Host-mediated zinc sequestration during Acinetobacter baumannii infection

鲍曼不动杆菌感染期间宿主介导的锌螯合

• 批准号: 10680779
• 负责人: WALTER J. CHAZIN
• 金额: $ 76.41万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680779
• 关键词: Acinetobacter baumannii; Antibiotics; Antimicrobial Resistance; Area; Bacteremia; Bacteria; Bacterial Infections; Binding; Biological; Biology; Cell Wall; Cells; Client; Communicable Diseases; Data; Deposition; Dietary Zinc; Disease; Enabling Factors; Endocarditis; Enzymes; Event; Family; Genes; Genome; Genomics; Growth; Guanosine Triphosphate Phosphohydrolases; Homeostasis; Host Defense; Immune; Infection; Intake; Intensive Care Units; Leukocyte L1 Antigen Complex; Lytic; Macromolecular Complexes; Measures; Mediating; Meningitis; Metabolism; Metalloproteins; Metals; Modeling; Names; Nutrient; Nutritional; Nutritional Immunity; Nutritional Requirements; Organism; Outcome; Pathogenesis; Peptidoglycan; Phenotype; Physiological; Pneumonia; Process; Proliferating; Property; Proteins; Public Health; Recycling; Regulation; Research; Resistance; Respiratory Tract Infections; Sentinel; Series; Signal Transduction; Starvation; Technology; Testing; Therapeutic Intervention; Urinary tract infection; Variant; Work; Wound Infection; Zinc; Zinc deficiency; cell envelope; chelation; clinically significant; combat; deprivation; dietary; dietary restriction; experimental study; genomic locus; human pathogen; lung colonization; member; metalloenzyme; mortality; new therapeutic target; nutrient deprivation; pathogen; pathogenic bacteria; pathogenic microbe; predictive modeling; response; therapeutic development; therapy design; virtual; zinc-binding protein

PROJECT SUMMARY Acinetobacter baumannii is an important nosocomial pathogen that causes a range of diseases, including respiratory and urinary tract infections, meningitis, endocarditis, wound infections, and bacteremia. In fact, A. baumannii is now responsible for up to 20% of all intensive care unit infections in some regions of the world with pneumonia being the most common presentation. The clinical significance of A. baumannii has been propelled by this organism’s rapid acquisition of resistance to virtually all antibiotics. The identification of novel targets for therapeutic intervention is critical to our ability to protect the public health from this emerging infectious threat. A promising area of therapeutic development exploits the idea that all bacterial pathogens require nutrient metal to cause infection. This approach mimics host-mediated metal sequestration, which is a potent defense against infection in a process termed “nutritional immunity”. Paradoxically, dietary restriction of metal exacerbates infection underscoring how alterations in metal abundance can profoundly impact the outcome of host-pathogen interactions. The host protein calprotectin (CP) is one of the most important contributors to immune-mediated metal restriction and CP protects against infection through the chelation of nutrient metals, including zinc (Zn). Using CP as a probe, we have uncovered a genetic locus within A. baumannii that is important for survival during conditions of CP-dependent Zn starvation. This locus encodes a member of the conserved COG0523 family of GTPases that we have named Zur-induced GTPase A (ZigA). We have also found a second COG0523 member within the A. baumannii genome that we refer to as 0934. ZigA and 0934 have biological properties consistent with metallochaperones that insert Zn into client proteins. Our preliminary data indicate that 0934 and ZigA bind and regulate client metalloenzymes involved in cell wall synthesis and recycling. Based on these fundamental discoveries, we hypothesize that A. baumannii colonization of the lung leads to massive accumulation of CP which starves A. baumannii for nutrient Zn. We further hypothesize that ZigA and 0934 regulate cell wall remodeling during Zn starvation to accommodate insertion of nutrient Zn transporters into the cell envelope that are necessary to combat host- or dietary-imposed Zn starvation. To test this central model, we propose a series of experiments aimed at understanding the mechanism and pathophysiological consequence of the A. baumannii response to dietary and host-imposed Zn deprivation during pneumonia. In these studies, we will (i) define the molecular interactions of ZigA and 0934 with their metalloprotein clients, (ii) interrogate the physiological function of ZigA and 0934 in A. baumannii, and (iii) determine the importance of ZigA and 0934 in response to Zn starvation during the pathogenesis of pneumonia. This research will establish a new paradigm for how bacteria respond to dietary- or immune-mediated Zn restriction during infection through metallochaperone-dependent regulation of cell wall homeostasis.

项目摘要 鲍曼不动杆菌是一种重要的院内致病菌，可引起一系列疾病，包括 呼吸道和泌尿道感染、脑膜炎、心内膜炎、伤口感染和菌血症。事实上，A. 在世界上的一些地区，鲍曼不动杆菌感染占所有重症监护病房感染的20%， 肺炎是最常见的症状。探讨了A.鲍曼不动杆菌 这种微生物对几乎所有抗生素都能迅速产生耐药性。新靶点的确定 治疗干预对于我们保护公众健康免受这一新出现的传染病威胁的能力至关重要。 一个有希望的治疗发展领域利用了所有细菌病原体都需要营养金属的想法 以引起感染。这种方法模拟了宿主介导的金属封存，这是一种有效的防御方法 感染过程称为“营养免疫”。奇怪的是，金属的饮食限制加剧了 感染强调金属丰度的改变如何深刻影响宿主-病原体的结果 交互.宿主蛋白钙卫蛋白（CP）是免疫介导的免疫应答的最重要的贡献者之一。 金属限制和CP通过螯合营养金属（包括锌（Zn））来防止感染。 利用CP作为探针，我们发现了A.鲍曼不动杆菌对生存很重要 在CP依赖性锌饥饿的条件下。该基因座编码保守的COG 0523的一个成员， GTPases家族，我们将其命名为ZigA（ZigA）。我们还发现了第二个COG 0523 A中的成员。我们称之为0934的鲍曼不动杆菌基因组ZigA和0934具有生物学特性 与将锌插入客户蛋白的金属伴侣蛋白一致。我们的初步数据表明，0934和 ZigA结合并调节参与细胞壁合成和再循环的客户金属酶。基于这些 基本发现，我们假设A.鲍曼不动杆菌在肺部的定植导致大规模的 使A饥饿的CP的积累。鲍曼不动杆菌对锌的营养作用。我们进一步假设ZigA和0934 在锌饥饿期间调节细胞壁重塑，以适应营养锌转运蛋白插入细胞壁， 细胞被膜，这是必要的，以打击主机或饮食强加的锌饥饿。 为了检验这个中心模型，我们提出了一系列旨在理解机制的实验， 病理生理后果的A.鲍曼不动杆菌对饮食和宿主锌剥夺的反应 在肺炎期间。在这些研究中，我们将（i）定义ZigA和0934的分子相互作用， 金属蛋白客户端，（ii）询问ZigA和0934在A.鲍曼不动杆菌，和（iii） 确定ZigA和0934在肺炎发病过程中响应锌饥饿的重要性。 这项研究将为细菌如何对饮食或免疫介导的锌做出反应建立一个新的范例 通过金属伴侣依赖性调节细胞壁稳态的感染期间的限制。