The Genomics and Antagonism of Pathobiont Colonization

致病生物定植的基因组学和拮抗作用

• 批准号: 10160780
• 负责人: ANTHONY W MARESSO
• 金额: $ 73.67万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160780
• 关键词: Address; Adherence; Adhesives; Alleles; Antibiotic Resistance; Apical; Back; Bacteria; Bacterial Adhesins; Bacterial Proteins; Biological Models; Biopsy; Blood; Clinical; Communicable Diseases; Communities; Complement; Digestion; Drug resistance; Ecosystem; Elements; Enteral; Enterobacteriaceae; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Epidemiology; Epithelial; Escherichia coli; Event; Family; Gastrointestinal tract structure; Gene Expression Profile; Gene Proteins; Genes; Genomics; Health; Human; Immune response; Infection; Intestinal Mucosa; Intestines; Klebsiella pneumoniae; Knowledge; Laboratories; Large Intestine; Lead; Libraries; Maps; Medical center; Medicine; Microbe; Modeling; Molecular; Movement; Mucous Membrane; Multi-Drug Resistance; Nosocomial Infections; Nutrient; Organ; Organism; Pathogenesis; Pathogenicity; Phase; Population; Predisposition; Property; Research Personnel; Rest; Role; Sampling; Sepsis; Shapes; Small Intestines; Source; Superbug; Surface; Therapeutic; Tissue Engineering; Vaccines; Virulence Factors; Virulent; college; colonization resistance; commensal bacteria; drug development; drug resistant bacteria; experimental study; fitness; genetic approach; genetic element; genetic variant; gut microbiota; host microbiome; immune function; member; microbiota; mucosal vaccine; new therapeutic target; novel; pandemic disease; pathobiont; pathogen; pathogenic bacteria; prevent; reference genome; response; reverse genetics; tool; transcriptome; transmission process; user-friendly

Project Summary The human intestine is an ecosystem of microbes. This ecosystem helps shape immune function, provides scarce nutrients, aids in digestion, and when balanced, maintains health. Amongst the many bacteria that colonize this organ, some harbor virulence factors and carry drug-resistance, the so-called pathobionts, which may be asymptomatic members of the intestinal microbiota. Under certain conditions, mostly related to a loss of immune function, these organisms can cause systemic bloodstream infections that can lead to sepsis or sepsis-like states. As such, they are leading causes of community and nosocomial infections. The most prominent of these are members of the superfamily of Enterobacteriaceae and Enterococcaceae. The most concerning pathobiont members of the Enterobacteriaceae are the Gram-negatives Eschericia coli and Klebsiella pneumoniae, while those of the Enterococcaceae include the Gram- positive Enterococcus faecalis and Enterocccus faecium. There are no vaccines for these species. The focus of this project is to generate the world's first fully annotated and searchable reference library of pathogenic and drug-resistant pathobionts that colonize the human intestine. This library will then be the source of intra-species competition in organotypic models of the human intestine to select for the most fit binders and colonizers of the apical mucosa. These strains then be assessed for their ability to breach the mucosa (translocation), induce global gene expression across a hundred different human lines, and be out-competed or antagonized by members of a small and large intestine commensal community. At the completion of the project, there will be numerous bacterial, host, and commensal targets for new drug development.

项目摘要 人体肠道是微生物的生态系统。这个生态系统有助于塑造免疫 功能，提供稀缺的营养素，帮助消化，当平衡时，保持 健康在许多细菌中，殖民这个器官，一些港口毒性 因子并携带耐药性，即所谓的致病菌， 肠道微生物群的无症状成员。在某些情况下，大多数 与免疫功能的丧失有关，这些生物体可引起全身血流 可能导致败血症或败血症样状态的感染。因此，它们是导致 社区和医院感染。其中最突出的是 肠杆菌科和肠球菌科的总科。最令人担忧的 肠杆菌科的致病菌成员是革兰氏阴性的大肠杆菌 和肺炎克雷伯氏菌（Klebsiella pneumoniae），而肠球菌科的那些包括革兰氏 粪肠球菌和屎肠球菌阳性。目前还没有疫苗 这些物种。 该项目的重点是生成世界上第一个完全注释和 一个可搜索的致病性和耐药性致病生物参考库， 人体肠道这个库将成为物种内竞争的来源， 人体肠道的器官型模型，以选择最合适的粘合剂， 顶端粘膜的定居者。然后评估这些菌株的能力 破坏粘膜（易位），诱导全球基因表达，跨越100个 不同的人类线路，并被一个小的， 大肠粘膜群落在项目完成后，将有 许多细菌、宿主和寄生虫靶标用于新药开发。