Uncovering the roles of phages in the ecology of Porphyromonas gingivalis in periodontal disease

揭示噬菌体在牙周病牙龈卟啉单胞菌生态学中的作用

• 批准号: 10646368
• 负责人: Kathryn M Kauffman
• 金额: $ 16.05万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10646368
• 关键词: Address; Bacteria; Bacteriophages; Bioinformatics; Biological; Biological Models; Chronic; Clinical; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Communities; Cross-Sectional Studies; Data Set; Development; Disease; Disease Progression; Ecology; Environment; Exposure to; Foundations; Future; Genome; Genomics; Goals; Health; Human; In Vitro; Individual; Infection; Information Systems; Knowledge; Link; Longitudinal Studies; Mediating; Methods; Microbe; Mouth Diseases; Oral; Oral cavity; Periodontal Diseases; Phylogenetic Analysis; Physiology; Play; Population; Population Dynamics; Porphyromonas gingivalis; Predatory Behavior; Prophages; Research; Resistance; Resources; Role; Saliva; Sampling; Sampling Studies; Shapes; Site; Source; Structure; Study models; Surface; System; Systemic disease; Technology; Testing; Therapeutic; Therapeutic Uses; Variant; Virulence; Virulence Factors; Virus; Work; acute infection; capsule; chronic infection; cohort; extracellular; in vivo; insight; knowledgebase; model organism; mutant; nanopore; novel therapeutics; oral bacteria; oral microbial community; oral microbiome; particle; pathogen; pathogenic bacteria; pressure; rational design; receptor; screening; symbiont; tool; volunteer

PROJECT SUMMARY/ABSTRACT The broad goal of the proposed work is to address the lack of knowledge about the roles of bacterial viruses (phages) in shaping the ecology of oral microbial communities. Phages are important predators and symbionts of bacteria in all environments, and they are abundant in the oral cavity (up to 108 ml-1 in saliva and 107 mg-1 plaque). Through acute and chronic infections of their bacterial hosts, phages have the potential to shape bacterial population structure, colonization dynamics, and strain level variation in virulence. Yet, though bacteria in the oral microbiome have been studied for decades, little is known about how phages shape the structure and function of these communities and thereby may play a role in human health and disease. In this application, a bacterial pathogen that has been – and continues to be - intensively studied for its role as keystone species and driver in periodontal disease, Porphyromonas gingivalis (Pg), is developed as a model for studying bacteria-phage interactions in the oral microbiome. To date, no phages able to infect or kill Pg have been isolated, nor have Pg genomes been systematically investigated for evidence of chronically infecting forms of phages (“prophages”). The central hypothesis of the proposed work is that Pg isolates harbor diverse phages integrated into their genomes as prophages, and that these prophages have the potential to alter the ecology of Pg in the oral microbiome. Two complementary aims, providing both breadth and depth of insight into the roles of phages in the ecology of Pg, are used to address this hypothesis. In Aim 1, the goal is to identify and functionally characterize prophages encoded in genomes of Pg. This is achieved by obtaining new isolates of Pg from volunteers with periodontal disease to expand the number of available Pg genomes, and bioinformatically identifying and characterizing prophages in these genomes, including with respect to their capacity to contribute to bacterial virulence and intraspecies competition. In Aim 2, the goal is to determine the receptors used by prophages to infect their Pg hosts. This is achieved by establishing model systems of Pg phages and using cultivation based methods to identify their host range determinants. Completion of these aims will provide the first view of the phylogenetic and functional diversity of Pg phages, insights into their host ranges, and the first identification of receptors that they use to infect their Pg hosts. This will provide the research community with the knowledgebase and tools necessary to test hypotheses (in vitro, in vivo, and in longitudinal and cross-sectional studies) that address how interactions with phages shape Pg genomes, physiology, population dynamics, inter-species and inter-kingdom interactions, and role in periodontal disease and its progression. Uncovering fundamental principles of how phage-bacteria interactions are structured in the oral microbiome will also lay an essential foundation for the rational design of robust, safe, and efficient phage-based therapeutics for use in oral and systemic disease including periodontal disease.

项目摘要/摘要 拟议工作的广泛目标是解决有关细菌病毒角色的知识 （噬菌体）塑造口腔微生物群落的生态学。噬菌体是重要的掠食者， 在所有环境中细菌的共生体 和107 mg-1斑块）。通过细菌宿主的急性和慢性感染，噬菌体具有 塑造细菌种群结构，定殖动态和应变水平变化的潜力 毒力。然而，尽管口服微生物组中的细菌已经研究了数十年，但对 噬菌体如何塑造这些社区的结构和功能，从而如何在人类中发挥作用 健康与疾病。在此应用中，一直存在的细菌病原体 - 强烈研究其在牙周疾病，卟啉念珠菌中作为基石物种和驱动器的作用 牙龈（PG）是作为研究口服微生物组中细菌 - 含量相互作用的模型开发的。到 日期，没有噬菌体可以被隔离或杀死PG，PG基因组也没有系统地。 调查是否有长期感染噬菌体形式的证据（“预言”）。中心假设 拟议的工作是，PG分离出来的潜水员噬菌体噬菌体纳入了其基因组，作为行为， 并且这些先知有可能改变口服微生物组中PG的生态。二 完全瞄准，提供对噬菌体在生态学中噬菌体作用的广度和深度 PG用于解决这一假设。在AIM 1中，目标是识别并在功能上表征 PG基因组中编码的预言。这是通过从志愿者那里获得PG的新分离株来实现的 牙周疾病扩大可用PG基因组的数量，并在生物信息上识别 并在这些基因组中表征先知，包括在其能力方面做出贡献的能力 细菌病毒和种内竞争。在AIM 2中，目标是确定 预言感染了PG宿主。这是通过建立PG噬菌体模型系统并使用的 基于培养的方法来确定其宿主范围的决定。这些目标的完成将提供 PG噬菌体的系统发育和功能多样性，对宿主范围的见解以及 他们用来感染PG宿主的接收器的首次识别。这将提供研究 具有检验假设所需的知识库和工具的社区（体外，体内和 纵向和横截面研究），解决与噬菌体相互作用的形状PG基因组的相互作用， 生理学，种群动态，种间和昆明间相互作用以及在牙周中的作用 疾病及其进展。发现噬菌体 - 细菌相互作用的基本原理 在口腔微生物组中结构的结构还将为坚固，安全， 以及有效的基于噬菌体的治疗，用于口服和全身性疾病，包括牙周疾病。