Regulation in Fusobacterium-mediated coaggregation

梭杆菌介导的共聚集的调节

• 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
• 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

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.

项目摘要 牙菌斑和相关的牙周疾病代表着一种常见的传染病，几乎遭受了 一半的美国成年人（CDC）。复杂的种内和间隔相互作用调节 多种族的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和革兰氏阴性anaerobe F.Nucleatum是 该微生物组凭借其独特的能力与许多早期和晚期殖民者物理汇总。 除了在牙周炎中作用外，F。nutleatum还与包括早产在内的几种口腔外疾病有关 出生和结直肠癌。尽管梭菌与其他细菌的相互作用已广泛 研究和四个识别的凝聚蛋白，对调节的机制知之甚少 梭菌介导的凝聚，主要是由于缺乏可操纵F的稳健遗传工具包。 核。为了克服这一点，我们最近开发了一种用于F. nucleatum和 产生了一个大的随机转座子突变体的文库，具有约10倍的基因组覆盖率。筛选 图书馆发现了几个凝聚因子，其中包括一个独特的两组分系统称为汽车 - CARR和一个编码赖氨酸降解途径（LDP）的Carr和一个九个operon，该途径控制量和 RADD的活性。 RADD是IV型自动转运蛋白，是一种多功能粘合剂，可介导 许多早期和一些晚期殖民者的锻造粘合剂。根据这些发现，我们计划 深入表征两个调节因素。我们将是第一次展示两个口腔细菌 组件信号传导成分以细胞密度依赖性方式调节细胞细胞粘附素的表达 并表征与细菌中赖氨酸分解代谢有关的赖氨酸核糖开关。成功完成后 这项研究，我们期望对多功能粘合剂的理解做出重大贡献 RADD通过识别和解密因素和涉及的机制来调节。因为Radd需要F。 将核纳入由初始共生殖民者制成的既定社区，例如 链球菌和放线菌，我们的发现将对对理解的理解产生重大影响 梭菌介导的凝聚作用在牙菌斑的发展中，将为您提供新的见解 开发针对这种重要病原体的有效治疗策略。