Leukotoxin production by A. actinomycetemcomitans

A. actinomycetemcomitans 产生白细胞毒素

• 批准号: 7385845
• 负责人: SCOTT C KACHLANY
• 金额: $ 30.74万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ DENTAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385845
• 关键词: Actinobacillus actinomycetemcomitans; Adenylate Cyclase; Adolescent; Affect; Amino Acids; Anabolism; Bacteria; Biochemical; Biochemical Genetics; Biological Assay; Cells; Class; Collaborations; Condition; Crystallization; DNA Sequence Analysis; Disease; Ensure; Failure; Frequencies; Gene Proteins; Genes; Genetic; Goals; Heart Valve Diseases; Hemolysin; Human; Immune response; Immunoprecipitation; Incidence; Infective endocarditis; Laboratories; Lead; Leukocytes; Light; Localized; Methods; Minority; Molecular; Molecular Structure; Mouth Diseases; Pathogenesis; Periodontitis; Pertussis; Play; Population Group; Production; Proteins; Regulation; Reporter Genes; Resolution; Role; Structure; Techniques; Testing; Therapeutic Agents; Tissues; Tooth Loss; Toxin; Vibrio cholerae; Virulence Factors; Work; design; factor A; gene function; intracellular protein transport; leukotoxin; mutant; pathogen; prevent; protein function; protein localization location; research study; success; three dimensional structure; tool; yeast two hybrid system

DESCRIPTION: Actinobacillus actinomycetemcomitans is a bacterium that is the etiologic agent for localized aggressive periodontitis (LAP). LAP is a destructive and aggressive disease of the oral cavity that affects adolescents. The incidence of LAP varies among population groups, but afflicts minorities and the underprivileged at a higher frequency. Failure to treat LAP results in the loss of teeth and other health-related problems. In addition, A. actinomycetemcomitans is part of the HACEK group of bacteria that causes infective endocarditis, a disease of heart valves and tissue. A. actinomycetemcomitans secretes a protein toxin known as leukotoxin. Leukotoxin destroys leukocytes of humans, and likely plays a significant role in the pathogenesis of A. actinomycetemcomitans by helping the bacterium evade the immune response. Leukotoxin is an RTX (repeats in toxin) toxin that includes other important toxins such as E. coil alpha-hemolysin, M. haemolytica leukotoxin, B. pertussis adenylate cyclase, and V. cholerae RTX toxin. To date, little is known about how A. actinomycetemcomitans leukotoxin is produced, activated, and secreted from bacterial cells. In addition, none of the RTX toxins have been crystallized to have their three-dimensional structures solved. Proposed here are experiments that will (1) identify the genes that are required for production of active leukotoxin, (2) study the genes and proteins using genetic and biochemical approaches, and (3) grow crystals of leukotoxin and solve its three-dimensional structure at the atomic level. We expect this work to lead to a better understanding of leukotoxin production and how the toxin contributes to disease. The structural information gained through these experiments will shed more light on the mechanism of action of this important class of toxins. This new information may lead to the design of therapeutic agents that can disrupt leukotoxin activity and ultimately treat or prevent disease.

描述：放线杆菌放线菌ceTemcitans是一种细菌，是局部攻击性牙周炎（LAP）的病因学剂。膝盖是影响青少年的口腔破坏性和侵略性疾病。人口组的发病率在人群群体之间有所不同，但遭受少数群体和弱势群体的困扰。无法治疗膝盖会导致牙齿丧失和其他与健康有关的问题。此外，放线菌菌是Hacek细菌的一部分，该细菌会导致感染性心内膜炎，一种心脏瓣膜和组织疾病。 A.放线菌co虫分泌一种称为白细胞毒素的蛋白质毒素。白细胞毒素会破坏人类的白细胞，并可能通过帮助细菌逃避免疫反应，在曲霉曲霉的发病机理中起重要作用。白细胞毒素是一种RTX（毒素中的重复）毒素，其中包括其他重要毒素，例如E. coil alpha-Hemolysin，M。hemoloselytica leukotoxin，B。the offtussis腺苷酸腺酸环化酶和V. cholerae RTX毒素。迄今为止，关于曲霉曲霉的白细胞毒素是如何从细菌细胞中产生，激活和分泌的。另外，没有任何RTX毒素结晶以解决其三维结构。 此处提出的实验将（1）确定生产活性白细胞毒素所需的基因，（2）使用遗传和生化方法研究基因和蛋白质，以及（3）生长白细胞毒素的晶体并溶解其在原子水平上的三维结构。我们希望这项工作能够更好地了解白细胞毒素的产生以及毒素如何对疾病贡献。通过这些实验获得的结构信息将更多地了解这一重要类毒素的作用机理。这些新信息可能会导致设计可以破坏白细胞毒素活性并最终治疗或预防疾病的治疗剂的设计。