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Tissue factor-related mechanisms of coagulation initiated on the virus envelope

University of British Columbia

Infectious diseases do not always manifest in a predictable manner and may go undetected, especially in asymptomatic individuals. Here, virus infection as an underlying cause of vascular disease is investigated. When considered independently, both have major impacts on healthcare systems globally. However, a relatively unexplored area of investigation is that many virus types have been tied to cardiovascular and haemostatic diseases. The mechanisms by which viruses accomplish this is not understood. As a model, I have used herpes simplex virus type 1 (HSV1) to explore the concept that viruses that obtain an outer phospholipid bilayer membrane can acquire the main physiological initiator of coagulation, tissue factor (TF). The Pryzdial lab has previously shown that several herpesviruses, including HSV1, incorporate TF when they are propagated in TF-expressing cells. TF is involved in the activation of the coagulation pro-enzyme factor X through the enhancement of factor VIIa proteolytic activity. This was shown to enhance virus infectivity through coagulation protease-dependent activation of cell signaling. HSV1 also expresses its self-encoded membrane protein, glycoprotein C (gC), which is involved in cell adhesion and immune escape. As gC is also capable of binding factor X, I postulated that gC regulates factor X activation through TF on the virus surface. To study how gC affects TF function, protein interactions were followed via cross-linking, chromogenic activity assays and microscale thermophoresis. In this study, I discovered that gC interacted with factor VIIa and factor X, rather than with TF, to form a unique enzyme complex that activates factor X. Similar to TF and factor VIIa interaction, gC requires factor X to efficiently assemble with factor VIIa. This complex can directly activate factor X and induce fibrin formation in plasma. Although this pro-coagulant function of gC may be restricted to homologous gene products in all herpesvirus family members, I have demonstrated that other viruses can incorporate TF into their membranes. In addition to purified viruses propagated in cell culture, I found that patient plasma-derived human immunodeficiency virus and hepatitis C virus can incorporate TF into their virus envelope. This could explain some of the haemostatic abnormalities associated with viral infection.

Text

2019-08-15

Attribution-NonCommercial 4.0 International

http://hdl.handle.net/2429/71296

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc/4.0/