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的病原体。牙周炎是一种影响青少年的口腔破坏性和侵袭性疾病。各人口群体的发病率各不相同，但少数群体和贫困人口发病率较高。不治疗牙齿脱落会导致牙齿脱落和其他与健康有关的问题。此外，A.伴放线菌是引起感染性心内膜炎（一种心脏瓣膜和组织疾病）的HACEK组细菌的一部分。 A.伴放线菌分泌一种称为白细胞毒素的蛋白质毒素。白细胞毒素破坏人体白细胞，可能在A.放线菌通过帮助细菌逃避免疫反应。白细胞毒素是一种RTX（毒素重复序列）毒素，包括其他重要的毒素，如大肠杆菌。螺旋α-溶血素、M.溶血性白细胞毒素，B.百日咳腺苷酸环化酶和霍乱弧菌RTX毒素。到目前为止，人们对A.伴放线菌白细胞毒素由细菌细胞产生、活化和分泌。此外，没有一种RTX毒素被结晶以解决其三维结构。 这里提出的实验将（1）确定产生活性白细胞毒素所需的基因，（2）使用遗传和生物化学方法研究基因和蛋白质，（3）生长白细胞毒素晶体并在原子水平上解决其三维结构。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类重要毒素的作用机制。这一新的信息可能会导致治疗剂的设计，可以破坏白细胞毒素的活性，并最终治疗或预防疾病。

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.