Probing the impact of polymicrobial interactions on the virulence of an oral pathogen

探讨多种微生物相互作用对口腔病原体毒力的影响

• 批准号: 9635590
• 负责人: Gina Lewin
• 金额: $ 1.96万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9635590
• 关键词: Probing; impact; polymicrobial; interactions; virulence

PROJECT SUMMARY/ABSTRACT Periodontitis, or gum disease, affects approximately 50% of the adult population in the United States and can result in tissue damage and bone loss [1,2]. This disease is unusual in that it is not caused by a specific organism, but by a consortia of microbes including opportunistic pathogens and commensals [2]. The complex interactions between oral microbes influence the progression and severity of disease, as well as its resistance to treatment [3–7]. Studying these interactions in vivo is challenging, hindering our ability to understand periodontal disease. Productive approaches to characterize polymicrobial interactions have included the use of model oral communities and animal models of periodontitis [5,8–10]. Previously, the Whiteley lab used these approaches to identify cross-feeding and cross-respiration mediated interactions between the opportunistic pathogen Aggregatibacter actinomycetemcomitans (Aa) and the oral commensal Streptococcus gordonii (Sg) [6,11,12]. In addition, these interactions increase Aa’s resistance to certain components of the innate immune system [8]. In this study, the overarching hypothesis is that metabolic interactions impact the survival of pathogens in the oral cavity. This proposal aims to expand our understanding of oral polymicrobial interactions in two significant ways. First, it proposes to characterize how interactions between Aa and Sg alter the ability of Aa to resist the innate immune system, antimicrobial compounds, and the invasion of other oral microbes using a combination of in vitro manipulations and transposon sequencing (Aim 1). Second, this proposal aims to use the framework developed in characterizing the interactions between Aa and Sg as a model to identify metabolically-driven interactions between Aa and a diverse set of microbes (Aim 2). The metabolic impact of interactions will be characterized by comparing the genes necessary for Aa fitness in co-culture in a murine abscess model of infection with those necessary in vitro in chemically defined manipulations. This Aim will also serve to improve the functional annotation of the Aa genome, and potentially genomes of other closely-related clinically relevant microbes in the Pasteurellaceae family, including Haemophilus. Overall, the proposed research will greatly expand our understanding of how metabolic interactions in the oral cavity influence the persistence of pathogens during periodontitis.

项目概要/摘要 牙周炎或牙龈疾病影响着美国大约 50% 的成年人口， 导致组织损伤和骨质流失[1,2]。这种疾病的不同寻常之处在于它不是由特定的生物体引起的， 而是由包括机会性病原体和共生体在内的微生物群落引起的[2]。复杂的相互作用 口腔微生物之间的相互作用影响疾病的进展和严重程度及其对治疗的抵抗力 [3-7]。在体内研究这些相互作用具有挑战性，阻碍了我们了解牙周病的能力。 表征多种微生物相互作用的有效方法包括使用口腔模型 牙周炎的社区和动物模型[5,8–10]。此前，怀特利实验室使用过这些方法 识别机会病原体之间交叉进食和交叉呼吸介导的相互作用 伴放线聚集菌 (Aa) 和口腔共生戈登链球菌 (Sg) [6,11,12]。在 此外，这些相互作用增加了 Aa 对先天免疫系统某些成分的抵抗力 [8]。在 这项研究的总体假设是代谢相互作用影响口腔中病原体的生存 空腔。该提案旨在以两种重要方式扩大我们对口腔多种微生物相互作用的理解。 首先，它建议描述 Aa 和 Sg 之间的相互作用如何改变 Aa 抵抗先天性的能力。 免疫系统、抗菌化合物和其他口腔微生物的入侵 体外操作和转座子测序（目标 1）。二、本提案旨在利用该框架 开发用于表征 Aa 和 Sg 之间的相互作用，作为识别代谢驱动的模型 Aa 与多种微生物之间的相互作用（目标 2）。相互作用对代谢的影响将是 通过比较小鼠脓肿模型中共培养中 Aa 适应性所需的基因来表征 在化学定义的操作中用体外必需的物质进行感染。这一目标也将有助于改善 Aa 基因组的功能注释，以及其他密切相关的临床相关的潜在基因组 巴氏杆菌科微生物，包括嗜血杆菌。总体而言，拟议的研究将极大地 扩大我们对口腔代谢相互作用如何影响病原体持续存在的理解 牙周炎期间。