Innate Immune Defense against Clostridium Difficile Infection

针对艰难梭菌感染的先天免疫防御

• 批准号: 8495909
• 负责人: Eric G. Pamer
• 金额: $ 34.86万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495909
• 关键词: Aerobic; Aftercare; Agonist; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Body Weight decreased; Bone Marrow; Cells; Cessation of life; Clindamycin; Clostridium difficile; Colitis; Complication; Cytokine Receptors; Defense Mechanisms; Dendritic Cells; Development; Diarrhea; Disease; Dose; Enteral; Environment; Epithelial Cells; Flagellin; Gastrointestinal tract structure; Germination; Goals; Gram-Positive Bacteria; Growth; Healthcare; Hospitals; Hydrocarbons; Immune; Immune system; Immunocompromised Host; Implant; Incidence; Infection; Inflammatory; Ingestion; Intestinal Diseases; Intestines; Laboratories; Lamina Propria; Ligands; Measures; Mediating; Metabolism; Microbe; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Nosocomial Infections; Pathogenesis; Pathology; Patients; Population; Predisposition; Prevention strategy; Recombinant DNA; Recurrence; Reporter; Reproduction spores; Resistance; Role; Route; Signal Transduction; TLR5 gene; TLR7 gene; Taxon; Time; Toxic Megacolon; United States; antimicrobial; antimicrobial peptide; bile salts; cancer therapy; commensal microbes; design; in vivo; insight; microbial; monocyte; mortality; novel; prevent; pyrosequencing; receptor; reconstitution; resiquimod

DESCRIPTION (provided by applicant): Clostridium difficile causes colitis following antibiotic-mediated perturbation of the intestinal microbiota. C. difficile causes over 500,000 infections per year, with an estimated 15,000 deaths annually in the United States. Ingestion of infectious spores from contaminated environments represents the major route by which this infection is acquired. Very little is known about interactions between C. difficile and the normal intestinal microbiota or with the host innate immune system. Our laboratory has investigated C. difficile infection in antibiotic treated mice and demonstrated that stimulating TLR-5 with bacterial flagellin or TLR7/8 with resiquimod markedly enhances resistance to C. difficile infection. We have also demonstrated that a single dose of clindamycin results in prolonged susceptibility to C. difficile infection. The goal of this project is to characterize innate immune defenses, includig those induced by the commensal microbial flora, in protection against C. difficile infection. The first aim is to characterize the mechanism by which stimulation of TLR5 by flagellin or TLR7/8 by resiquimod enhances resistance to C. difficile infection. We will investigate the role IL22, the arl hydrocarbon receptor and primary and secondary bile salts in TLR-mediated defense against C. difficile infection. The second aim is to determine whether intestinal dendritic cells or inflammatory monocytes contribute to resistance to C. difficile infection. We will use CCR2-reporter and CCR2-depletor mice that were generated in our laboratory to determine the impact of inflammatory monocytes on the pathogenesis of C. difficile colitis. The third aim is to determine the effect of different antibiotic treatments on the composition of the intestinal microbial flora. We will use the Roche 454 massively parallel pyrosequencing platform to determine microbial complexity in the GI tract, and to correlate changes in the flora with susceptibility to C. difficile infection. Mice will be reconstituted with fractionated intestinal microbiota and resistance to C. difficile infection will be measured. These studies will identify microbial populations that inhibit germination and/or vegetative growth of C. difficile. Our ultimate goal is to identify the in vivo mechanisms protecting the host from C. difficile infection and to discover practicable approaches, such as selective TLR or cytokine receptor stimulation or microbiota manipulation, to re-induce these mechanisms in vulnerable patients.

描述（由申请人提供）：艰难梭菌在抗生素介导的肠道微生物群紊乱后引起结肠炎。艰难梭菌每年造成50万例感染