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 人类的肠道是一个微生物生态系统。这个生态系统有助于形成免疫力 功能，提供稀缺的营养，帮助消化，当平衡时，维持 健康。在寄生在这个器官上的许多细菌中，有些细菌具有毒力。 因子和携带抗药性，即所谓的病原体，这可能是 肠道微生物区系中无症状的成员。在某些情况下，大多数情况下 与免疫功能的丧失有关，这些生物可以引起全身血液循环。 感染可导致败血症或脓毒症样状态。因此，它们是主要的原因 社区和医院感染的风险。其中最突出的是 肠杆菌科和肠球菌科的超家族。最令人担忧的 肠杆菌科病原菌为革兰氏阴性杆菌 和肺炎克雷伯氏菌，而肠球菌科包括革兰氏阴性杆菌。 粪肠球菌和粪肠球菌阳性。目前还没有疫苗可以预防 这些物种。 该项目的重点是生成世界上第一个完全注释和 可搜索的定植致病和耐药病原菌参考库 人类的肠道。这个文库将成为物种内竞争的来源 人体肠道的器官类型模型，以选择最合适的粘合剂和 根尖粘膜的殖民者。然后对这些菌株进行评估，以确定它们是否具有 突破粘膜(易位)，诱导100多个全球基因表达 不同的人类路线，并被竞争对手或敌手的小和 大肠共生群落。在该项目完成后，将有 新药开发的众多细菌、宿主和共生靶点。