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A particle-based computational model to analyse remodelling of the red blood cell cytoskeleton during malaria
Julia Jäger1,2, Pintu Patra1,2, Cecilia P Sanchez3
1Institute for Theoretical Physics, Heidelberg University, Heidelberg, Germany.
Abstract:
Red blood cells can withstand the harsh mechanical conditions in the vasculature only because the bending rigidity of their plasma membrane is complemented by the shear elasticity of the underlying spectrin-actin network. During an infection by the malaria parasite Plasmodium falciparum, the parasite mines host actin from the junctional complexes and establishes a system of adhesive knobs, whose main structural component is the knob-associated histidine rich protein (KAHRP) secreted by the parasite. Here we aim at a mechanistic understanding of this dramatic transformation process. We have developed a particle-based computational model for the cytoskeleton of red blood cells and simulated it with Brownian dynamics to predict the mechanical changes resulting from actin mining and KAHRP-clustering. Our simulations include the three-dimensional conformations of the semi-flexible spectrin chains, the capping of the actin protofilaments and several established binding sites for KAHRP. For the healthy red blood cell, we find that incorporation of actin protofilaments leads to two regimes in the shear response. Actin mining decreases the shear modulus, but knob formation increases it. We show that dynamical changes in KAHRP binding affinities can explain the experimentally observed relocalization of KAHRP from ankyrin to actin complexes and demonstrate good qualitative agreement with experiments by measuring pair cross-correlations both in the computer simulations and in super-resolution imaging experiments.
Insights
Malaria parasite Plasmodium falciparum alters red blood cell mechanics by mining actin and forming knobs. Computational models reveal how actin depletion softens cells, while knob formation stiffens them, impacting disease progression.
Area of Science:
- Biophysics
- Cell Biology
- Computational Biology
Background:
- Red blood cells (RBCs) possess mechanical resilience due to their plasma membrane and spectrin-actin cytoskeleton.
- Infection by Plasmodium falciparum, the malaria parasite, disrupts RBC mechanics through actin sequestration and knob formation.
Purpose of the Study:
- To mechanistically understand how malaria parasite infection transforms RBC mechanical properties.
- To investigate the roles of actin mining and knob-associated histidine-rich protein (KAHRP) clustering in RBC structural changes.
Main Methods:
- Developed a particle-based computational model of the RBC cytoskeleton.
- Simulated RBC mechanics using Brownian dynamics, incorporating spectrin chains, actin protofilaments, and KAHRP binding.
- Compared simulation results with super-resolution imaging experiments.
Main Results:
- Simulations predicted distinct mechanical responses to actin mining (decreased shear modulus) and KAHRP-mediated knob formation (increased shear modulus).
- Demonstrated that dynamic changes in KAHRP binding affinities explain its relocalization from ankyrin to actin complexes.
- Achieved qualitative agreement between computational pair cross-correlations and experimental super-resolution imaging data.
Conclusions:
- The study provides a mechanistic model for RBC mechanical alterations during malaria infection.
- KAHRP dynamics and clustering are critical in modulating RBC mechanics in response to Plasmodium falciparum.
- Computational modeling combined with experimental imaging offers powerful insights into host-pathogen interactions.
