RmpA, a unique virulence regulator in emerging Klebsiella pneumoniae

RmpA，新出现的肺炎克雷伯菌的独特毒力调节剂

• 批准号: 8190101
• 负责人: Valley J. Stewart
• 金额: $ 21.46万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190101
• 关键词: Adult; Affect; Alleles; Animals; Antibiotic Resistance; Binding; Biochemical; Biological Models; Candidate Disease Gene; Cell surface; Cells; Collaborations; Communities; Complex; DNA; DNA Binding; Development; Electrophoretic Mobility Shift Assay; Employee Strikes; Encapsulated; Enterobacteriaceae; Escherichia; Exhibits; Family; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Transcription; Goals; Homo; Human; Immunity; In Vitro; Infection; Intestines; Klebsiella; Klebsiella pneumonia bacterium; Liver Abscess; Medicine; Mobile Genetic Elements; Modification; Molecular Weight; Monitor; National Institute of Allergy and Infectious Disease; Nosocomial pneumonia; Operon; Pathogenesis; Pathogenicity; Pathology; Phagocytosis; Phenotype; Phosphorylation; Plants; Polysaccharides; Proteins; Pyogenic Liver Abscess; Regulation; Regulon; Relative (related person); Research; Research Design; Role; Salmonella; Sepsis; Shigella; Solutions; Structural Genes; Taiwan; Testing; Transcript; Universities; Virulence; Virulence Factors; Virulent; capsule; college; dimer; gastrointestinal infection; improved; in vivo; innovation; liver infection; meetings; member; mucoid; mutant; pathogen; programs; public health relevance; research study; response

DESCRIPTION (provided by applicant): The family Enterobacteriaceae includes an array of human, animal and plant pathogens. Human intestinal and extraintestinal infections are caused by specific strains of the closely-related species Escherichia, Shigella, Salmonella and Klebsiella. Although relatively little-studied, Klebsiella pneumoniae nevertheless is a notorious nosocomial pathogen responsible for widespread dissemination of antibiotic resistance. Recently, K. pneumoniae has been identified as the cause of an emerging community-acquired pyogenic liver infection termed KLA (K. pneumoniae liver abscess). This infection is due to specific clones expressing the Hmv (hypermucoviscosity) phenotype, which results from unknown modifications of capsule composition or synthesis. Capsule is an essential pathogenicity factor for K. pneumoniae infections, and Hmv is important for virulence of KLA strains. The Hmv phenotype depends on the auxiliary regulator RmpA, a unique protein that likely forms heterodimers with the global RcsB response regulator. Characterized strains contain multiple rmpA alleles on mobile genetic elements. The relevance to NIAID, and the long-term objectives for this project, are to identify and understand genetic determinants for K. pneumoniae pathogenicity and virulence. The goal of this proposal is to initiate genetic and biochemical analysis in a virulent KLA strain of K. pneumoniae. Studies are designed to identify the functions of RmpA and interacting regulators in the control of virulence factors including capsule and the Hmv phenotype. Research will be in collaboration with a leader in the study of KLA, Prof. Jin-Town Wang at the National Taiwan University College of Medicine. Specific aims will apply a variety of in vivo and in vitro approaches to test five hypotheses: (1a) Duplicate rmpA alleles are at least partially redundant; (1b) RmpA is integrated into the RcsB regulatory network; (2) The RmpA regulon includes virulence genes beyond those involved directly in capsule synthesis and assembly; (3a) RcsB-RmpA heterodimers control capsule biosynthetic operon expression; and (3b) RmpA activity is modulated by phosphorylation. Impacts of the proposed research are: (i) identification and analysis of virulence factors in an emerging pathogen notorious for developing antibiotic resistance; (ii) improved understanding of the unique Hmv phenotype and its control by the RmpA regulon; and (iii) modified concepts regarding global RcsB regulatory network interactions with auxiliary regulators. PUBLIC HEALTH RELEVANCE: Klebsiella pneumoniae, a notorious nosocomial pathogen, has emerged recently as the cause of pyogenic liver abscess in otherwise healthy adults. Hypermucoviscous capsule, a protective layer surrounding the cell surface, is important for this pathology. The public health relevance of this research is to understand a unique regulator that controls hypermucoviscous capsule formation and composition.

描述（由申请人提供）：肠杆菌科包括一系列人，动物和植物病原体。人类肠道和肠外感染是由密切相关物种的特异性菌株，志贺氏菌，沙门氏菌和克雷伯氏菌引起的。尽管相对较少研究，但肺炎克雷伯菌是一种臭名昭著的医院病原体，负责广泛传播抗生素耐药性。最近，肺炎链球菌被确定为称为KLA（K。肺炎肝脓肿）的新兴社区获得的化脓性肝感染的原因。这种感染是由于表达HMV（高敏度）表型的特定克隆引起的，这是由于胶囊组成或合成的未知修饰而引起的。胶囊是K.肺炎感染的基本致病因子，HMV对于KLA菌株的毒力很重要。 HMV表型取决于辅助调节剂RMPA，这是一种独特的蛋白质，可能与全局RCSB响应调节剂形成异二聚体。特征菌株在移动遗传元件上包含多个RMPA等位基因。与NIAID的相关性以及该项目的长期目标是识别和理解K.肺炎致病性和毒力的遗传决定因素。该提案的目的是在肺炎的毒性KLA菌株中启动遗传和生化分析。研究旨在确定RMPA和相互作用调节剂在控制毒力因子（包括胶囊和HMV表型）中的功能。研究将与KLA研究的领导者合作，台湾大学医学院的Jin-Town Wang教授。具体目的将采用各种体内和体外方法来检验五个假设：（1A）重复的RMPA等位基因至少部分冗余； （1B）RMPA已集成到RCSB监管网络中； （2）RMPA调节子包括直接参与胶囊合成和组装的毒力基因； （3A）RCSB-RMPA异二聚体控制胶囊生物合成操纵子的表达； （3B）RMPA活性通过磷酸化调节。拟议的研究的影响是：（i）以发展抗生素耐药性臭名昭著的新兴病原体中毒力因子的鉴定和分析； （ii）提高了RMPA法规对独特的HMV表型及其控制的理解； （iii）有关与辅助调节器的全球RCSB监管网络相互作用的修改概念。 公共卫生相关性：臭名昭著的医院病原体Klebsiella肺炎最近出现了作为成年成年成年成年成年脓肿的原因。高胶囊胶囊是细胞表面周围的保护层，对这种病理很重要。这项研究的公共卫生相关性是要了解一个独特的调节器，该调节器控制高胶囊的形成和组成。