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

幽门螺杆菌感染仍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，目前越来越多的问题，治疗感染和不成功的疫苗开发突出了必要性，提高我们的把握病原体和宿主之间的免疫串扰在这种感染。了解针对H.由于缺乏合适的动物模型，包括缺乏良好表征的小鼠感染模型，幽门螺杆菌的研究受到阻碍。小鼠、修饰小鼠和人源化小鼠以前常用于实验感染H。幽门。然而，在细菌方面，这些小鼠模型的定义不足以得出有效的结论，细菌因素的作用，影响宿主先天免疫防御这些细菌。这种缺乏了解涉及细菌基因组内容和基因组完整性及其在小鼠初始感染期间的基因组适应。基于我们最近开发的沙鼠感染模型，该模型具有稳定适应的H。pylori菌株，我们现在想利用类似的方法来产生新的H. pylori小鼠模型涉及遗传稳定的、小鼠适应的和良好表征的H. pylori菌株。在小鼠的持续定植过程中也可能发生连续的基因组适应，我们希望通过细菌基因组测序结合功能测定来澄清这一点。我们将进一步使用这种小鼠模型，以产生对H的先天免疫反应的深入表征。pylori野生型菌株具有或不具有cag致病岛。在未来，我们希望应用并提供这种小鼠模型，包括在转基因小鼠中的工作，以剖析细菌因子如cag IV型分泌系统和脂多糖在宿主先天免疫应答中的作用。

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.