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Multiple stiffening effects of nanoscale knobs on human red blood cells infected with Plasmodium falciparum malaria
Yao Zhang1, Changjin Huang2, Sangtae Kim3
1Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, PA 16802;
Abstract:
During its asexual development within the red blood cell (RBC), Plasmodium falciparum (Pf), the most virulent human malaria parasite, exports proteins that modify the host RBC membrane. The attendant increase in cell stiffness and cytoadherence leads to sequestration of infected RBCs in microvasculature, which enables the parasite to evade the spleen, and leads to organ dysfunction in severe cases of malaria. Despite progress in understanding malaria pathogenesis, the molecular mechanisms responsible for the dramatic loss of deformability of Pf-infected RBCs have remained elusive. By recourse to a coarse-grained (CG) model that captures the molecular structures of Pf-infected RBC membrane, here we show that nanoscale surface protrusions, known as "knobs," introduce multiple stiffening mechanisms through composite strengthening, strain hardening, and knob density-dependent vertical coupling. On one hand, the knobs act as structural strengtheners for the spectrin network; on the other, the presence of knobs results in strain inhomogeneity in the spectrin network with elevated shear strain in the knob-free regions, which, given its strain-hardening property, effectively stiffens the network. From the trophozoite to the schizont stage that ensues within 24-48 h of parasite invasion into the RBC, the rise in the knob density results in the increased number of vertical constraints between the spectrin network and the lipid bilayer, which further stiffens the membrane. The shear moduli of Pf-infected RBCs predicted by the CG model at different stages of parasite maturation are in agreement with experimental results. In addition to providing a fundamental understanding of the stiffening mechanisms of Pf-infected RBCs, our simulation results suggest potential targets for antimalarial therapies.
Insights
Malaria parasite Plasmodium falciparum (Pf) infection stiffens red blood cells (RBCs) via surface knobs. These knobs strengthen the membrane through composite effects, strain hardening, and increased vertical coupling, impacting malaria pathogenesis.
Area of Science:
- Biophysics
- Parasitology
- Computational Biology
Background:
- Plasmodium falciparum (Pf) infection alters red blood cell (RBC) membrane properties, increasing stiffness and cytoadherence.
- This altered RBC biomechanics contributes to severe malaria pathogenesis and parasite evasion from the spleen.
- The precise molecular mechanisms behind the loss of RBC deformability in Pf-infected cells remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanisms responsible for the increased stiffness of Plasmodium falciparum-infected red blood cells.
- To investigate the role of nanoscale surface protrusions (knobs) in altering RBC membrane mechanics.
- To provide a computational model for predicting the mechanical properties of infected RBCs.
Main Methods:
- Development and application of a coarse-grained (CG) model of the Pf-infected RBC membrane.
- Simulation of nanoscale surface protrusions (knobs) and their impact on membrane structural integrity.
- Analysis of composite strengthening, strain hardening, and vertical coupling effects.
Main Results:
- Nanoscale knobs introduce multiple stiffening mechanisms: composite strengthening, strain hardening, and knob density-dependent vertical coupling.
- Knobs act as structural reinforcements and induce strain inhomogeneity, leading to network stiffening.
- Increasing knob density during parasite maturation (24-48h) enhances vertical constraints, further stiffening the membrane.
- CG model predictions of RBC shear moduli align with experimental data across parasite maturation stages.
Conclusions:
- The study reveals key molecular mechanisms by which Pf-induced knobs stiffen RBCs.
- The findings enhance fundamental understanding of malaria pathogenesis at the cellular level.
- The identified stiffening mechanisms suggest potential therapeutic targets for antimalarial drug development.
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