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（由申请人提供）：鲍曼尼杆菌是一种重要的医院病原体，可引起一系列疾病，包括呼吸道和尿路感染，脑膜炎，心内膜炎，伤口感染和菌血症。实际上，鲍曼尼（A. 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这种生物体迅速获得对所有抗生素的耐药性的迅速获得。这 确定治疗干预的新目标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。治疗发育的一个有希望的潜在领域是针对细菌获得营养金属。该策略是基于这样一个事实，即所有细菌病原体都需要营养金属才能定居其宿主。尽管在脊椎动物内生长过程中，细菌病原体需要多种金属，但铁隔离被认为是宿主对感染的先天免疫反应期间宿主积极隔离的主要养分。在本应用中，我们提供了证据表明，先天免疫因子钙粘蛋白通过螯合营养锌（Zn）来抗肺炎肺炎。使用钙卫蛋白作为探针，我们已经确定了A. baumannii中的传输系统，该传输系统与Zn竞争，并由Zn依赖性调节剂进行转录控制。钙骨蛋白在炎症部位丰富，是一种已知的炎性分子，是晚期糖基化终终产物（RAGE）受体的配体。尽管它明显地参与，但尚未对钙染色素介导的金属隔离和对防御感染的愤怒结合的贡献进行了彻底评估。基于本应用程序中描述的初步数据，我们假设钙蛋白钙蛋白酶介导的锌固存和愤怒结合是宿主 - 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，旨在了解鲍果氏菌肺炎链球菌介导的锌介导的锌固相结合和愤怒结合的机理和病理生理后果。在这些研究中，我们将（i）确定钙特染色素的结构特征，使其能够颅骨过渡金属，例如Zn并结合愤怒，（ii）阐明钙骨和愤怒对鲍曼尼曲霉的发病机理的影响，（iii）（iii）确定CP介导的Zn Zn螯合对A. Baumannii的物理学的影响。这些结果将提供有关A. baumannii如何在脊椎动物宿主中获得营养的基本见解，并为基于基于钙蛋白钙蛋白钙蛋白钙蛋白辣膜激素支架创建肽疗法奠定了基础，从而通过营养金属螯合抑制微生物的生长。