Host-pathogen interaction in a novel in vivo model of enteropathogenic Escherichia coli (EPEC) infection

肠道病原性大肠杆菌 (EPEC) 感染的新型体内模型中宿主与病原体的相互作用

• 批准号: 396639086
• 负责人: Dr. Aline Dupont, Ph.D.
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/396639086?language=en
• 关键词: Host; pathogen; interaction; novel; vivo

Enteropathogenic Escherichia coli (EPEC) represent an important causative agent of human infant diarrhea worldwide and are associated with a high attributable risk of death in young infants in developing countries. Whereas the interaction between EPEC and mammalian cells has been extensively studied in co-culture models in vitro over the last decades, the mechanisms employed by EPEC to induce disease in the more complex intestinal tissue environment in vivo have remained ill-defined due to the lack of a suitable small animal infection model. We have recently established a new in vivo infection model in neonate mice that displays many of the characteristics of EPEC infection in humans, such as the age-dependent susceptibility, the formation of typical attachment and effacement (A/E) lesions and the critical role of bacterial virulence factors such as the encoded type 3 secretion system (T3SS) (Dupont et al., 2016). Exploiting this novel infection model, the present research proposal aims at characterizing the biological role of bacterial virulence factors and identifying host factors that determine the susceptibility to infection with this non-invasive small intestinal pathogen. Specifically, the proposed project addresses the three following issues:(i) Characterizing the mucosal immune response to enteric infection of the neonate host.(ii) Analyzing the role of bacterial effector molecules during host-microbial interaction.(iii) Identifying host factors that determine the host susceptibility to bacterial challenge.The proposed work is expected to significantly expand our knowledge of the mechanism employed by EPEC to evade the antimicrobial defense of the host and induce enteric disease in infants. It will also help to better understand the protective host response and might ultimately help to develop future preventive and therapeutic strategies to reduce the morbidity and mortality associated with EPEC infection in small children.

肠病性大肠杆菌 (EPEC) 是全世界人类婴儿腹泻的重要病原体，并且与发展中国家幼儿的高死亡风险相关。尽管过去几十年来，EPEC 与哺乳动物细胞之间的相互作用已在体外共培养模型中得到了广泛研究，但由于缺乏合适的小动物感染模型，EPEC 在体内更复杂的肠道组织环境中诱导疾病的机制仍然不明确。我们最近在新生小鼠中建立了一种新的体内感染模型，该模型显示了人类 EPEC 感染的许多特征，例如年龄依赖性易感性、典型附着和消失 (A/E) 病变的形成以及编码的 3 型分泌系统 (T3SS) 等细菌毒力因子的关键作用 (Dupont et al., 2016)。利用这种新型感染模型，本研究计划旨在表征细菌毒力因子的生物学作用，并确定决定这种非侵入性小肠病原体感染易感性的宿主因素。具体来说，该项目解决了以下三个问题：(i) 表征新生儿宿主对肠道感染的粘膜免疫反应。(ii) 分析细菌效应分子在宿主-微生物相互作用过程中的作用。(iii) 识别决定宿主对细菌攻击易感性的宿主因素。这项工作预计将显着扩展我们对 EPEC 逃避抗菌药物机制的了解。 防御宿主并诱发婴儿肠道疾病。它还将有助于更好地了解宿主的保护性反应，并可能最终有助于制定未来的预防和治疗策略，以降低幼儿中与 EPEC 感染相关的发病率和死亡率。