Exploiting commensal-pathogen competition to treat mucosal infection

利用共生病原体竞争来治疗粘膜感染

• 批准号: MR/N00695X/1
• 负责人: Gad Frankel
• 金额: $ 31.64万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN00695X%2F1
• 关键词: Exploiting; commensal; pathogen; competition; treat

Recently, there has been a dramatic rise in the number of bacteria that cause disease acquiring resistance to antibiotics that are commonly used to treat them. These bacteria are known as antimicrobial resistant (AMR) and carry gene/s that mediate insensitivity to, degradation of, or expulsion of, these drugs. In the not too distant future, we are facing a situation where once trivial, easily treatable, infections could potentially prove fatal. Currently, E. coli, a bacterium that constitutes an important part of the normal gut flora, is one of the most frequently isolated AMR hospital acquired infections in Europe and the UK and is a major cause of blood poisoning, diarrhoea and recurrent urinary tract infections. Misuse and overuse of antibiotics (e.g. during chemotherapy or in intensive care units) is at the heart of the AMR problem. However, little research has been performed to date to elucidate the in vivo consequences of AMR in relevant animal models. For the last 20 years my lab has been modelling human intestinal infections with pathogenic E. coli in mice, using the mouse pathogen Citrobacter rodentium. C. rodentium infection is an excellent bacterial colonisation model as it does not cause severe disease in mice. Recently, we found that when treatment of mice infected with C. rodentium that is resistant to the antibiotic kanamycin (Kan), with high level of Kan leads to a phenomenon we termed antibiotic induced bacterial persistence (AIBP). C. rodentium in the AIBP state persists within the gastrointestinal tract for many days and develops a new relationship with the host, which is different from a typical pathogen-host interaction. In particular, virulence genes are turned off in C. rodentium in the AIBP state and the pathogen is non-infectious. In contrast, treating infections with Kan resistant C. rodentium with low levels of Kan leads to delay clearance of the pathogen, which coincided with growth of commensal gut bacteria, which could potentially outcompete or kill C. rodentium.In this study we will characterise C. rodentium in the AIBP state and its relationship with commensal bacteria. Although we appreciate that the mouse intestinal microbiota is not identical to that in humans, this project will reveal common transferable principles underpinning bacterial competition and adaptation in the intestine during antibiotic treatment, the consequences of using the wrong antibiotics to treat AR infections and lead to the identification of novel new natural products expressed by the microbiome that impact on pathogen-host interactions. These principles are likely to be applicable to other enteric pathogens that have to compete with the gut microbiota during colonisation.

最近，导致疾病的细菌数量急剧增加，这些细菌对通常用于治疗它们的抗生素产生了耐药性。这些细菌被称为抗微生物剂抗性（AMR），并且携带介导对这些药物不敏感、降解或排出的基因。在不久的将来，我们将面临这样一种情况：曾经微不足道、易于治疗的感染可能会致命。目前，E.大肠杆菌是一种构成正常肠道植物群重要组成部分的细菌，是欧洲和英国最常见的AMR医院获得性感染之一，也是血液中毒、腹泻和复发性尿路感染的主要原因。滥用和过度使用抗生素（例如在化疗期间或重症监护病房）是AMR问题的核心。然而，迄今为止，很少有研究阐明AMR在相关动物模型中的体内后果。在过去的20年里，我的实验室一直在模拟人类肠道感染致病性大肠杆菌。使用小鼠病原体啮齿类柠檬酸杆菌在小鼠中培养大肠杆菌。C.啮齿动物感染是一种很好的细菌定植模型，因为它不会引起小鼠严重疾病。最近，我们发现当治疗感染C.啮齿动物对抗生素卡那霉素（Kan）具有抗性，高水平的Kan导致我们称之为抗生素诱导的细菌持久性（AIBP）的现象。C.处于AIBP状态的啮齿类动物在胃肠道内持续多日，并与宿主形成新的关系，这不同于典型的病原体-宿主相互作用。特别是，在C中，毒力基因被关闭。啮齿动物处于AIBP状态，病原体是非传染性的。相反，用抗Kan的C.低Kan水平的啮齿动物导致病原体的延迟清除，这与肠道细菌的生长相一致，其可能潜在地胜过或杀死C.在这项研究中，我们将cardiac。AIBP状态下的啮齿动物及其与肠道细菌的关系。虽然我们意识到小鼠肠道微生物群与人类的微生物群并不相同，但该项目将揭示抗生素治疗期间肠道细菌竞争和适应的共同可转移原则，使用错误抗生素治疗AR感染的后果，并导致识别微生物组表达的影响病原体-宿主相互作用的新型天然产物。这些原则可能适用于在定植期间必须与肠道微生物群竞争的其他肠道病原体。

项目成果

Citrobacter rodentium Relies on Commensals for Colonization of the Colonic Mucosa.

• DOI: 10.1016/j.celrep.2017.11.086
• 发表时间: 2017-12-19
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Mullineaux-Sanders C;Collins JW;Ruano-Gallego D;Levy M;Pevsner-Fischer M;Glegola-Madejska IT;Sågfors AM;Wong JLC;Elinav E;Crepin VF;Frankel G
• 通讯作者: Frankel G