Leukotoxin production by A. actinomycetemcomitans

伴放线放线杆菌是一种引起局部侵袭性的细菌。 牙周炎(LAP)。LAP是一种破坏性和侵袭性的口腔疾病，影响青少年。 LAP的发病率在不同的人口群体中有所不同，但在一个国家中困扰着少数族裔和弱势群体 更高的频率。不治疗LAP会导致牙齿脱落和其他与健康相关的问题。在……里面 此外，伴生放线杆菌是引起感染性疾病的Hacek细菌群的一部分。 心内膜炎，一种心脏瓣膜和组织的疾病。 伴生放线菌会分泌一种称为白毒素的蛋白质毒素。白血杆菌毒素破坏 在伴生放线菌的致病机制中可能起着重要作用。 帮助细菌逃避免疫反应。白斑毒素是一种RTX(在毒素中重复)毒素 包括其他重要的毒素，如大肠杆菌α-溶血素、溶血分枝杆菌白毒素、百日咳杆菌。 腺苷环化酶和霍乱弧菌RTX毒素。到目前为止，人们对放线菌如何伴生知之甚少。 白毒素是由细菌细胞产生、激活和分泌的。此外，所有的RTX毒素都没有 被结晶以解决它们的三维结构。 这里提出的实验将(1)确定产生活性所需的基因。 白毒素，(2)用遗传和生化方法研究基因和蛋白质，以及(3)生长 并在原子水平上解决了白毒素的三维结构。我们希望这项工作能够 使我们更好地了解白毒素的产生以及这种毒素如何导致疾病。这个 通过这些实验获得的结构信息将为进一步阐明其作用机制提供更多的线索 这类重要的毒素。这一新信息可能会导致设计出能够 破坏白毒素活性，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.