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: 10396592
• 负责人: ANTHONY W MARESSO
• 金额: $ 55.71万
• 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/10396592
• 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; antagonist; 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 人类肠道是微生物的生态系统。该生态系统有助于塑造免疫力 功能，提供稀缺的营养，辅助消化，并在平衡时保持 健康。在殖民该器官的许多细菌中，有些携带毒力 因素并携带抗药性，即所谓的病原体，这可能是 肠菌群的无症状成员。在某些条件下，主要是 与免疫功能的丧失有关，这些生物会导致全身性血液 可能导致败血症或败血症状态的感染。因此，他们是主要原因 社区和医院感染。其中最突出的是 肠杆菌科和肠球科的超家族。最令人担忧的 肠杆菌科的病原体成员是革兰氏阴性菌 和克雷伯氏菌肺炎，而肠球菌的肺炎包括 粪肠球菌阳性和肠肠粪。没有疫苗 这些物种。 该项目的重点是生成世界上的第一个完全注释和 可搜索的病原和抗药性病原体参考文献库 人类肠道。然后，该图书馆将成为内部竞争的来源 人类肠道模型，以选择最合适的粘合剂和 顶端粘膜的殖民者。然后，对这些菌株的能力进行评估 违反粘膜（易位），诱导一百个全球基因表达 不同的人类线，并由小型和 大肠共生社区。项目完成时，将会有 许多新药开发的细菌，宿主和共生靶标。