Impact of Binary Toxin on Recurrent Clostridium difficile Infection

二元毒素对复发性艰难梭菌感染的影响

基本信息

  • 批准号:
    9045377
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-04-01 至 2019-03-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Clostridium difficile infection (CDI) has been an increasingly common and complicated treatment issue for veteran and non-veteran patients over the past decade. One of the most difficult management issues is that of recurrent CDI. ~20% of patients who are successfully treated with either metronidazole or vancomycin will have a recurrent episode. Those who have already had a recurrent episode have ~50% chance of third diarrheal episode and some patients will have recurrent CDI for months or years. In addition, recurrent CDI has had a major impact on healthcare facilities because of frequent readmission rates to acute care facilities. Several host factors have been implicated as risks for recurrent CDI. However, there has been relatively little attention paid to pathogen or bacterial factors that might influence the risk of recurrence. The increase in rates of CDI and complications such as recurrent CDI over the past decade has coincided with the emergence of the epidemic C. difficile BI/027/NAP1 strain. Several potential virulence factors expressed by this strain have been proposed, but recent evidence suggests that binary toxin (CDT) produced by this strain and other clinically important (e.g., BK/078/NAP7) strains may play a critical adjunctive role in CDI pathogenesis. C. difficile binary toxin (CDT) is unrelated to the large, single unit glycosylating toxins, toxin A and B. This 2-component (binary) toxin acts by ADP-ribosylation of the cytoskeletal protein, actin, resulting in microtubular structural changes and epithelial cell membrane protrusions which increase adherence and colonization of C. difficile. Our research aims are designed to test the hypothesis that binary toxin increases the risk of recurrent CDI by two experimental lines of investigation. First, we will use the hamster model of CDI to demonstrate the effect of binary toxin by using isogenic mutants of C. difficile in which the binary gene toxin is knocked out. Second, we will use a newly developed immunoassay for binary toxin to test patient stool specimens and correlate the presence of fecal binary toxin with clinical recurrence of CDI. The specific aims of this proposal include: 1. Establish a reproducible hamster model of CDI recurrence. Aim 1a) Construct binary toxin mutants in the epidemic-associated BI and BK strains (CDTneg) for the baseline experiments in the hamster model Aim 1b) Establish a reproducible recurrence rate in the hamster model using binary toxin mutants (CDTneg) & confirm increased recurrence rates using respective parent (CDTpos) strains 2. Determine the mechanism of increased CDI recurrence due to binary toxin Aim 2a) Determine the mechanism in vitro using a human intestinal epithelial cell line Aim 2b) Determine the mechanism in vivo in hamsters 3. Correlate the expression of binary toxin in patients with CDI recurrence Aim 3a) Correlate fecal binary toxin detection with CDI recurrence Aim 3b) Correlate the presence of binary toxin-positive C. difficile strains with CDI recurrence
 描述(由申请人提供): 在过去的十年里,艰难梭菌感染(CDI)对于退伍军人和非退伍军人来说已经成为一个越来越常见和复杂的治疗问题。最困难的管理问题之一是经常性的CDI。在甲硝唑或万古霉素治疗成功的患者中,约有20%会出现复发。那些已经复发的患者有大约50%的机会发生第三次腹泻发作,一些患者将反复发生CDI数月或数年。此外,经常性的CDI对医疗机构产生了重大影响,因为急性护理机构的再住院率很高。一些宿主因素被认为是CDI复发的危险因素。然而,对可能影响复发风险的病原体或细菌因素的关注相对较少。在过去十年中,CDI发生率和并发症(如复发性CDI)的增加与艰难梭菌BI/027/NAP1菌株的流行同时出现。目前已经提出了该菌株表达的几种潜在毒力因子,但最近的证据表明,该菌株和其他临床上重要的菌株(如BK/078/NAP7)产生的二元毒素(CDT)可能在CDI的发病中起着关键的辅助作用。艰难梭菌二元毒素(CDT)与大的单一单位糖基化毒素A和B无关,这种两组分(二元)毒素通过细胞骨架蛋白肌动蛋白的ADP核糖基化作用,导致微管结构的改变和上皮细胞膜的突出,从而增加艰难梭菌的黏附和定植。我们的研究目的是通过两个实验研究路线来检验二元毒素增加CDI复发风险的假设。首先,我们将使用CDI的仓鼠模型,通过使用艰难梭菌的同基因突变株来演示二元毒素的作用,在该突变株中,二元基因毒素被敲除。其次,我们将使用一种新开发的二元毒素免疫分析方法来检测患者粪便样本,并将粪便二元毒素的存在与CDI的临床复发联系起来。本方案的具体目的包括:1.建立可复制的CDI复发仓鼠模型。目的1a)在BI和BK流行相关株中构建二元毒素突变体(CDTneg),用于仓鼠模型的基线实验目的1b)使用二元毒素突变体(CDTneg)在仓鼠模型中建立可重复性的复发率,并使用各自的亲本菌株(CDTpos)确认增加的复发率2.确定二元毒素增加CDI复发的机制目的2a)利用人肠上皮细胞系体外确定机制目的2b)确定仓鼠体内的机制3)CDI复发患者的二元毒素表达与CDI相关复发目标3b)二元毒素阳性艰难梭菌菌株的存在与CDI复发相关

项目成果

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Stuart Brian Johnson其他文献

Stuart Brian Johnson的其他文献

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{{ truncateString('Stuart Brian Johnson', 18)}}的其他基金

Impact of Binary Toxin on Recurrent Clostridium difficile Infection
二元毒素对复发性艰难梭菌感染的影响
  • 批准号:
    9339553
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Clinical Significance of Clostridium difficile Toxin Variants
艰难梭菌毒素变异体的临床意义
  • 批准号:
    8262607
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Clinical Significance of Clostridium difficile Toxin Variants
艰难梭菌毒素变异体的临床意义
  • 批准号:
    8195597
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Clinical Significance of Clostridium difficile Toxin Variants
艰难梭菌毒素变异体的临床意义
  • 批准号:
    7686663
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Clinical Significance of Clostridium difficile Toxin Variants
艰难梭菌毒素变异体的临床意义
  • 批准号:
    7783810
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:

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