Advancing studies of polymicrobial diseases via streptococcal genetics

项目总结/摘要 无数的人类粘膜疾病与栖息在胃肠道的植物群的生态学密切相关。 疾病现场。这些复杂的多微生物疾病的病因学很少被Koch's 多微生物致病的基本假设和关键机制仍在该领域出现。的 传统抗生素治疗的有限效用以及我们对多种微生物的认识不足 疾病病因学是目前有效治疗这些疾病的重要障碍。的 目前建议的主题基础是利用口腔植物群中遗传上易处理的成员作为 模型系统，以调查多微生物协同作用的机制和监管基础， 以及在这些类型的疾病中对抗协同发病机制的潜在机制。的 拟议的研究计划将包括3个概念互补的研究重点：1）遗传 控制毒力，2）多微生物协同作用的机制，以及3）靶向的新策略 抑制细菌。在每个重点领域的成功将由我们的既定 在口腔细菌遗传学和应用最先进的遗传系统的优势。我们 建议进一步发展变形链球菌作为遗传学的杰出模式生物， 植物群病理生物学的研究，同时还开发了一种新的多微生物协同作用的模型系统， 脓肿临床分离的咽峡炎群链球菌与脓肿临床分离的组合 梭杆菌属（Fusobacterium spp.）和普雷沃氏菌属（Prevotella spp.）对于心绞痛链球菌的研究 口腔植物群的成员与严重的多微生物菌群的形成密切相关， 口腔和整个身体。这样的行为令人惊讶的普遍，但很少有人知道 除了多微生物协同作用的重要作用外， 特别是梭杆菌属和普雷沃氏菌属。因此，我们设想利用长期支持 R35机制提供的资源，既可以增强我们现有的方案优势， 我们在一个具有重要临床意义的未被充分研究的领域的研究计划。

PROJECT SUMMARY/ABSTRACT A myriad of human mucosal diseases are intimately connected with the ecology of the flora residing at disease sites. The etiology of these complex polymicrobial diseases is poorly described by Koch's Postulates and the key mechanisms of polymicrobial pathogenesis are still emerging in the field. The limited utility of traditional antibiotic therapies as well as our inadequate understanding of polymicrobial disease etiology are both currently significant hurdles for the effective treatment of these diseases. The thematic basis for the current proposal is to utilize genetically tractable members of the oral flora as a model system to investigate the mechanistic and regulatory foundations of polymicrobial synergy as well as potential mechanisms to counteract synergistic pathogenesis in these types of diseases. The proposed research program will consist of 3 conceptually complementary research foci: 1) the genetic control of virulence, 2) mechanisms of polymicrobial synergy, and 3) novel strategies for targeted inhibition of bacteria. Success in each of these focus areas will be leveraged by our established strengths in oral bacterial genetics and the application of a state-of-the-art genetic system. We are proposing to further develop Streptococcus mutans as a preeminent model organism for genetic studies of flora pathobiology, while also developing a new model system of polymicrobial synergy using abscess clinical isolates of Anginosus group streptococci in combination with abscess clinical isolates of Fusobacterium spp. and Prevotella spp. The Anginosus streptococci are vastly understudied members of the oral flora strongly associated with the formation of severe polymicrobial abscesses in the oral cavity and throughout the body. Such abscesses are surprisingly common, yet little is known about the pathogenic mechanisms involved, other than the essential role of polymicrobial synergy, especially with Fusobacterium and Prevotella species. Thus, we envision utilizing the long-term support provided by the R35 mechanism to both augment our existing programmatic strengths and also to grow our research program in an understudied area of major clinical significance.