The Staphylococcus aureus response to nutrient zinc restriction during infection

金黄色葡萄球菌感染期间对营养锌限制的反应

• 批准号: 10335212
• 负责人: Eric P Skaar
• 金额: $ 42.46万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-19 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10335212
• 关键词: Abscess; Antibiotic Resistance; Antibiotics; Area; Bacteria; Bacterial Infections; Binding; Cells; Client; Coupled; DNA Repair; Development; Ensure; Environment; Enzymes; Exposure to; Family; Gene Expression; Genome; Genus staphylococcus; Heterogeneity; Host Defense; Image; Imaging technology; Immune; Immune system; Immunologic Factors; Individual; Infection; Inflammatory; Invaded; Iron; Knowledge; Lead; Leukocyte L1 Antigen Complex; Maintenance; Manganese; Mediating; Metabolic; Metalloproteins; Metals; Modeling; Molecular; Morbidity - disease rate; Nutrient; Nutritional Immunity; Oxygen; Pathogenesis; Phagocytes; Physiology; Positioning Attribute; Process; Property; Proteins; Public Health; Research; Resistance; Role; Site; Staphylococcus aureus; Staphylococcus aureus infection; Starvation; Stress; System; Testing; Therapeutic; United States; Up-Regulation; Vertebrates; Work; Zinc; antimicrobial; base; cofactor; combat; defined contribution; deprivation; experience; experimental study; human pathogen; immunoregulation; infectious disease treatment; innovation; insight; member; metal chelator; microbial; mortality; novel therapeutics; pathogen; pathogenic bacteria; pathogenic microbe; recruit; resistant strain; response; therapeutic development

PROJECT SUMMARY Staphylococcus aureus is a significant cause of morbidity and mortality that is increasingly acquiring resistance to all available antibiotics. One promising area for antimicrobial development involves targeting bacterial acquisition and utilization of nutrient metal. This strategy exploits the fact that all bacterial pathogens require nutrient metal to colonize their hosts. In response to this requirement, vertebrates have evolved powerful defense strategies that sequester nutrient metals from invading pathogens in a process known as nutritional immunity. One of the most effective metal chelating factors of the immune system is calprotectin, an abundant protein that sequesters nutrient manganese, iron, and zinc and defends against microbial infection. In addition to its metal chelating properties, calprotectin is a potent pro-inflammatory molecule. The individual importance of each of these activities to protection against infection has not been parsed, and the contribution of calprotectin metal binding to its immunomodulatory properties is not known. Prevailing models suggest that nutritional immunity ensures that pathogens are uniformly metal starved during vertebrate colonization. We have challenged this concept through the application of innovative imaging technologies, revealing S. aureus is differentially metal starved within abscesses. This discovery necessitates a reevaluation of the environment encountered by S. aureus during infection, particularly as it pertains to nutrient metal levels. We have also discovered that the S. aureus response to metal restriction includes the up-regulation of members of the newly described COG0523 family of zinc metallochaperones. Our preliminary results reveal that these enzymes enable S. aureus to combat calprotectin-mediated zinc depletion by delivering zinc to critical metalloproteins involved in genome maintenance. Based on these fundamental discoveries, we hypothesize that following colonization of the vertebrate host, S. aureus encounters immune-mediated metal restriction through the delivery of calprotectin to the site of infection. In response, S. aureus up-regulates the expression of systems to combat this nutrient limitation. We envision that this microbial response is heterogeneous, and occurs in a manner dependent on the level of metal restriction experienced at distinct sites of infection. Finally, we predict that an important aspect of this response to nutrient limitation is the up-regulation of dedicated metallochaperones that deliver metal to proteins involved in DNA repair and are required for survival upon exposure to the reactive oxygen burst of the phagocyte. Experiments in this proposal will test this model by (i) defining the heterogeneous S. aureus response to metal starvation, (ii) elucidating the mechanism by which calprotectin protects against infection, and (iii) determining the subcellular fate of metal acquired by S. aureus during metal deprivation. This work will provide a mechanistic framework for understanding the importance of nutritional immunity during bacterial infection and reveal the corresponding S. aureus response to this host defense.

项目摘要 金黄色葡萄球菌是发病率和死亡率的重要原因，越来越多地获取 对所有可用抗生素的耐药性。抗菌发育的一个有希望的领域涉及靶向 营养金属的细菌采集和利用。该策略利用了所有细菌的事实 病原体需要营养金属才能定植其宿主。根据此要求，脊椎动物具有 进化的强大防御策略在过程中隔离了入侵病原体的营养金属 称为营养免疫。免疫系统最有效的金属螯合因子之一是 钙染色蛋白是一种含有含有营养锰，铁和锌的丰富蛋白质，并防御 微生物感染。除了其金属螯合特性外，钙卫蛋白还具有有效的促炎 分子。这些活动中每一种对防御感染的重要性都不是 尚不清楚解析，以及钙骨金属与其免疫调节特性结合的贡献。 流行模型表明，营养免疫可确保病原体均匀金属饥饿 在脊椎动物定植期间。我们通过应用创新挑战了这一概念 成像技术，揭示金黄色葡萄球菌的差异金属在脓肿内饥饿。这个发现 需要对金黄色葡萄球菌在感染期间遇到的环境进行重新评估，尤其是在 与营养金属水平有关。我们还发现金黄色葡萄球菌对金属限制的响应 包括新描述的COG0523锌金属蛋白家族的成员的上调。 我们的初步结果表明，这些酶使金黄色葡萄球菌能够打击钙蛋白钙蛋白酶介导的锌 通过将锌传递到涉及基因组维持的临界金属蛋白的耗竭。 基于这些基本发现，我们假设脊椎动物定植后 主机，金黄色葡萄球菌通过将钙染色素递送到现场遇到免疫介导的金属限制 感染。作为回应，金黄色葡萄球菌上调了系统的表达，以打击这种营养限制。 我们设想这种微生物反应是异质的，并且以取决于水平的方式出现 在不同感染部位经历的金属限制。最后，我们预测 对营养限制的这种反应是专用金属伴侣的上调，将金属输送到 参与DNA修复的蛋白质，在暴露于活性氧爆发后生存需要 吞噬细胞。该提案中的实验将通过（i）定义异质金黄色葡萄球菌测试该模型 对金属饥饿的反应，（ii）阐明钙染色素可以防止感染的机制， （iii）决定金属剥夺过程中金黄色链球菌获得的金属的亚细胞命运。这项工作 将提供一个机械框架，以了解营养免疫的重要性 细菌感染并揭示了对该宿主防御的相应金黄色葡萄球菌反应。