Microbial Ecology and Molecular Pathogenesis of Clostridium difficile

艰难梭菌的微生物生态学和分子发病机制

• 批准号: 8026743
• 负责人: VINCENT B YOUNG
• 金额: $ 41.28万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-02 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8026743
• 关键词: Address; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Area; Arts; Bacillus (bacterium); Bacteria; Biological Models; Biology; Characteristics; Clinical; Clostridium; Clostridium difficile; Colitis; Communities; Data; Diarrhea; Disease; Ecology; Elements; Enrollment; Environment; Experimental Designs; Gastrointestinal tract structure; Germination; Gnotobiotic; Goals; Human; Immune response; In Vitro; Indigenous; Individual; Infection; Kinetics; Lead; Mediating; Modeling; Molecular; Mus; Nosocomial Infections; Organism; Outcome; Pathogenesis; Patients; Predisposition; Process; Recurrence; Relapse; Reproduction spores; Research; Research Personnel; Resistance; Role; Severities; Specimen; Structure; Testing; Therapeutic; Toxin; United States; Variant; Work; base; contagion; cost; disease transmission; gastrointestinal; gut microbiota; insight; microbial; multidisciplinary; mutant; novel; novel therapeutic intervention; pathogen; prevent; research study; resistance mechanism; transmission process

The toxin producing bacterium Clostridium difficile causes an estimated 1,000,000 to 3,000,000 cases of diarrhea and colitis in the United States each year at an annual cost of $1.1 Billion dollars for nosocomial infections alone. Most cases are associated with the administration of broad-spectrum antibiotics. It has been assumed that the administration of antibiotics causes changes in the normal gastrointestinal microbiota. These changes allow overgrowth of C. difficile, which has either been present in low numbers in the gastrointestinal tract before the administration of antibiotics, or is acquired from the environment during antibiotic administration. Furthermore, it is likely that C. difficile spores and not the vegetative bacilli are the direct contagion analogous to other pathogenic Clostridia sp. Spores are hardy, not easily cleared from the body by natural means and are resistant to antibiotics. We theorize that the normal gastrointestinal microbiota interferes with gut colonization by C. difficile and may also regulate expression of toxin by the organism. Additionally, we hypothesize that the spore morphotype itself contributes heavily to not only the initial introduction of C. difficile to the host, but also to recurrent relapse and shedding/transmission. To address these hypotheses, three specific aims are proposed for this project. In the first aim, we will compare the fecal microbiota in asymptomatically colonized individuals and patients with initial or recurrent C. difficile infection of varied severity. We will determine if specific community structures correlate with susceptibility to disease and with clinical outcomes/severity. The second aim will extend these observations in a murine model of C. difficile infection to define the microbiologic factors that contribute to colonization resistance against C. difficile. In the third aim the contribution of germination and sporulation to clinical disease and transmission will be determined. We will characterize clinical C. difficile isolates for sporulation/germination attributes and test naturally occurring variants and defined mutants in the murine C. difficile model. These aims will provide important insight in the roles of microbial ecology and molecular bacterial pathogenesis in C. difficile infection.

产毒素细菌艰难梭菌每年在美国引起估计1，000，000至3，000，000例腹泻和结肠炎，仅医院感染每年花费11亿美元。大多数病例与使用广谱抗生素有关。据推测，抗生素的施用会导致正常胃肠道微生物群的变化。这些变化使得C.艰难梭菌，其在施用抗生素之前以低数量存在于胃肠道中，或者在抗生素施用期间从环境中获得。此外，C.艰难梭菌孢子而不是营养体杆菌是类似于其他致病性梭菌属的直接传染物。孢子是哈代的，不容易通过自然方式从体内清除，并且对抗生素具有抗性。 我们的理论是正常的胃肠道微生物群干扰了C.艰难 并且还可以调节生物体的毒素表达。此外，我们假设孢子形态型本身不仅对最初引入C。难以感染宿主，而且还导致复发和脱落/传播。为了解决这些假设，本项目提出了三个具体目标。在第一个目标中，我们将比较无症状定植个体和初始或复发的C。不同严重程度的艰难感染。我们将确定特定的社区结构是否与疾病易感性和临床结果/严重程度相关。第二个目标是在C.艰难梭菌感染，以确定有助于对C.很难在第三个目标中，将确定萌发和孢子形成对临床疾病和传播的贡献。我们将描述临床C。艰难梭菌分离株的孢子形成/萌发属性，并测试鼠C. difficile模型这些目标将为C.中微生物生态学和分子细菌发病机制的作用提供重要见解。艰难感染