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: 8504420
• 负责人: WALTER J. CHAZIN
• 金额: $ 43.14万
• 依托单位: VANDERBILT UNIVERSITY
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8504420
• 关键词: Acinetobacter; Acinetobacter baumannii; Advanced Glycosylation End Products; Affect; Antibiotics; Antimicrobial Effect; Antimicrobial Resistance; Area; Bacteremia; Bacteria; Bacterial Drug Resistance; Bacterial Infections; Binding; Biology; Communicable Diseases; Coupled; Data; Development; Disease; Endocarditis; Ensure; Event; Exhibits; Foundations; Growth; Host Defense; Immune; Immune response; Immunity; In Vitro; Infection; Infectious Agent; Inflammation; Inflammatory; Intensive Care Units; Iron; Lead; Leukocyte L1 Antigen Complex; Ligands; Lung; Manganese; Measures; Mediating; Meningitis; Metals; Molecular; Mus; Mutation; Nutrient; Nutritional; Organism; Outcome; Pathogenesis; Peptides; Physiology; Pneumonia; Process; Production; Proteins; Public Health; Receptor Activation; Recruitment Activity; Regulon; Relative (related person); Resistance; Respiratory System; Respiratory tract structure; Role; Sentinel; Series; Signal Pathway; Signal Transduction; Site; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Transition Elements; Urinary tract infection; Vertebrates; Work; Wound Infection; Zinc; antimicrobial; base; chelation; clinically significant; combat; defined contribution; design; insight; microbial; mutant; neutrophil; new therapeutic target; novel; pathogen; prevent; public health relevance; receptor; receptor binding; research study; scaffold; therapeutic development; therapy design; three dimensional structure; uptake

DESCRIPTION (provided by applicant): 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 he public health from this emerging infectious threat. One promising potential area of therapeutic development involves targeting bacterial access to nutrient metal. This strategy is based on the fact that all bacterial pathogens require nutrient metal in order to colonize their hosts. Despite the fact that a variety of metals are required by bacterial pathogens during growth within vertebrates, iron sequestration is considered to be the primary nutrient that is actively sequestered by the host during the innate immune response to infection. In the present application, we provide evidence that the innate immune factor calprotectin defends against Acinetobacter pneumonia by chelating nutrient zinc (Zn). Using calprotectin as a probe, we have identified a transport system in A. baumannii that competes with calprotectin for Zn and is transcriptionally controlled by a Zn-dependent regulator. Calprotectin is abundant at sites of inflammation and is a known pro- inflammatory molecule that is a ligand for the receptor for advanced glycation end products (RAGE). Despite its clear involvement, the contributions of calprotectin-mediated metal sequestration and RAGE binding to defense against infection have not been thoroughly evaluated. Based on preliminary data described in this application, we hypothesize that calprotectin-mediated Zn sequestration and RAGE binding are critical factors during the host-pathogen interaction. To test this central hypothesis, we propose a series of experiments aimed at understanding the mechanism and pathophysiological consequence of calprotectin-mediated Zn sequestration and RAGE binding during A. baumannii pneumonia. In these studies, we will (i) identify the structural features of calprotectin that enable it to chelae transition metals such as Zn and to bind RAGE, (ii) elucidate the impact of calprotectin and RAGE on A. baumannii pathogenesis, and (iii) determine the impact of CP-mediated Zn chelation on the physiology of A. baumannii. These results will provide fundamental insight into how A. baumannii acquires nutrients in the vertebrate host, and lay the foundation for the creation of peptide therapeutics based on a calprotectin scaffold that inhibit microbial growth through nutrient metal chelation.

描述（申请人提供）：鲍曼不动杆菌是一种重要的医院病原体，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，在世界某些地区，鲍曼不动杆菌现在占所有重症监护病房感染的 20%，其中肺炎是最常见的表现。鲍曼不动杆菌的临床意义是由于该生物体迅速获得对几乎所有抗生素的耐药性。这 确定治疗干预的新目标对于我们保护公众健康免受这种新出现的传染病威胁的能力至关重要。治疗开发的一个有前景的潜在领域涉及靶向细菌获取营养金属。该策略基于以下事实：所有细菌病原体都需要营养金属才能在其宿主中定殖。尽管细菌病原体在脊椎动物生长过程中需要多种金属，但铁螯合被认为是宿主在对感染的先天免疫反应期间主动螯合的主要营养素。在本申请中，我们提供了先天免疫因子钙卫蛋白通过螯合营养物锌（Zn）来防御不动杆菌肺炎的证据。使用钙卫蛋白作为探针，我们在鲍曼不动杆菌中鉴定了一个转运系统，该系统与钙卫蛋白竞争锌，并由锌依赖性调节剂进行转录控制。钙卫蛋白在炎症部位含量丰富，是一种已知的促炎分子，是晚期糖基化终末产物 (RAGE) 受体的配体。尽管有明确的参与，但钙卫蛋白介导的金属螯合和 RAGE 结合对感染防御的贡献尚未得到彻底评估。基于本申请中描述的初步数据，我们假设钙卫蛋白介导的锌螯合和RAGE结合是宿主-病原体相互作用期间的关键因素。为了检验这一中心假设，我们提出了一系列实验，旨在了解鲍曼不动杆菌肺炎期间钙卫蛋白介导的锌螯合和 RAGE 结合的机制和病理生理学后果。在这些研究中，我们将 (i) 确定钙卫蛋白的结构特征，使其能够螯合过渡金属（如 Zn）并结合 RAGE，(ii) 阐明钙卫蛋白和 RAGE 对鲍曼不动杆菌发病机制的影响，以及 (iii)确定 CP 介导的锌螯合对鲍曼不动杆菌生理学的影响。这些结果将为鲍曼不动杆菌如何在脊椎动物宿主中获取营养提供基础见解，并为创建基于钙卫蛋白支架的肽疗法奠定基础，该支架通过营养金属螯合抑制微生物生长。