Predicting forces and shapes for invasion of apicomplexan parasites into host cells

• Applicants: Professor Dr. Thorsten Auth; Dr. Anil Kumar Dasanna
• Subject Area: Statistical Physics, Nonlinear Dynamics, Complex Systems, Soft and Fluid Matter, Biological Physics ; Biophysics ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 492014218

Invasion into host cells is a vital step in the life cycle of apicomplexan parasites. Therefore, understanding the invasion mechanism is key for identifying potential therapeutic measures to prevent the disease. Advances in microscopy have led to a significant increase of our knowledge on the parasite architecture in the past years: microtubules that extend from the apical end throughout a large part of the parasite, an actin network at the dorsal end, and a perforated inner membrane complex that spreads along the microtubules. The architecture hints several invasion mechanisms that include the classical linear-motor model and the push-and-pull model. Recent experiments also hint important roles of the lipid-bilayer membranes; in particular, parasites have been observed to invade into giant unilamellar vesicles. State-of-the-art theory and computer simulations will allow us to test hypotheses for the invasion mechanism based on optical microscopy images and to quantitatively predict the involved forces. For Toxoplasma, we aim to address the following questions: What can we learn from parasite shape about its cytoskeletal architecture? Can discrete bond-adhesion explain the apical end of the banana-shaped parasite get into contact with the host plasma membrane? What is the role of parasite deformability for adhesion and invasion? Which passive and active forces and parasite shapes occur while the parasite squeezes through the tight junction? How does the tight junction hinder invasion of the entire parasite and in particular the stiff nucleus of the parasite? What is a minimum size of a pore that a parasite can actively squeeze through? What is the time for complete invasion? What is the role of reorganisation of the cytoskeleton, linear-motor forces at the tight junction, and contractile actin forces within the push-and-pull model for invasion of wild-type and genetically modified parasites? In particular, we will stdy: (a) Forces on microtubules, actin network, and plasma membrane for maintaining the non-spherical shape of free parasites. (b) Formation of discrete bonds in early stages of parasite adhesion to the host and resulting parasite and host deformation. (c) Forces and parasite shape deformations that occur while the parasite squeezes through a circular pore. (d) Forces and parasite shapes upon interaction with giant unilamellar vesicles.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2332: Physics of Parasitism