Physical principles of parasite-host interactions in Giardia muris infection

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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.