Leukotoxin production by A. actinomycetemcomitans

伴放线放线杆菌是一种细菌，是局部侵袭性 牙周炎（periodontitis，PPH）。牙周炎是一种影响青少年的口腔破坏性和侵袭性疾病。 艾滋病的发病率因人口群体而异，但少数群体和贫困群体的发病率较高， 更高的频率。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。在 addition，A.伴放线菌是引起感染性疾病的细菌的HACEK组的一部分。 心内膜炎，心脏瓣膜和组织的疾病。 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 人白细胞，并可能在A.伴放线菌 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E。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. actinomycetemcomitans 白细胞毒素由细菌细胞产生、活化和分泌。此外，RTX毒素中没有一种 被结晶化以解决它们的三维结构。 这里提出的实验将（1）确定产生活性物质所需的基因， 白细胞毒素，（2）使用遗传和生物化学方法研究基因和蛋白质，以及（3）生长 白细胞毒素的晶体，并在原子水平上解决其三维结构。我们希望这项工作 从而更好地了解白细胞毒素的产生以及毒素如何导致疾病。的 通过这些实验获得的结构信息将进一步阐明 这类重要的毒素这一新的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。

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.