Physical principles of parasite-host interactions in Giardia muris infection

贾第虫是寄生原生动物，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排泄物排泄。此外，与快速更新的上皮细胞的密切接触需要定期改变位置，并且接近潜在的免疫细胞使滋养体成为宿主防御的容易靶点。此外，这种不确定的地形被粘弹粘液覆盖，其中充满了宿主的防御物质。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。一个粘附盘允许滋养体在几分之一秒内锚住，而在细胞分裂期间这个细胞器的更新只需要几分钟。此外，贾第鞭毛虫拥有四对鞭毛，可以在粘液中穿透和移动。这说明贾第鞭毛虫利用物理原理来适应其栖息地，从而影响宿主。我们的项目集中在这些类型的相互作用，并解决两个首要问题：1）如何灵活的贾第鞭毛虫在他们的生活方式，以响应在宿主器官的动力学？2)宿主细胞是否感知贾第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。 利用活体显微镜，我们将定量分析G.小鼠肠道中的muris作为自然环境。机械力介导G.将使用原子力显微镜在肠类器官中测定肠上皮细胞的MURIS。为了说明寄生-宿主关系的双边性质，我们将进一步剖析G。小鼠附着在宿主细胞上。在这里，我们将专注于不同类型的细胞如何感知这一过程，以及所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优先计划2332中，我们的项目提供了一个实现各种协同效应的机会。一方面，我们正在研究一种寄生虫，这种寄生虫与本优先计划中的其他寄生虫共享其自身运动和粘附的物理原理，以及来自殖民环境的挑战。第二，我们正在使用和分享专门的技术以及新的报告系统，以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.