Biophysics of Immune-cell Hijacking by Toxoplasma gondii

• Applicants: Professor Dr. Jörg Renkawitz; Professor Dr. Benedikt Sabass
• Subject Area: Biophysics ; Parasitology and Biology of Tropical Infectious Disease Pathogens ; Statistical Physics, Nonlinear Dynamics, Complex Systems, Soft and Fluid Matter, Biological Physics ; Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 492014049

Upon entry into multicellular organisms, parasites like Toxoplasma gondii (T.gondii) disseminate within the host. Inside the host, they encounter tight tissue pores, large traveling distances, and maze-like extracellular fibrillar networks. To overcome these challenges, parasites can invade migratory host cells to be transported intracellularly. T.gondii (phylum Apicomplexa) is a well-studied model parasite that hijacks migrating immune cells, taking advantage of their abilities to cross tissue barriers and rapidly migrate throughout the host. Moreover, T.gondii replicates inside intracellular parasitophorous vacuoles, thus turning immune cells into “Trojan horses”. Although some molecular biological data on parasitic immune-cell hijacking are increasingly available, key biophysical aspects of the trojan-horse mechanism are currently almost completely unresolved.Our preliminary results show that infected immune cells are able to migrate through extraordinarily tight constrictions in spite of a large, bulky parasite ‘cargo’. The cargo is protected by a delicate, yet extremely resilient anatomy of the parasitophorous vacuole thatcontains a dynamic actin network and is surrounded by a cage-like host microtubule network.How locomotion of the host-parasite system is driven, how it is adapted to cargo, and how the active vacuole system gains its protective role and mechanical resilience is not known.This knowledge gap will be filled by combining our expertise in experimental and theoretical methodology. To discover biophysical principles of immune-cell hijacking by T.gondii, we will employ advanced microscopy techniques (STED, STORM, TIRF), custom-designed microchannels and 3D matrices, parasite and immune cell mutants (cytoskeletal components), mechanical measurements (traction force microscopy, micropipette aspiration), and mathematical models for describing the viscoelastic response of the vacuole as well as for describing the locomotion of immune cells with parasite cargo. Our work will elucidate design principles and dynamics of the immune-cell parasite system, investigate possible synchronization of the mechanical activity of the host and the parasitophorous vacuole, and reveal the role of mechanical adaptation in optimal parasite cargo transport. Overall, these findings will shed light on the fundamental biophysical mechanisms underlying evolved parasitic strategies for generating Trojan horses, and explain how an optimized biological system for organism-wide transport of large foreign bodies can function.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2332: Physics of Parasitism
• Co-Investigator: Javier Periz, Ph.D.