Leukotoxin production by A. actinomycetemcomitans

A. actinomycetemcomitans 产生白细胞毒素

基本信息

批准号：
7434168
负责人：
SCOTT C KACHLANY
金额：
$ 1.25万
依托单位：
UNIV OF MED/DENT OF NJ-NJ DENTAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7434168
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

项目摘要

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.

Actinobacillus actinomycetemcomitans 是一种细菌，是局部侵袭性病原体的病原体牙周炎（LAP）。 LAP 是一种影响青少年的破坏性、侵袭性口腔疾病。 LAP 的发病率因人群而异，但对少数族裔和弱势群体的影响最大更高的频率。不治疗 LAP 会导致牙齿脱落和其他健康相关问题。在此外，A. actinomycetemcomitans 是 HACEK 细菌群的一部分，可引起感染心内膜炎，一种心脏瓣膜和组织疾病。伴放线放线菌分泌一种称为白细胞毒素的蛋白质毒素。白细胞毒素破坏人类白细胞，并且可能在 A. actinomycetemcomitans 的发病机制中发挥重要作用帮助细菌逃避免疫反应。白细胞毒素是一种 RTX（毒素重复）毒素，包括其他重要的毒素，如大肠杆菌α-溶血素、溶血支原体白细胞毒素、百日咳博德特氏菌腺苷酸环化酶和霍乱弧菌 RTX 毒素。迄今为止，人们对伴放线放线菌如何白细胞毒素由细菌细胞产生、激活和分泌。此外，RTX 毒素均不具有被结晶以解决其三维结构。这里提出的实验将（1）鉴定产生活性物质所需的基因。白细胞毒素，(2) 使用遗传和生化方法研究基因和蛋白质，以及 (3) 生长白细胞毒素晶体并在原子水平上解析其三维结构。我们期望这项工作能够有助于更好地了解白细胞毒素的产生以及毒素如何导致疾病。这通过这些实验获得的结构信息将进一步阐明其作用机制这一类重要的毒素。这一新信息可能会导致治疗药物的设计破坏白细胞毒素活性并最终治疗或预防疾病。