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 鲍曼尼（Baumannii）的杆菌是重要的医院病原体，可引起一系列疾病，包括 呼吸道和尿路感染，脑膜炎，心内膜炎，伤口感染和细菌。实际上，A。 鲍曼尼（Baumannii）现在负责世界上某些地区所有重症监护病房感染的20％ 肺炎是最常见的表现。鲍曼尼曲霉的临床意义已被推进 通过这种有机体对几乎所有抗生素的抗药性的迅速获得。确定新颖目标的 治疗干预对于我们保护公共卫生免受这种新兴传染性威胁的能力至关重要。 热发展的有前途的领域利用了所有细菌病原体都需要营养金属的想法 引起感染。这种方法模仿了宿主介导的金属隔离，这是针对的潜在防御 在称为“营养免疫学”过程中的感染。矛盾的是，金属加剧的饮食限制 感染强调金属丰度的改变如何深刻影响宿主病原的结果 互动。宿主蛋白钙卫蛋白（CP）是免疫介导的最重要的因素之一 金属限制和CP通过包括锌（Zn）在内的养分金属的螯合来防止感染。 使用CP作为探针，我们发现了鲍曼尼氏菌中的遗传基因座，这对于生存很重要 在CP依赖性Zn饥饿的条件下。该基因座编码组成的COG0523的成员 我们命名为ZUR诱导的GTPase A（Ziga）的GTPases家族。我们还发现了第二个COG0523 我们称为0934的鲍曼曼尼基因组中的成员。Ziga和0934具有生物学特性 与将锌插入客户端蛋白中的金属伴侣一致。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回收利用的客户金属酶。基于这些 基本发现，我们假设鲍曼尼a。 CP的积聚，该CP颗星a。Baumannii用于营养锌。我们进一步假设Ziga和0934 调节Zn饥饿期间的细胞壁重塑，以适应营养锌转运蛋白的插入 对抗宿主或饮食施加的锌饥饿所必需的细胞包膜。 为了测试此中心模型，我们提出了一系列旨在了解机制和的实验 鲍曼尼曲霉对饮食和宿主施加的锌剥夺的病理生理后果 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的物理功能，在A. Baumannii中询问0934，以及（iii） 在肺炎发病机理期间，确定Ziga和0934的重要性。 这项研究将建立一个新的范式，以对细菌如何对饮食或免疫介导的锌做出反应 通过金属伴侣依赖细胞壁稳态调节感染期间的限制。