Environmental Adaptation and Membrane Physiology of an Oral Pathogen

口腔病原体的环境适应和膜生理学

基本信息

批准号：
8230811
负责人：
KEITH Peter MINTZ
金额：
$ 35.77万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-10 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8230811
关键词：
Actinobacillus actinomycetemcomitans Amino Acid Sequence Amino Acids Anaerobic Bacteria Appearance Bacteria Bacterial Adhesins Bacterial Infections Bacterial Proteins Biochemical Genetics Biogenesis Biological Assay Biological Process Biology Cardiovascular Diseases Cell Membrane Permeability Characteristics Communicable Diseases Complement Data Defect Development Disease Etiology Family Gene Proteins Genes Gram-Negative Bacteria Growth Habitats Health Human Hydrophobicity Infection Infective endocarditis Intergenic Sequence LacZ Genes Life Life Cycle Stages Medicine Membrane Membrane Proteins Methodology Microbial Biofilms Molecular Morphogenesis Morphology Nitrates Nitrites Operon Oral cavity Organism Outcome Parents Pathogenicity Peptide Sequence Determination Periodontal Diseases Periodontal Infection Periodontal Ligament Periodontitis Permeability Phase Phenotype Physiological Physiological Processes Physiology Pneumonia Promoter Regions Property Protein Region Proteins Regulation Reporter Role Sequence Alignment Sequence Homology Signal Transduction Simulate Sodium Chloride Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Starvation Stress Structure System Systemic disease Systemic infection Taxon Tooth Loss Toxin Transmission Electron Microscopy Upper respiratory tract Virulence alveolar bone base biological adaptation to stress combat deletion analysis environmental adaptation environmental change gene conservation leukotoxin membrane biogenesis microorganism mutant novel novel therapeutics oral infection oral pathogen pathogen prevent promoter protein protein interaction protein structure function protein-histidine kinase public health relevance research study response restoration therapeutic development yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Aggregatibacter (Actinobacillus) actinomycetemcomitans is a gram-negative, facultative anaerobic bacterium that colonizes the human oral cavity and the upper respiratory tract. This bacterium is strongly associated with localized aggressive periodontitis (LAP). The organism is an opportunistic pathogen causing serious systemic diseases including pneumonia, infective endocarditis, and may contribute to cardiovascular disease. The pathogenicity of the organism has been ascribed to virulence determinants including adhesins, invasins and toxin secretion. These factors must translocate two distinct membranes to be functionally active. In A. actinomycetemcomitans, the biogenesis and protein composition of the inner and outer membranes remain largely undefined. We have identified a novel gene morC, encoding a 141 kDa membrane protein with previously unknown function. The null mutant showed changes in the morphology of the outer membrane, membrane permeability and a marked decreased secretion of leukotoxin. The importance of MorC to maintain membrane morphology and function is supported by these findings. The morphogenesis protein (MorC) is highly conserved among gram-negative human pathogens. In Aggregatibacter and related genera, the gene is located in a three-gene operon under the control of a promoter responsive to environmental changes. This operon may be regulated by a two-component signal transduction system. The conservation of this gene and the operon structure among a variety of bacterial species implies an important role of this protein in the biology of these microorganisms. To better understand the role of MorC in membrane biogenesis and pathogenicity, we propose the following aims: 1) molecular characterization of the morC operon; 2) determination of the functional domain(s) of MorC; and 3) determination of the role of MorC in leukotoxin secretion and membrane biogenesis. The information obtained from the accomplishment of the stated aims can be applied to the development of therapeutics directly targeted to the MorC protein or synergistically with existing therapies t reduce the pathogenic potential of A. actinomycetemcomitans and other pathogens. PUBLIC HEALTH RELEVANCE: Bacteria are the cause of serious, life threatening infections worldwide. Understanding the fundamental properties of the physiology and structure of these pathogens will aid in the development of medicines which interrupt the life cycle of these microorganisms and prevent bacterial infections.

描述（由申请人提供）：聚集（肌动杆菌）放线菌Cetemcomitans是一种革兰氏阴性的，兼性的厌氧菌细菌，可在人类口腔和上呼吸道上定位。该细菌与局部攻击性牙周炎（LAP）密切相关。该生物是一种机会性病原体，引起严重的全身性疾病，包括肺炎，感染性心内膜炎，可能导致心血管疾病。生物体的致病性已归因于毒力决定因素，包括粘附素，入侵素和毒素分泌。这些因素必须转移两个不同的膜才能在功能上活跃。在A.放线菌中，内膜和外膜的生物发生和蛋白质组成在很大程度上不确定。我们已经确定了一种新型基因MORC，编码具有先前未知功能的141 kDa膜蛋白。无效突变体显示出外膜的形态，膜渗透性和白细胞毒素分泌显着降低。这些发现支持MORC保持膜形态和功能的重要性。形态发生蛋白（MORC）在革兰氏阴性人的病原体中高度保守。在聚集的和相关的属中，该基因位于响应环境变化的启动子的控制下，位于三基因操纵子中。该操纵子可以通过两个组件信号转导系统调节。多种细菌物种中该基因和操纵子结构的保存意味着该蛋白在这些微生物的生物学中的重要作用。为了更好地了解MORC在膜生物发生和致病性中的作用，我们提出以下目的：1）MORC操纵子的分子表征； 2）确定MORC的功能域； 3）确定MORC在白细胞毒素分泌和膜生物发生中的作用。从所陈述的目标获得的信息可以应用于直接针对MORC蛋白的治疗剂的开发，或与现有疗法进行协同作用t降低了曲霉曲霉的病原体潜力和其他病原体。公共卫生相关性：细菌是全球严重威胁生命感染的原因。了解这些病原体的生理学和结构的基本特性将有助于开发中断这些微生物生命周期并预防细菌感染的药物。