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Virulence determinants of Fusobacterium nucleatum

具核梭杆菌的毒力决定因素

基本信息

批准号：
9982064
负责人：
Hung Ton-That
金额：
$ 44.39万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982064
关键词：
Adherence Affect Anaerobic Bacteria Anti-Infective Agents Antibiotic Resistance Attenuated Bacteria Biochemical Biogenesis Biological Process Cell Communication Cell Proliferation Cell physiology Cells Code Colorectal Cancer Complex Cryo-electron tomography Defect Dental Plaque Development Electron Microscopy Endothelial Cells Epithelial Cells Functional disorder Fusobacterium nucleatum Future Gene Deletion Generations Genes Genetic Genome Gingiva Goals Growth Halitosis Hydrogen Peroxide Hydrogen Sulfide Immune Immune response Immunomodulators Impairment Individual Infection Inflammasome Inflammation Inflammatory Inflammatory Response Investigation Knowledge Laboratories Libraries Link Mass Spectrum Analysis Mediating Membrane Methods Microbial Biofilms Microbiology Molecular Mutagenesis Names Odontogenesis Open Reading Frames Oxidative Stress Pathogenesis Pathogenicity Pathway interactions Periodontitis Porphyromonas gingivalis Premature Birth Production Proteins Reporting Rodent Model Role Saliva Science Signal Transduction Streptococcus mutans System Technology Time Tube Virulence Virulence Factors adverse pregnancy outcome antimicrobial cell growth regulation colon carcinogenesis cytokine disorder prevention fitness forward genetics human disease in vivo methionine sulfoxide reductase mouse model mutant novel oral biofilm oral infection oral pathogen oxidative damage pathogen public health relevance repaired response reverse genetics therapeutic development tool

项目摘要

PROJECT SUMMARY The Gram-negative anaerobe Fusobacterium nucleatum is a key colonizer in the development of oral biofilms, or dental plaque, and also known for its association with human diseases including oral infections, adverse pregnancy outcomes, and colorectal cancer. F. nucleatum has an inherent ability to interact or aggregate with many early and late colonizers of the oral biofilms. It induces inflammatory responses and preterm birth in rodent models of infection, as well as promoting colorectal carcinogenesis in vivo. Despite its pathogenic potential, we have limited knowledge about the mechanisms of fusobacterial virulence and associated factors; to date only six fusobacterial factors have been reported, i.e. FomA, FadA, Fap2, RadD, aid1, and FAD-I, although more than 2,000 open reading frames are annotated in the genome of many F. nucleatum strains. A major obstacle limiting progress is the lack of robust genetic tools and systematic investigations. We have begun to tackle this problem, successfully developing a facile gene deletion system for F. nucleatum, and generating a large library of random transposon mutants with 10-fold genome coverage. With these previously unavailable tools, we aim to identify virulence determinants of F. nucleatum using multiple complementary approaches including forward and reverse genetics, cryo-electron tomography, biochemical methods, and rodent models of infection. By electron microscopy, we discovered that F. nucleatum produces outer membrane tubules (OMTs) and identified a key factor required for OMT formation. By gene deletion, we found pathways that mediate oxidative stress defense and host cell adherence and invasion. By transposon mutagenesis, we revealed several biofilm-associated factors that are required for production of hydrogen sulfide, which largely contributes to bad breath, or halitosis. In this application, we aim to elucidate the mechanism of OMT biogenesis and OMT-mediated pathogenesis, reveal the mechanisms of host immune defense and host cell interactions, and establish the role of biofilm- associated factors in halitosis, polymicrobial interactions, and bacterial virulence. Our studies will greatly contribute to our understanding of the molecular virulence mechanisms of this pathogen and significantly move the field forward with the application of newly developed genetic tools and advanced technology. The results generated from these studies may also provide promising targets for the future development of therapeutic strategies.

项目总结