DETERMINANTS OF ALPHA DEFENSIN RESISTANCE IN THE INTESTINAL MICROBIOTA

肠道微生物群中α防御素抵抗的决定因素

• 批准号: 8484747
• 负责人: Christine Tzy-Yuh Luo
• 金额: $ 2.85万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484747
• 关键词: Adult; Aerobic Bacteria; Affect; Anaerobic Bacteria; Antimicrobial Effect; Bacteria; Bacteroidaceae; Bacteroides; Bacteroides thetaiotaomicron; Biochemical; Biological Assay; Biological Models; California; Candidate Disease Gene; Cell physiology; Cloning; Defensins; Disease; Disease Resistance; Ecology; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Evaluation; Family; Family member; Gastrointestinal tract structure; Genes; Genetic; Genomics; Goals; HDAC5 gene; Homeostasis; Human; In Vitro; Indigenous; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestinal Diseases; Intestines; Laboratories; Libraries; Link; Martens; Maryland; Metagenomics; Michigan; Microbe; Modeling; Mus; Paneth Cells; Pathogenesis; Peptides; Phenotype; Pilot Projects; Play; Population; Process; Production; Property; Reagent; Reporting; Resistance; Role; Sampling; Sequence Analysis; Shapes; Small Intestines; Stem cells; Testing; United States; Universities; Washington; Work; alpha-Defensins; antimicrobial; antimicrobial peptide; candidate identification; cell type; commensal microbes; cryptdin; disease phenotype; experience; in vivo; insight; killings; member; microbial; microbial community; microbicide; mutant; novel; pathogen; resistance mechanism; screening

DESCRIPTION (provided by applicant): Homeostasis in the gastrointestinal tract is characterized by a balanced relationship between the host and indigenous microbes, collectively referred to as the microbiota. Paneth cells are an intestinal epithelial cell type tha plays a significant role in shaping the microbiota by secreting antimicrobial peptides, including alpha- defensins. Alpha-defensins have been shown to have a significant role in determining the composition of the intestinal microbiota. Therefore, I hypothesize that the intestinal microbial ecology is, in part, defined by alpha- defensin resistance. Analyses from fecal metagenomic library screening with intestinal alpha-defensins are proposed to identify novel genes conferring resistance mechanisms. In an initial pilot analysis, candidate resistance genes in Faecalibacterium prausnitzii have been identified. These studies aim to provide an explanation for why certain microbes are enriched or present in the intestinal tract. Bacteria in the Bacteroidaceae family are present in the intestinal tract, and select members are suggested to be resistant to intestinal alpha-defensins. However, the candidate genes for resistance mechanisms have not been defined. My laboratory has established that members in the Bacteroidaceae family induce disease in a murine model system of inflammatory bowel disease (IBD). Using this model, I can functionally test the relevance of alpha-defensin resistance to disease. Moreover, my laboratory has a panel of Bacteroidaceae isolates and a mutant that induce different levels of disease in this model system. I will compare these isolates to determine whether Bacteroidaceae have specific mechanisms for alpha-defensin resistance and whether defensin resistance can define the disease-inducing potential of a microbe. Results from this study may have implications for human IBD, which is estimated to affect about a million people in the United States. Microbial contributions to IBD pathogenesis are recognized. Thus, understanding alpha-defensin resistance in the intestinal microbiota during homeostasis and a possible link between defensin resistance and disease-inducing potential, may aid in the identification of candidate opportunistic pathogens for IBD and other intestinal diseases.

描述（由申请人提供）：胃肠道内稳态的特征是宿主和本土微生物（统称为微生物群）之间的平衡关系。潘氏细胞是一种肠上皮细胞类型，通过分泌抗菌肽（包括α-防御素）在塑造微生物群中发挥重要作用。 α-防御素已被证明在确定肠道微生物群的组成方面具有重要作用。因此，我假设肠道微生物生态部分是由α-防御素耐药性决定的。建议通过肠道α-防御素筛选粪便宏基因组文库进行分析，以确定赋予抵抗机制的新基因。在初步初步分析中，已鉴定出普拉梭菌中的候选抗性基因。这些研究旨在解释为什么某些微生物在肠道中富集或存在。 拟杆菌科细菌存在于肠道中，并且某些成员被认为对肠道α-防御素具有抗性。然而，耐药机制的候选基因尚未确定。我的实验室已确定拟杆菌科成员会在炎症性肠病 (IBD) 小鼠模型系统中诱发疾病。使用这个模型，我可以在功能上测试α-防御素抵抗力与疾病的相关性。此外，我的实验室有一组拟杆菌科分离株和一个突变体，可在该模型系统中诱导不同程度的疾病。我将比较这些分离株，以确定拟杆菌科是否具有特定的α-防御素抗性机制，以及防御素抗性是否可以定义微生物的致病潜力。 这项研究的结果可能对人类炎症性肠病有影响，据估计，炎症性肠病影响了美国约一百万人。微生物对 IBD 发病机制的贡献已得到认可。因此，了解稳态期间肠道微生物群中的α-防御素耐药性以及防御素耐药性与疾病诱发潜力之间可能存在的联系，可能有助于识别 IBD 和其他肠道疾病的候选机会性病原体。