Biophysical Tools and Concepts Enable Understanding of Asexual Blood Stage Malaria

Abstract

Forces and mechanical properties of cells and tissues set constraints on biological functions, and are key determinants of human physiology. Changes in cell mechanics may arise from disease, or directly contribute to pathogenesis. Malaria gives many striking examples. Plasmodium parasites, the causative agents of malaria, are single-celled organisms that cannot survive outside their hosts; thus, thost-pathogen interactions are fundamental for parasite’s biological success and to the host response to infection. These interactions are often combinations of biochemical and mechanical factors, but most research focuses on the molecular side. However, Plasmodium infection of human red blood cells leads to changes in their mechanical properties, which has a crucial impact on disease pathogenesis because of the interaction of infected red blood cells with other human tissues through various adhesion mechanisms, which can be probed and modelled with biophysical techniques. Recently, natural polymorphisms affecting red blood cell biomechanics have also been shown to protect human populations, highlighting the potential of understanding biomechanical factors to inform future vaccines and drug development. Here we review biophysical techniques that have revealed new aspects of Plasmodium falciparum invasion of red blood cells and cytoadhesion of infected cells to the host vasculature. These mechanisms occur differently across Plasmodium species and are linked to malaria pathogenesis. We highlight promising techniques from the fields of bioengineering, immunomechanics, and soft matter physics that could be beneficial for studying malaria. Some approaches might also be applied to other phases of the malaria lifecycle and to apicomplexan infections with complex host-pathogen interactions.

Enhanced Antimalarial and Antisequestration Activity of Methoxybenzenesulfonate-Modified Biopolymers and Nanoparticles for Tackling Severe Malaria

“…Future work is necessary to test activity under physiological flow to confirm suitability in a more realistic scenario. 51 Our previous finding that incorporation of PEGylated lipids in this nanoparticle formulation extended blood circulation time, 30 together with the antisequestration activity found herein also for this nanoparticle version (PLN–PEG), provides supportive arguments for the development of a nanoscale inhibitor. Further, a nanoparticle-based strategy allows straightforward combination with controlled release of additional drugs to adjust the overall treatment response.…”

“…Targeting different Pf EMP1 variants with the same construct is beneficial as it might allow broad-spectrum applicability against various strains using the same inhibitor. Future work is necessary to test activity under physiological flow to confirm suitability in a more realistic scenario . Our previous finding that incorporation of PEGylated lipids in this nanoparticle formulation extended blood circulation time, together with the antisequestration activity found herein also for this nanoparticle version (PLN–PEG), provides supportive arguments for the development of a nanoscale inhibitor.…”

Adhesion-driven vesicle translocation through membrane-covered pores

“…However, recent microscopy images show that Plasmodium merozoites contain only two to three very short subpellicular microtubules [50] and experience major shape deformations during invasion [15, 51]. Furthermore, contrary to the widely accepted notion of invasion occurring from the merozoite’s pointed end, recent experiments indicate that invasion for Plasmodium knowlesi starts from the flattened end [52, 53]. Our results for vesicle-pore translocation provide a basis for studying the invasion of Plasmodium merozoites into red blood cells.…”

The structure of a Plasmodium vivax Tryptophan Rich Antigen suggests a lipid binding function for a pan-Plasmodium multi-gene family

“…Videos were acquired in bright-field with a red filter using a CMOS camera (model GS3-U3-23S6M-C, Point Grey Research/FLIR Integrated Imaging Solutions (Machine Vision), Ri Inc., Canada). The equatorial contour for each frame was tracked by an in-house Matlab program as previously described [41, 75].…”