Leukotoxin production by A. actinomycetemcomitans

描述：伴放线放线杆菌是一种细菌，是局部侵袭性牙周炎 (LAP) 的病原体。 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，但少数族裔和弱势群体的发病率较高。不治疗 LAP 会导致牙齿脱落和其他健康相关问题。此外，A. actinomycetemcomitans 是引起感染性心内膜炎（一种心脏瓣膜和组织疾病）的 HACEK 细菌群的一部分。 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，在伴放线放线菌的发病机制中发挥重要作用。白细胞毒素是一种 RTX（毒素重复）毒素，包括其他重要毒素，例如大肠杆菌 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 A. actinomycetemcomitans 白毒素是如何从细菌细胞中产生、激活和分泌的知之甚少。此外，RTX毒素还没有被结晶以解决其三维结构。 这里提出的实验将（1）识别产生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）生长白细胞毒素晶体并在原子水平上解析其三维结构。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导致疾病。通过这些实验获得的结构信息将进一步阐明这一类重要毒素的作用机制。这一新信息可能会导致设计出能够破坏白细胞毒素活性并最终治疗或预防疾病的治疗剂。

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.