Metallobiochemistry of innate immunity and bacterial physiology

先天免疫的金属生物化学和细菌生理学

基本信息

批准号：
10686285
负责人：
ELIZABETH M NOLAN
金额：
$ 32.05万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-20 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686285
关键词：
Address Aerobic Affect Antimicrobial Resistance Applications Grants Bacterial Infections Bacterial Physiology Binding Biochemical Bioinorganic Chemistry Biological Availability Caring Chronic Coculture Techniques Collaborations Communities Complex Cues Cystic Fibrosis Dehydration Development Disease Disease Progression Early identification Environment Epithelial Cells Etiology Extracellular Space Foundations Funding Future Genetic Goals Growth Hereditary Disease Heritability Heterogeneity Homeostasis Host Defense Human Hypoxia Immune Immune response Immunity Immunocompromised Host Individual Infection Infection prevention Innate Immune System Invaded Investigation Ions Iron Lactoferrin Leukocyte L1 Antigen Complex Life Lung Lung infections Manganese Metabolism Metals Microbial Biofilms Modeling Morbidity - disease rate Mucous body substance Natural Immunity Nutrient Nutrient availability Nutritional Immunity Organism Outcome Oxygen Pathogenesis Pathogenicity Pathway interactions Physiology Proteins Pseudomonas aeruginosa Pulmonary Cystic Fibrosis Quality of life Reporting Research Research Proposals Role S100A12 gene Site Sputum Staphylococcus aureus Starvation Structure System Testing Therapeutic Thick Time Transition Elements United States Virulence Work Zinc bacterial genetics chelation chronic infection cystic fibrosis patients cystic fibrosis serum factor design diabetic expectation experience human pathogen improved in vitro Model insight microbial microbial community microorganism competition neutrophil novel diagnostics novel therapeutic intervention pH gradient pathogen pathogenic bacteria pathogenic microbe patient population prevent pulmonary function response uptake

项目摘要

PROJECT SUMMARY The primary objective of this renewal application is to elucidate how the metal-sequestering host-defense protein calprotectin (CP) modulates the physiology and interactions of Pseudomonas aeruginosa (Pa) and Staphylococcus aureus (Sa) using models that consider environmental cues relevant to infection. Metal ions are essential nutrients for all organisms, and pathogens must acquire these nutrients from the host to replicate and cause infection. In response to pathogen invasion, the human innate immune system enacts a metal- withholding response to limit the bioavailability of transition metal nutrients including manganese (Mn), iron (Fe), and zinc (Zn). This host response includes the deployment of CP and other metal-sequestering proteins at sites of infection. We discovered that CP withholds Fe(II) from and induces Fe-starvation responses by Pa and Sa, two bacterial pathogens that cause chronic polymicrobial infections in diverse patient populations, including lung infections in individuals with cystic fibrosis (CF). This hereditary disease predisposes individuals to life-long pulmonary infections, marked by debilitating exacerbations that reduce lung function. Notably, the CF lung becomes increasingly acidic and hypoxic as disease progresses, and Fe(II) becomes a predominant form of bioavailable Fe in this environment. Nevertheless, few studies have addressed how acidic pH and hypoxia impact microbial Fe homeostasis and the host metal-withholding response. We hypothesize that the Fe(II)-sequestering activity of CP has profound consequences on the physiology and virulence potential of Pa and Sa in diverse environmental milieus relevant to infection. We further propose that interactions between CP and these pathogens depend on environmental cues that vary both temporally and spatially at infection foci. In Aim 1, we will evaluate how mildly-acidic pH affects the metal-sequestration profile of CP as well as the physiology of Pa and Sa and their responses to CP and metal starvation. In Aim 2, we will examine how hypoxia affects the responses of Pa and Sa to metal starvation and CP. In Aim 3, we will extend these investigations to more complex in vitro models that incorporate relevant aspects of infection including co- cultures, biofilms, and additional metal-sequestering host-defense factors such as lactoferrin and S100A12. These investigations will enable future studies that address how CP and Fe drive the progression of CF lung infections and may guide the design and development of novel diagnostic, preventative, and therapeutic approaches to treat bacterial infections.

项目概要该更新申请的主要目标是阐明金属螯合宿主防御如何蛋白钙卫蛋白 (CP) 调节铜绿假单胞菌 (Pa) 的生理学和相互作用金黄色葡萄球菌 (Sa) 使用考虑与感染相关的环境线索的模型。金属离子是所有生物体必需的营养物质，病原体必须从宿主那里获取这些营养物质才能复制并引起感染。为了应对病原体入侵，人类先天免疫系统会产生一种金属- 抑制反应以限制过渡金属营养素（包括锰 (Mn)、铁）的生物利用度 (Fe) 和锌 (Zn)。这种宿主反应包括部署 CP 和其他金属螯合蛋白在感染部位。我们发现 CP 抑制 Fe(II) 并诱导 Pa 的 Fe 饥饿反应和 Sa，两种细菌病原体，可在不同患者群体中引起慢性多种微生物感染，包括囊性纤维化 (CF) 患者的肺部感染。这种遗传性疾病使个体易感导致终生肺部感染，其特点是病情恶化，肺功能下降。值得注意的是，随着疾病进展，CF 肺变得越来越酸性和缺氧，Fe(II) 成为主要成分在此环境中形成生物可利用的铁。然而，很少有研究探讨酸性 pH 值和缺氧影响微生物铁稳态和宿主金属扣留反应。我们假设 CP 的 Fe(II) 螯合活性对 Pa 的生理学和毒力潜力具有深远的影响和 Sa 在与感染相关的不同环境中。我们进一步提出CP之间的相互作用这些病原体依赖于感染灶处随时间和空间变化的环境线索。在目标 1，我们将评估弱酸性 pH 值如何影响 CP 的金属螯合特性以及 Pa 和 Sa 的生理学及其对 CP 和金属饥饿的反应。在目标 2 中，我们将研究如何缺氧影响 Pa 和 Sa 对金属饥饿和 CP 的反应。在目标 3 中，我们将扩展这些对更复杂的体外模型的研究，其中包含感染的相关方面，包括共同培养物、生物膜和其他金属螯合宿主防御因子，例如乳铁蛋白和 S100A12。这些研究将使未来的研究能够解决 CP 和 Fe 如何驱动 CF 肺的进展感染，并可能指导新型诊断、预防和治疗方法的设计和开发治疗细菌感染的方法。