Advancing studies of polymicrobial diseases via streptococcal genetics

项目摘要/摘要 无数的人类粘膜疾病与栖息于 疾病现场。Koch‘s对这些复杂的多微生物疾病的病因学描述很差 多菌致病的假设和关键机制仍在该领域不断涌现。这个 传统抗生素疗法的应用有限，以及我们对多菌类药物的认识不足 疾病病因学目前都是有效治疗这些疾病的重大障碍。这个 当前提案的主题基础是利用口腔菌群中遗传易驯化的成员作为 研究多种微生物协同作用的机制和调控基础的模型系统 以及在这些类型的疾病中抵消协同发病的潜在机制。这个 拟议的研究计划将由3个概念互补的研究重点组成：1)基因 毒力控制，2)多菌剂协同作用的机制，3)靶向的新策略 对细菌的抑制。在这些重点领域中的每一个方面的成功都将由我们现有的 口腔细菌遗传学的优势和最先进的遗传系统的应用。我们是 建议进一步发展变形链球菌作为遗传研究的优秀模式生物 菌群病理生物学的研究，同时还开发了一种新的多菌剂协同作用模式系统 脓肿临床分离株与脓肿临床分离株合并感染的研究 梭杆菌属(Fusbacterium spp.)和普雷沃特拉(Prevoella spp.)对绞股蓝链球菌的研究严重不足。 口腔菌群成员与严重的多菌脓肿的形成密切相关 口腔和全身。这种脓肿令人惊讶地常见，但人们对此知之甚少。 关于涉及的致病机制，除了多菌协同的基本作用外， 尤其是梭杆菌和普雷沃特氏菌。因此，我们设想利用长期的支持 由R35机制提供，既增强了我们现有的计划优势，也增长了 我们的研究计划在一个未被充分研究的领域具有重大的临床意义。

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.