Regulation of endothelial cell function by p. falciparum

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dc.contributor.advisorHo, May
dc.contributor.authorGillrie, Mark
dc.date.accessioned2017-12-18T22:32:34Z
dc.date.available2017-12-18T22:32:34Z
dc.date.issued2012
dc.descriptionBibliography: p. 201-244en
dc.descriptionSome pages are in colour.en
dc.descriptionIncludes copy of ethics approval and copyright permissions. Original copies with original Partial Copyright Licence.en
dc.description.abstractPlasmodiumfalciparum 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.
dc.format.extentxiv, 244 leaves : ill. ; 30 cm.en
dc.identifier.citationGillrie, 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/4818en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/4818
dc.identifier.urihttp://hdl.handle.net/1880/105819
dc.language.isoeng
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.titleRegulation of endothelial cell function by p. falciparum
dc.typedoctoral thesis
thesis.degree.disciplineMicrobiology, Immunology and Infectious Diseases
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
ucalgary.thesis.accessionTheses Collection 58.002:Box 2086 627942958
ucalgary.thesis.notesUARCen
ucalgary.thesis.uarcreleaseyen
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