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，引起疾病的细菌数量急剧增加，这些细菌因抗生素的耐药性而通常用于治疗它们。这些细菌被称为抗菌抗药性（AMR），并携带基因，可介导这些药物的不敏感，降解或驱逐。在不太遥远的未来，我们正面临着一种曾经琐碎，易于治疗的感染的情况，可能会证明是致命的。目前，大肠杆菌是一种构成正常肠道菌群的重要组成部分的细菌，是欧洲和英国最常见的AMR医院收到的感染之一，是血液中毒，腹泻和经常性尿路感染的主要原因。滥用和过度使用抗生素（例如，在化学疗法或重症监护病房中）是AMR问题的核心。但是，迄今为止，很少进行研究以阐明相关动物模型中AMR的体内后果。在过去的20年中，我的实验室一直在使用小鼠病原体柠檬杆菌啮齿动物对人类肠道感染进行建模。 C.啮齿动物感染是一种极好的细菌定植模型，因为它不会引起小鼠的严重疾病。最近，我们发现，当感染对抗生素卡纳米霉素（KAN）具有耐药性的小鼠治疗时，kan含量高会导致一种现象，我们称为抗生素诱导的细菌持久性（AIBP）。 AIBP状态中的啮齿动物念珠菌在胃肠道内持续了很多天，并与宿主建立了新的关系，这与典型的病原体宿主相互作用不同。特别是，在AIBP状态下的啮齿动物念珠菌中，毒力基因被关闭，病原体是非感染的。相比之下，用较低的KAN治疗抗Kan抗性鼠尾草的感染会导致病原体的清除延迟，这与共生肠道细菌的生长相吻合，这可能会超过或杀死啮齿动物。尽管我们赞赏小鼠肠道菌群与人类的相同，但该项目将揭示抗生素治疗过程中肠道竞争和适应性的普遍可转移原理，这是抗生素治疗过程中的肠道，这是使用错误的抗生素治疗AR感染的后果，并导致对互动互动的新型天然产物的鉴定，并导致对病原体的影响。这些原理可能适用于在定植期间必须与肠道菌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