Regulation in Fusobacterium-mediated coaggregation

梭杆菌介导的共聚集的调节

基本信息

批准号：
10277533
负责人：
Chenggang Wu
金额：
$ 36.55万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10277533
关键词：
Actinobacillus actinomycetemcomitans Actinomyces Address Adhesions Adult American Anaerobic Bacteria Bacteria Bacterial Adhesins Binding Butyrates Catabolism Cell Communication Cell Density Cells Centers for Disease Control and Prevention (U.S.)Colorectal Cancer Communicable Diseases Communities Complex Complication Data Dental Plaque Development Disease Environment Enzymes Exhibits Experimental Models Fusobacterium Fusobacterium nucleatum Gene Deletion Gene Expression Genes Genetic Genetic Transcription Genome Goals Health In Vitro Investigation Libraries Link Lysine Mediating Microbial Biofilms Mouth Diseases Mutate Names Odontogenesis Operon Oral Oral Microbiology Organism Pathogenicity Pathway interactions Periodontal Diseases Periodontitis Porphyromonas gingivalis Premature Birth Process Proliferating RNA Regulation Research Role Signal Pathway Signal Transduction Streptococcus Structure Surface System Testing Therapeutic Time Untranslated RNA VAI-2 Work base design driving force fitness insight microbial microbial community microbiome microorganism mutant novel novel therapeutic intervention oral bacteria oral biofilm oral microbial community oral pathogen pathogen polymicrobial biofilm prevent promoter public health relevance receptor response screening social transcription factor

项目摘要

PROJECT SUMMARY Dental plaque and associated periodontal diseases represent a common infectious disease afflicting nearly half of American adults (CDC). The complex intra- and interspecies interactions regulate the development of multispecies oral microbial communities called dental plaque. The dental plaque is made of an organized, highly complex microbial social community and the Gram-negative anaerobe F.nucleatum is a key organism of this microbiome by virtue of its unique capability to physically aggregate with many early and late colonizers. Besides its role in periodontitis, F. nucleatum has been linked to several extra-oral diseases including preterm birth and colorectal cancer. Although the fusobacterial interactions with other bacteria have been widely studied and four coaggregation adhesins identified, little is known about mechanisms that regulate Fusobacterium-mediated coaggregation, mainly due to the lack of a robust genetic toolkit for manipulation of F. nucleatum. To overcome this, we recently developed a convenient gene deletion system for F. nucleatum and generated a large library of random transposon mutants with ~10-fold genome coverage. Screening of this library uncovered several coaggregation factors, which include a unique two-component system termed CarS- CarR and a nine-gene-operon that encodes a lysine-degrading pathway (LDP) that controls the amount and activity of RadD, respectively. RadD, a type IV autotransporter, is a versatile adhesin that mediates fusobacterial adhesion with many early and some late colonizers. Based on these findings, we plan to characterize the two regulatory factors in-depth. We will be the first time to show an oral bacterial two component signaling component regulates expression of cell-cell adhesin in a cell density-dependent manner and characterize a lysine riboswitch related to lysine catabolism in bacteria. Upon the successful completion of this research, we expect to have significantly contributed to the understanding of how the versatile adhesin RadD is regulated by identifying and deciphering factors and mechanism involved. Because RadD requires F. nucleatum to incorporate into an established community made of initial commensal colonizers, such as streptococci and actinomyces, our discoveries will have a significant impact on the understanding of fusobacterium-mediated coaggregation role in development of dental plaque, will provide new insights into the development of potent therapeutic strategies against this important pathogen.

项目概要牙菌斑和相关的牙周病是一种常见的传染病，几乎困扰着人们。一半的美国成年人（CDC）。复杂的种内和种间相互作用调节着多物种口腔微生物群落称为牙菌斑。牙菌斑是由有组织的、高度复杂的微生物社会群落，革兰氏阴性厌氧菌 F.nucleatum 是微生物的关键生物体这种微生物组凭借其独特的能力与许多早期和晚期殖民者进行物理聚集。除了在牙周炎中的作用外，具核梭菌还与包括早产在内的多种口腔外疾病有关出生和结直肠癌。尽管梭杆菌与其他细菌的相互作用已被广泛研究研究并确定了四种共聚集粘附素，但人们对调节机制知之甚少梭杆菌介导的共聚集，主要是由于缺乏用于操纵梭杆菌的强大遗传工具包。有核细胞。为了克服这个问题，我们最近开发了一种方便的 F. nucleatum 基因删除系统，生成了一个大型随机转座子突变体库，基因组覆盖率约为 10 倍。对此进行筛选图书馆发现了几个共聚集因素，其中包括一个独特的两组分系统，称为 CarS- CarR 和一个编码赖氨酸降解途径 (LDP) 的九基因操纵子，该途径控制赖氨酸的量和 RadD 的活性，分别。 RadD 是一种 IV 型自转运蛋白，是一种多功能粘附素，可介导梭杆菌与许多早期和一些晚期定殖者粘附。根据这些发现，我们计划深入描述这两个监管因素。我们将首次展示口腔细菌二信号成分以细胞密度依赖性方式调节细胞间粘附素的表达并表征了与细菌中赖氨酸分解代谢相关的赖氨酸核糖开关。成功完成后这项研究，我们希望对了解多功能粘附素如何发挥重要作用 RadD 通过识别和破译所涉及的因素和机制来调节。因为RadD需要F。 nucleatum 融入由最初的共生殖民者组成的已建立的社区，例如链球菌和放线菌，我们的发现将对理解它们产生重大影响梭杆菌介导的共聚集在牙菌斑形成中的作用将为研究提供新的见解开发针对这种重要病原体的有效治疗策略。