcus Goals Healthcare Hemolysin Hospitalization Human Human Genetics Immunity Individual Infection Infectious Skin Diseases Injury Intervention Knowledge Mediating Membrane Metalloproteases Modification Molecular Monoclonal Antibodies Morbidity - disease rate Mus Nature Odds Ratio Outcome Pathogenesis Patient risk Patients Pneumonia Population Predisposition Proteins Proteolysis Recurrence Research Retrospective Studies Risk Role Sepsis Septic Shock Shapes Single Nucleotide Polymorphism Skin Skin Tissue Soft Tissue Infections Staphylococcus aureus Staphylococcus aureus infection Surface Therapeutic Tissues Toxin Translations United States Vaccine Design Vaccines Variant Virulence Factors alpha Toxin cell injury cell type clinical care clinical practice comparative disorder risk genetic epidemiology individual patient infection risk insight microbiome mortality mouse model novel pathogen pediatric patients personalized care personalized medicine precision medicine prevent progression risk promoter receptor recurrent infection resistant strain response risk prediction risk stratification soft tissue tissue injury tool transcription factor trend vaccine candidate vaccine development

项目摘要

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.

项目摘要金黄色葡萄球菌感染在其他健康的成人和儿童中是发病的重要原因，死亡率和经济损失。感染复发很常见，这凸显了S.金黄色颠覆保护性免疫力的发展。预防S.金黄色葡萄球菌感染一直是这是该领域二十多年来的首要目标，但多种人类候选疫苗在临床试验中失败了。审判了解病原体和宿主特异性因素，调节敏感性的S。金黄色葡萄球菌感染是预计将为推进疫苗设计和实施提供见解，但也提供了一个机会，开发具体的床边可访问工具，用于客观评估个体患者风险。需要这些工具以推动该领域朝着个性化和精准医疗的目标发展。广泛的研究，包括我们的自己的研究，支持针对S。金黄色葡萄球菌α-毒素（Hla）作为毒力因子来保护免受感染。 Hla与其真核受体ADAM 10的相互作用提供了一个额外的机会窗口，评估宿主特异性因素是否改变ADAM10表达或细胞活性影响易感性对鼠伤寒沙门氏金黄色葡萄球菌病我们已经成功地利用了S.感染金黄色葡萄球菌的儿童，在小鼠模型系统中对ADAM 10进行实验扰动，以检查单个核苷酸是否 ADAM10启动子（rs653765）中的SNP改变了对S.金黄色葡萄球菌感染。两互补的数据线提供了初步的见解，即这种SNP具有功能相关性：1）患有 rs653765 GG基因型与侵袭性S.金黄色葡萄球菌感染; 2）工程新型小鼠品系中的ADAM 10 SNP变体反映了在人类中观察到的初步临床结果， rs653765 GG基因型，并表明SNP类型影响皮肤和软组织的易感性感染在本项目中，我们建议利用正在进行的研究中现有的人类基因组DNA生物样本儿童对沙门氏菌免疫研究金黄色葡萄球菌感染，以充分表征ADAM 10 rs653765 SNP的影响对S.金黄色葡萄球菌感染。我们将把这种分析与假设驱动的研究结合起来， rs653765 SNP改变宿主对疾病易感性的分子和细胞机制。这些人类遗传流行病学和机制研究的交叉研究提供了一个罕见的有机会定义一个集中的生物标志物，可以了解S.金黄色葡萄球菌病的这些研究的成功完成将为利用SNP分型提供无与伦比的机会，在传染病的背景下推进个性化护理。