Regulation of endothelial cell function by p. falciparum

Date
2012
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Plasmodiumfalciparum is a protozoan infection of human erythrocytes. Despite optimal therapy, mortality due to multi-organ failure in severe falciparum malaria remains high at 5 to 20%. Correlation of disease severity to multiple clinical markers of endothelial activation suggest a central role for endothelial cells in the pathophysiology of severe malaria. Detailed studies in models of other systemic infections, including bacterial sepsis, have highlighted the central role of endothelial cells in pathogen recognition, barrier function and proinflammatory signaling in determining organ failure and mortality. We hypothesized that in addition to providing points of attachment for sequestering infected red blood cells (IRBC), microvascular endothelial cells can directly recognize parasite products released by adherent IRBC at the time of schizogony through innate receptors. Using clinical P. falciparum isolates we showed that parasite sonicates but not intact IRBC disrupted primary human dermal and lung endothelial cell barrier function in a Src-family kinase-dependent manner. Increased endothelial permeability was characterized by redistribution of junctiona1 proteins Z0-1 and VE-cadherin away from sites of cell-cell contact. The active parasite component appeared to be a merozoite­associated protein. We further examined the ability of P. falciparum sonicates and merozoites to induce proinflammatory signaling and discovered production of broad proinflammatory responses including endothelial chemokines and adhesion molecules. We defined a critical role for Src-family kinase Lyn and downstream p38 MAPK in endothelial proinflammatory responses to P. falciparum sonicate using IL-8 protein production as a functional readout. Further characterization of the active component in P. falciparum sonicates and merozoites revealed parasite histones as an activator of both endothelial permeability and proinflamrnatory protein production. Both activities of histones were found to be dependent on the strong cationic charge of these proteins. Proinflammatory responses to P. falciparum histones were were partially dependent on Toll-like receptor 2 (TLR2). Recombinant human activated protein C (rhAPC) cleaved parasite histones and abrogated the increases in endothelial permeability and IL-8 production. More importantly, levels of both parasite and human histones were markedly elevated in patients with severe malaria as compared to healthy controls, and patients with uncomplicated infection and bacterial sepsis. Together, these findings strongly suggest Src-family kinases and parasite histones as targets for adjunctive therapies in severe falciparum malaria.
Description
Bibliography: p. 201-244
Some pages are in colour.
Includes copy of ethics approval and copyright permissions. Original copies with original Partial Copyright Licence.
Keywords
Citation
Gillrie, M. (2012). Regulation of endothelial cell function by p. falciparum (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/4818
Collections