Physical principles of parasite-host interactions in Giardia muris infection

贾第鞭毛虫是寄生原生动物，其滋养体阶段感染人类和许多其他脊椎动物的上肠道。这个栖息地营养丰富，但寄生虫必须避免通过蠕动排出体外。此外，与快速更新的上皮细胞密切接触需要定期改变位置，并且靠近潜在的免疫细胞使滋养体容易成为宿主防御的目标。此外，这个不确定的地形被粘弹性粘液覆盖，粘弹性粘液上布满了宿主防御物质。为了克服这些挑战，贾第虫进化出了几种令人印象深刻的适应性。一个粘附的圆盘可以让滋养体在几分之一秒内固定，在细胞分裂过程中，这个细胞器的更新只需要几分钟。此外，贾第鞭毛虫有四对鞭毛，可以在粘液中穿透和移动。这说明贾第虫利用物理原理来适应它们的栖息地，从而对宿主产生影响。我们的项目重点关注这些类型的相互作用，并解决两个首要问题：1)贾第虫的生活方式对宿主器官的力动态反应有多灵活？2)宿主细胞是否能感知贾第鞭毛虫施加的机械力并作出反应？在研究自然寄生虫-宿主相互作用的物理方面时，我们将首先关注寄生虫。利用活体显微技术，我们将定量分析鼠g.m uris在自然环境下小鼠肠道内的运动性。机械力介导鼠g.m oli对肠上皮的粘附将在肠类器官中测定，使用原子力显微镜。为了解决寄主关系的双边性质，我们将进一步剖析G. muris附着对宿主细胞的影响。在这里，我们将重点关注不同类型的细胞如何感知这个过程，以及产生的力如何传递到肠道组织。最后，我们将使用遗传和药理学干预来研究肠道屏障的机械感觉是否影响感染的控制。在DFG 2332优先项目中，我们的项目提供了实现各种协同效应的机会。一方面，我们正在研究一种具有自身运动和粘附的物理原理的寄生虫，以及与该优先计划中针对的其他寄生虫的殖民环境的挑战。其次，我们正在使用和分享专门的技术以及新的报告系统来研究宿主对体内寄生虫施加的机械力的反应。

Giardia are parasitic protozoa whose trophozoite stage infects the upper intestinal tract of humans and of many other vertebrates. This habitat is rich in nutrients, but the parasite must avoid being excreted via peristalsis. In addition, close contact with the rapidly renewing epithelial cells necessitates regular changes of location, and the proximity to underlying immune cells makes trophozoites an easy target for host defense. Furthermore, this uncertain terrain is covered by the viscoelastic mucus studded with host defense substances. To overcome these challenges, Giardia have evolved several impressive adaptations. An adhesive disc allows trophozoites to anchor within fractions of a second, and renewal of this organelle during cell division only takes a few minutes. In addition, giardia possess four pairs of flagella that allow penetration and locomotion in mucus. This illustrates that giardia use physical principles to adapt to their habitat, thereby impacting on the host. Our project focuses on these types of interaction, and addresses two overarching questions: 1) How flexible are giardia in their lifestyle in response to force dynamics in the host organ? 2) Do host cells sense and respond to mechanical forces exerted by Giardia? In examining the physical aspects of a natural parasite-host interaction, we will first focus on the parasite. Using intravital microscopy, we will quantitatively analyze the motility of G. muris in the mouse intestine as the natural environment. Mechanical forces mediating the adhesion of G. muris to the intestinal epithelium will be determined in intestinal organoids, using atomic force microscopy. To address the bilateral nature of the parasite-host relationship, we will further dissect the effects of G. muris attachment on host cells. Here, we will focus on how the process is perceived by different cell types and how the resulting forces are transmitted to the intestinal tissue. Finally, we will use genetic and pharmacological interventions to investigate whether the mechanosensation of the intestinal barrier influences the control of infection. Within the DFG priority program 2332, our project offers the opportunity to work out a variety of synergies. On the one hand, we are working on a parasite that shares physical principles of its own locomotion and adhesion, as well as challenges from the colonized environment with other parasites targeted in this priority program. Second, we are using and sharing specialized techniques as well as novel reporter systems to study host responses to mechanical forces exerted by parasites in vivo.