The interactions between Clostridium difficile, intestinal microbiota and the host response in hospitalised patients

住院患者中艰难梭菌、肠道微生物群和宿主反应之间的相互作用

• 批准号: MR/K000551/1
• 负责人: Brendan Wren
• 金额: $ 308.34万
• 依托单位: London School of Hygiene & Tropical Medicine
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK000551%2F1
• 关键词: interactions; between; Clostridium; difficile; intestinal

Clostridium difficile is a bacterium that causes chronic diarrhoea and sometimes life-threatening disease (referred to as C. difficile infection or CDI) mainly in elderly and hospitalized patients. C. difficile is now the most significant hospital acquired infection with over 34,000 UK cases last year and an estimated cost to be £500 million per annum. The reported incidence of CDI has risen dramatically over the last decade and is related to the emergence of aggressive strains. Given the ability of C. difficile to evolve to be highly virulent coupled with the ageing population and increasing rates of hospitalization, the problem of CDI is likely to continue. It is a current NHS imperative to reduce the burden of CDI. CDI is unique among infections in that in almost all cases, disease follows the administration of antibiotics that disrupt the "normal" bacteria (called microbiota) present in the gut. It provides C. difficile the opportunity to overgrow, produce toxins and cause disease. It has become apparent that the balance of the microbiota plays a key role in disease. One of the most perplexing questions concerning CDI is the diversity of clinical symptoms. For example, C. difficile colonization can result in a spectrum of clinical outcomes ranging from asymptomatic carriage to death. The relative virulence of C. difficile organism clearly plays a role in determining clinical outcome, but the nature of this role has not been identified. Up to 30% of patients treated successfully for symptomatic CDI succumb to recurrent disease, but it is unclear why only some patients relapse. In addition to the pathogen, the host immune response and/or host microbiota are also likely important determinants of clinical outcome, but remain largely unexplored. Our central hypothesis is that variations in C. difficile genetics, the composition of the resident intestinal microbiota and the host immune response to the bacterium shape the clinical outcome. We will investigate the three-way interaction between pathogen, host and microbiota by monitoring a unique group of patients with and without CDI. C. difficile serum and faecal samples will be studied in unprecedented detail to provide a platform for follow up studies to understand how C. difficile causes disease. We have established a high quality prospectively collected bioarchive comprising bacterial, blood and serum samples from 300 patients with CDI and full clinical history. These samples are linked to detailed clinical data and a disease severity-scoring index along with 150 control samples from hospitalised patients who have been exposed to antibiotics but did not develop CDI. We will use the existing cohort to validate methodologies and then also recruit another cohort of 150 confirmed CDI cases, 100 diarrhoea controls and 100 healthy volunteers (e.g. patient's spouses) to confirm our findings. This unique resource will be used to monitor the host response (including how the immune system responds to the infection), determine the complete genome sequence of infecting C. difficile and identify the intestinal microbiota by sequencing and culturing. The studies will also allow us to distinguish between re-infection (infection caused by another strain) and relapse (re-infection caused by the same strain). Robust statistical analysis comparing disease severity, host response, infecting pathogen and the composition of intestinal microbiota will facilitate subsequent studies on C. difficile to determine how and why it causes disease. This will be achieved by selecting C. difficile genes and constructing defined mutants and studying these alongside the parent strain in a range of assays established in the applicants' laboratories.A comprehensive understanding of C. difficile, the host response and the intestinal microbiota will strengthen our understanding of the microorganism and to develop novel strategies to reduce the burden of CDI.

艰难梭菌是一种主要在老年人和住院患者中引起慢性腹泻和有时危及生命的疾病（称为艰难梭菌感染或CDI）的细菌。艰难梭菌现在是最重要的医院获得性感染，去年英国有超过34,000例病例，估计每年的成本为5亿英镑。据报道，CDI的发病率在过去十年中急剧上升，这与侵袭性菌株的出现有关。鉴于艰难梭菌进化为高毒力的能力，再加上人口老龄化和住院率的上升，CDI的问题可能会继续存在。减轻CDI负担是当前NHS的当务之急。CDI在感染中是独特的，因为在几乎所有情况下，疾病都是在使用抗生素破坏肠道中存在的“正常”细菌（称为微生物群）之后发生的。它为艰难梭菌提供了过度生长、产生毒素和致病的机会。很明显，微生物群的平衡在疾病中起着关键作用。关于CDI最令人困惑的问题之一是临床症状的多样性。例如，艰难梭菌定植可导致一系列临床结果，从无症状携带到死亡。艰难梭菌的相对毒力显然在决定临床结果中起作用，但这种作用的性质尚未确定。在成功治疗症状性CDI的患者中，高达30%的患者会复发，但目前尚不清楚为什么只有一些患者复发。除了病原体外，宿主免疫反应和/或宿主微生物群也可能是临床结果的重要决定因素，但在很大程度上仍未被探索。我们的中心假设是艰难梭菌遗传学的变化，常驻肠道微生物群的组成和宿主对细菌的免疫反应塑造了临床结果。我们将通过监测一组独特的CDI患者和非CDI患者来研究病原体、宿主和微生物群之间的三方相互作用。艰难梭菌血清和粪便样本将以前所未有的细节进行研究，为后续研究提供平台，以了解艰难梭菌如何引起疾病。我们建立了一个高质量的前瞻性生物档案，包括300例CDI患者的细菌、血液和血清样本和完整的临床病史。这些样本与详细的临床数据和疾病严重程度评分指数以及150个来自暴露于抗生素但未发生CDI的住院患者的对照样本相关联。我们将使用现有队列来验证方法，然后还将招募另一个队列，其中包括150例确诊的CDI病例、100例腹泻对照和100名健康志愿者（例如患者配偶），以确认我们的发现。这种独特的资源将用于监测宿主反应（包括免疫系统对感染的反应），确定感染艰难梭菌的完整基因组序列，并通过测序和培养鉴定肠道微生物群。这些研究还将使我们能够区分再感染（由另一种菌株引起的感染）和复发（由同一菌株引起的再感染）。比较疾病严重程度、宿主反应、感染病原体和肠道微生物群组成的稳健统计分析将有助于对艰难梭菌的后续研究，以确定它如何以及为什么引起疾病。这将通过选择艰难梭菌基因，构建确定的突变体，并在申请人实验室建立的一系列检测中与亲本菌株一起研究这些突变体来实现。全面了解艰难梭菌、宿主反应和肠道菌群将加强我们对微生物的认识，并制定新的策略来减轻CDI的负担。

项目成果

Additional file 5: of Population-based analysis of ocular Chlamydia trachomatis in trachoma-endemic West African communities identifies genomic markers of disease severity

附加文件 5：对沙眼流行的西非社区眼部沙眼衣原体进行基于人群的分析，确定疾病严重程度的基因组标记

• DOI: 10.6084/m9.figshare.5927821
• 发表时间: 2018
• 作者: A. Last

Additional file 8: of Population-based analysis of ocular Chlamydia trachomatis in trachoma-endemic West African communities identifies genomic markers of disease severity

附加文件 8：对沙眼流行的西非社区眼部沙眼衣原体进行基于人群的分析，确定了疾病严重程度的基因组标记

• DOI: 10.6084/m9.figshare.5927857
• 发表时间: 2018
• 作者: A. Last

Additional file 11: of Population-based analysis of ocular Chlamydia trachomatis in trachoma-endemic West African communities identifies genomic markers of disease severity

附加文件 11：对沙眼流行的西非社区眼部沙眼衣原体进行基于人群的分析，确定了疾病严重程度的基因组标记

• DOI: 10.6084/m9.figshare.5927731
• 发表时间: 2018
• 作者: A. Last

Additional file 9: of Population-based analysis of ocular Chlamydia trachomatis in trachoma-endemic West African communities identifies genomic markers of disease severity

附加文件 9：对沙眼流行的西非社区眼部沙眼衣原体进行基于人群的分析，确定了疾病严重程度的基因组标记

• DOI: 10.6084/m9.figshare.5927866
• 发表时间: 2018
• 作者: A. Last

Additional file 4: of Population-based analysis of ocular Chlamydia trachomatis in trachoma-endemic West African communities identifies genomic markers of disease severity

附加文件 4：对沙眼流行的西非社区眼部沙眼衣原体进行基于人群的分析，确定了疾病严重程度的基因组标记

• DOI: 10.6084/m9.figshare.5927803
• 发表时间: 2018
• 作者: A. Last