A sticky situation: the influence of microvessel mechanics on cerebral malaria pathogenesis 2. Brain barriers in disease
Matt Govendir 1, 2 , Rory Long 1 , Alba Diz Muñoz 2 , Maria Bernabeu 1
1 EMBL Barcelona, Barcelona, Spain;
2 EMBL Heidelberg, Heidelberg, Germany
Correspondence: Matt Govendir - <
Cerebral malaria is the most severe and fatal consequence of malaria infection and occurs when Plasmodium falciparum-infected red blood cells (iRBCs) become sequestered in the brain vasculature, leading to vascular obstruction and disruption of the blood brain barrier (BBB). Interactions between iRBCs and cerebral endothelial cells that line the blood vessels occur under dynamic mechanical conditions due to changing flow conditions within vessels and heterogeneity in tissue stiffness surrounding the vessels. We utilise both 2D brain endothelial monolayers and 3D bio-engineered cerebral blood vessels that allow for the visualisation of iRBC binding, disruption of flow and BBB breakdown in real-time. By customising both the matrix composition, geometry and flow rate in these models we can precisely tune the mechanics of our system to observe their role in endothelial cell function and cerebral malaria pathogenesis. We reveal that when brain endothelial cells and vessels are cultured with iRBC products they demonstrate increased permeability and altered adherens junctions and increased actomyosin contractility, ICAM-1 expression. Furthermore, when cultured on collagen I coated matrices or substrates, brain endothelial cells show reduced disruption by these iRBC toxins. Our results demonstrate that both intracellular mechanics (cytoskeletal organisation) and extracellular mechanics (cell-matrix interactions) play critical roles in regulating brain endothelial cell and BBB function in both health and disease. Further work is currently ongoing to directly measure changes to endothelial monolayers and 3D vessel mechanics, via atomic force and Brillouin microscopy, when cultured on substrates of varying stiffness and after iRBC addition.