Developing a novel mouse model for dissecting innate immune responses against Helicobacter pylori

开发一种新的小鼠模型来剖析针对幽门螺杆菌的先天免疫反应

• 批准号: 280354483
• 负责人: Professorin Dr. Christine Josenhans
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie und Krankenhaushygiene
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280354483?language=en
• 关键词: Developing; novel; mouse; model; dissecting

The human Helicobacter pylori infection is still one of the major infectious diseases worldwide. Severe infection sequelae such as cancer, currently increasing problems with treating the infection and unsuccessful vaccine development highlight the necessity of improving our grasp of the immunological crosstalk between pathogen and host during this infection. Understanding innate immune responses against H. pylori has been hampered by a lack of suitable animal models, including a dearth of well-characterised mouse infection models. Mice, modified mice and humanized mice have been frequently used previously for experimental infection with H. pylori. However, on the bacterial side, these mouse models are not sufficiently defined to be able to draw valid conclusions concerning the role of bacterial factors in influencing the host innate immune defense against these bacteria. This lack of understanding concerns the bacterial genome content and genome integrity and their genome adaptation during the initial infection of mice. Based on our recently developed gerbil infection model with a stably adapted H. pylori strain, we would now like to make use of a similar approach to generate a novel H. pylori mouse model involving a genetically stable, mouse-adapted and well-characterized H. pylori strain. It is possible that continuous genome adaptation occurs as well during persistent colonization of the mouse, which we would like to clarify by bacterial genome sequencing in combination with functional assays. We would further use this mouse model in order to generate an in-depth characterization of innate immune responses against H. pylori wild type strains with or without the cag pathogenicity island. In the future, we would like to apply and provide this mouse model, including work in genetically modified mice, to dissect the role of bacterial factors such as the cag type IV secretion system and lipopolysaccharide in the host innate immune responses.

人类幽门螺杆菌感染仍然是世界范围内的主要传染病之一。严重的感染后遗症，如癌症，目前治疗感染的问题越来越多，以及疫苗开发不成功，突显了在这种感染期间加强我们对病原体和宿主之间的免疫串扰的把握的必要性。由于缺乏合适的动物模型，包括缺乏具有良好特征的小鼠感染模型，对幽门螺杆菌的先天免疫反应的了解一直受到阻碍。小鼠、改良小鼠和人源化小鼠以前经常用于幽门螺杆菌的实验性感染。然而，在细菌方面，这些小鼠模型还没有得到足够的定义，无法得出关于细菌因素在影响宿主对这些细菌的天然免疫防御中所起作用的有效结论。这种缺乏了解的问题涉及细菌基因组内容和基因组完整性以及它们在小鼠初始感染期间的基因组适应。在我们最近开发的具有稳定适应的H.Pylori菌株的沙土鼠感染模型的基础上，我们现在希望利用类似的方法来建立一种新的Hp小鼠模型，该模型包括一种遗传稳定的、小鼠适应的和具有良好特征的Hp菌株。在小鼠的持续定植过程中，也可能发生持续的基因组适应，我们希望通过细菌基因组测序和功能分析来澄清这一点。我们将进一步使用这个小鼠模型，以产生对幽门螺杆菌野生型菌株的先天免疫反应的深入表征，无论是否有CAG致病岛。在未来，我们希望应用和提供这个小鼠模型，包括在转基因小鼠中的工作，以剖析细菌因素，如CAG IV型分泌系统和脂多糖在宿主先天性免疫反应中的作用。