Effective cell membrane tension protects red blood cells against malaria invasion
Authors: Alimohamadi Haleh , Rangamani Padmini 
Published: May 2023

AbstractA critical step in how malaria parasites invade red blood cells (RBCs) is the wrapping of the membrane around the egg-shaped merozoites. Recent experiments have revealed that RBCs can be protected from malaria invasion by high membrane tension. While cellular and biochemical aspects of parasite actomyosin motor forces during the malaria invasion have been well studied, the important role of the biophysical forces induced by the RBC membrane-cytoskeleton composite has not yet been fully understood. In this study, we use a theoretical model for lipid bilayer mechanics, cytoskeleton deformation, and membrane-merozoite interactions to systematically investigate the influence of effective RBC membrane tension, which includes contributions from the lipid bilayer tension, spontaneous tension, interfacial tension, and the resistance of cytoskeleton against shear deformation on the progression of membrane wrapping during the process of malaria invasion. Our model reveals that this effective membrane tension creates a wrapping energy barrier for a complete merozoite entry. We calculate the tension threshold required to impede the malaria invasion. We find that the tension threshold is a nonmonotonic function of spontaneous tension and undergoes a sharp transition from large to small values as the magnitude of interfacial tension increases. We also predict that the physical properties of the RBC cytoskeleton layer – particularly the resting length of the cytoskeleton – play key roles in specifying the degree of the membrane wrapping. We also found that the shear energy of cytoskeleton deformation diverges at the full wrapping state, suggesting the local disassembly of the cytoskeleton is required to complete the merozoite entry. Additionally, using our theoretical framework, we predict the landscape of myosin-mediated forces and the physical properties of the RBC membrane in regulating successful malaria invasion. Our findings on the crucial role of RBC membrane tension in inhibiting malaria invasion can have implications for developing novel antimalarial therapeutic or vaccine-based strategies.SignificanceRBC membrane tension plays an important role in regulating RBC shape and functionality. In particular, recent experimental studies have shown that elevated RBC membrane tension protects against severe malaria infection. In this study, we sought to identify how different contributions to the the effective membrane tension can contribute to this mechanically-driven protection against malaria invasion. Using a mathematical model, we derived a relationship between the effective tension of the RBC membrane – comprising a lipid bilayer and a cytoskeleton layer– and the degree of membrane wrapping during malaria invasion. Our model shows that the shear resistance of the RBC cytoskeleton plays an important role in inhibiting malaria invasion. Our findings can be generalized to the role of cell membrane mechanics in many wrapping phenomena providing insight into the crucial contributions of the host-cell membrane in protection against severe infections.