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A particle-based computational model to analyse remodelling of the red blood cell cytoskeleton during malaria infections

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 parasit...

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Autores principales: Jäger, Julia, Patra, Pintu, Sanchez, Cecilia P., Lanzer, Michael, Schwarz, Ulrich S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9020725/
https://www.ncbi.nlm.nih.gov/pubmed/35394995
http://dx.doi.org/10.1371/journal.pcbi.1009509
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author Jäger, Julia
Patra, Pintu
Sanchez, Cecilia P.
Lanzer, Michael
Schwarz, Ulrich S.
author_facet Jäger, Julia
Patra, Pintu
Sanchez, Cecilia P.
Lanzer, Michael
Schwarz, Ulrich S.
author_sort Jäger, Julia
collection PubMed
description 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.
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spelling pubmed-90207252022-04-21 A particle-based computational model to analyse remodelling of the red blood cell cytoskeleton during malaria infections Jäger, Julia Patra, Pintu Sanchez, Cecilia P. Lanzer, Michael Schwarz, Ulrich S. PLoS Comput Biol Research Article 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. Public Library of Science 2022-04-08 /pmc/articles/PMC9020725/ /pubmed/35394995 http://dx.doi.org/10.1371/journal.pcbi.1009509 Text en © 2022 Jäger et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Jäger, Julia
Patra, Pintu
Sanchez, Cecilia P.
Lanzer, Michael
Schwarz, Ulrich S.
A particle-based computational model to analyse remodelling of the red blood cell cytoskeleton during malaria infections
title A particle-based computational model to analyse remodelling of the red blood cell cytoskeleton during malaria infections
title_full A particle-based computational model to analyse remodelling of the red blood cell cytoskeleton during malaria infections
title_fullStr A particle-based computational model to analyse remodelling of the red blood cell cytoskeleton during malaria infections
title_full_unstemmed A particle-based computational model to analyse remodelling of the red blood cell cytoskeleton during malaria infections
title_short A particle-based computational model to analyse remodelling of the red blood cell cytoskeleton during malaria infections
title_sort particle-based computational model to analyse remodelling of the red blood cell cytoskeleton during malaria infections
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9020725/
https://www.ncbi.nlm.nih.gov/pubmed/35394995
http://dx.doi.org/10.1371/journal.pcbi.1009509
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