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.

项目摘要/摘要 牙周炎或牙龈疾病会影响美国大约50％的成年人口，并且可以 导致组织损伤和骨质流失[1,2]。这种疾病是不寻常的，因为它不是由特定生物引起的 但是由包括机会性病原体和共生的微生物财团[2]。复杂的相互作用 口腔微生物影响疾病的进展和严重程度，及其对治疗的抗药性 [3–7]。在体内研究这些相互作用是具有挑战性的，阻碍了我们理解牙周疾病的能力。 表征多数菌相互作用的生产方法包括使用模型 牙周炎的社区和动物模型[5,8-10]。以前，Whiteley实验室使用了这些方法 确定机会性病原体之间的交叉进食和交叉响应介导的相互作用 聚集的放线菌菌（AA）和口腔共生链球菌Gordonii（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组成部分的抵抗力[8]。在 这项研究，总体假设是代谢相互作用会影响口腔中病原体的存活 腔。该提案旨在通过两种重要方式扩展我们对口腔多生物相互作用的理解。 首先，它建议表征AA和SG之间的相互作用如何改变AA抵抗先天的能力 免疫系统，抗菌化合物和其他口服微生物的侵袭 体外操纵和转座子测序（AIM 1）。其次，该建议旨在使用框架 开发以表征AA和SG之间的相互作用作为识别代谢驱动的模型 AA和潜水员集合的微生物之间的相互作用（AIM 2）。互动的代谢影响将是 以比较在鼠类脓肿模型中的共培养中AA适应度所必需的基因的特征 在化学定义的操作中被所必需的体外感染。这个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 巴氏菌科家族中的微生物，包括嗜血杆菌。总体而言，拟议的研究将大大 扩展我们对口腔代谢相互作用如何影响病原体持久性的理解 牙周炎期间。