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）：鲍曼不动杆菌是一种重要的院内病原体，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。事实上，鲍曼不动杆菌目前在世界某些地区的所有重症监护病房感染中占20%，肺炎是最常见的表现。鲍曼不动杆菌对几乎所有抗生素的快速耐药性推动了它的临床意义。的