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：
8448543
负责人：
KEITH Peter MINTZ
金额：
$ 34.34万
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 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448543
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.

描述（由申请人提供）：伴随放线菌（Actinobacillus）放线菌是一种革兰氏阴性、兼性厌氧细菌，定植于人类口腔和上呼吸道。这种细菌与局部侵袭性牙周炎（LAP）密切相关。该微生物是一种机会性病原体，可引起严重的全身性疾病，包括肺炎、感染性心内膜炎，并可能导致心血管疾病。该生物体的致病性归因于毒力决定因素，包括粘附素、侵袭素和毒素分泌。这些因子必须使两个不同的膜易位才能发挥功能活性。在 A. actinomycetemcomitans 中，内膜和外膜的生物发生和蛋白质组成在很大程度上仍不清楚。我们发现了一个新的基因 morC，它编码一种 141 kDa 的膜蛋白，具有以前未知的功能。无效突变体表现出外膜形态、膜通透性的变化以及白细胞毒素分泌的显着减少。这些发现支持了 MorC 对维持膜形态和功能的重要性。形态发生蛋白（MorC）在革兰氏阴性人类病原体中高度保守。在聚集杆菌属和相关属中，该基因位于三基因操纵子中，受对环境变化作出反应的启动子的控制。该操纵子可以由二元信号转导系统调节。该基因和操纵子结构在多种细菌物种中的保守性意味着该蛋白质在这些微生物的生物学中发挥着重要作用。为了更好地理解 MorC 在膜生物发生和致病性中的作用，我们提出以下目标：1）morC 操纵子的分子表征； 2) MorC功能域的确定； 3)确定MorC在白细胞毒素分泌和膜生物合成中的作用。从实现既定目标中获得的信息可应用于开发直接针对 MorC 蛋白的疗法或与现有疗法协同以降低 A. actinomycetemcomitans 和其他病原体的致病潜力。