INVASION AND ADHESION OF PERIOPATHOGENS

伴放线放线杆菌（Actinobacillusactinomycetemcomitans，Aa）是革兰氏阴性， 兼性 定植于人类口腔和鞋面的球杆菌 呼吸道 微生物、免疫学和临床研究 有 提示Aa在成人和青少年的发病机制中均起作用 牙周炎 AA还与更严重的人类疾病有关。 感染，如心内膜炎和软组织脓肿。 虽然 牙周组织被认为是这些感染的来源， 之甚少 我们知道Aa用来维持自身的机制， 口服 并在组织中浸润和扩散。 病原体已经发展出非常复杂和多样的策略 的 宿主细胞感染和组织分散。 入侵机制 使用 肠道病原体引起的疾病已经被广泛研究。 的 过程包括多个步骤， 细菌 基因. 口腔病原体的入侵还没有得到充分的 研究了 我们的实验室提供了唯一一项关于 入侵 牙周病微生物。Aa入侵是一种动态的 多步 这一过程涉及宿主和细菌之间的相互作用。 Aa的粘附和随后的进入与宿主细胞相关 肌动蛋白 重排，并且可能由转铁蛋白受体介导。 出口 这似乎取决于微管结构。 AA传播到 相邻 细胞通过宿主细胞表面突起介导。 这些 研究 促使我们提出了一个Aa入侵过程的模型。 在这 建议，我们计划专注于宿主细胞如何响应 的 入侵Aa 为了进一步了解 AA 发病机制，我们建议（1）评估的作用， 铁蛋白 受体在Aa进入上皮细胞中的作用，（2）建立 的 微管在Aa细胞内的扩散，（3）确定 生物发生 含Aa的液泡，（4）确定 事件 在侵袭过程中，（5）研究瞬时钙 通量 入侵过程。 理解在Aa中发挥关键作用的元素 发病机制 应该为合理的发展提供见解， 化疗 牙周病的治疗方法

Actinobacillus actinomycetemcomitans (Aa) is a Gram-negative, facultative coccobacillus which colonizes the human oral cavity and the upper respiratory tract. Microbial, immunological and clinical studies have implicated Aa in the pathogenesis of both adult and juvenile periodontitis. Aa has also been associated with more serious human infections such as endocarditis and soft tissue abscesses. Although the periodontium is believed to be the source of these infections, little is known about the mechanisms used by Aa to maintain itself within the oral cavity and to infiltrate and disseminate in tissues. Pathogens have developed remarkably complex and diverse strategies of host cell infection and tissue dispersion. The invasion mechanisms used by the intestinal pathogens have been investigated extensively. The processes include multiple steps and the involvement of myriad bacterial genes. The invasion of oral pathogens has not been adequately studied. Our laboratory has provided the only extensive study on the invasion of a periodontopathic microorganism. Aa invasion is a dynamic multistep process which involves cross-talk between the host and bacterium. Adhesion and subsequent entry of Aa is correlated with host cell actin rearrangement, and is likely mediated by transferrin receptor. Exit appears to be dependent on microtubule structure. Aa spread to adjacent cells is mediated through host cell surface protrusions. These studies promoted us to propose a model of the Aa invasion process. In this proposal, we plan to concentrate on how the host cell responds to the invasion of Aa. In order to further our understanding of the critical elements of Aa pathogenesis, we propose to (1) evaluate the role of the transferrin receptor in Aa entry into epithelial cells, (2) establish the role of microtubules in Aa intracellular spread, (3) determine the biogenesis of the Aa-containing vacuole, (4) determine the real-time sequence of events in the invasion process, and (5) investigate transient calcium fluxes in the invasion process. An understanding of the elements that play key roles in Aa pathogenesis should provide insights for the development of rational chemotherapeutic interventions in the treatment of periodontal diseases.