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Title: Varicella zoster virus vasculopathy
Author: Moraitis, E.
ISNI:       0000 0004 7232 5349
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Varicella zoster virus (VZV) associated vasculopathy has long been identified as a major risk factor for arterial ischaemic stroke (AIS) in both adults and children. The exact mechanisms of VZV-induced pathological vascular remodelling leading to AIS have however not been fully elucidated, thus hampering current therapeutic approaches for AIS prevention. Previous immunohistochemical analysis of the morphology and composition of the arterial wall, and the location of viral antigen in the adventitia of patients with early VZV cerebral vasculopathy suggested that human brain vascular adventitial fibroblasts (HBVAF) may be the point of VZV entry into the cerebral arterial wall. In this thesis, I explored the hypothesis that VZV exerts direct pathogenic effects affecting different cells of the vasculature that could result in occlusive cerebral vasculopathy. I showed that following infection in vitro, VZV promotes HBVAF transdifferentiation to myofibroblasts, with subsequent proliferation and migration as identified by induction of α-SMA and EdU expression, and scratch assay repair. RNAseq profile analysis of VZV-infected HBVAF revealed significant upregulation of a number of genes in the infected cells, highlighting pathways possibly underlying the morphological changes described. I also examined the interaction of VZV-infected HBVAF with endothelial cells, and showed activation and dysfunction in cultured endothelial cells induced by conditioned media from VZV-infected HBVAF. Further experiments revealed that VZV-infected HBVAF release proinflammatory cytokines and chemokines that could contribute to the pathogenesis of cerebral arteriopathy. Lastly, I explored whether some of these effects on endothelial cells could be mediated by microparticle (MP) release. MP are membrane vesicles that are released from cells upon activation or during apoptosis, and are key inflammatory and endothelial dysfunction mediators in several vascular diseases. I showed that MP derived from VZV infected HBVAF contain VZV particles as detected by flow cytometry, electron microscopy and mass spectrometry. These MP-VZV complexes could infect healthy HBVAF, and might suggest a completely novel mechanism of VZV infectivity with potential relevance to viral induced changes locally in the cerebral vasculature. In conclusion, these novel findings suggest that in the context of VZV related cerebral arteriopathy, HBVAF are important players for initiation and propagation of vascular inflammation and remodelling, and that MP act as key facilitators of cross talk an viral propagation between endothelial cells and neighbouring HBVAFs. These observations suggest an entirely novel mechanism of VZV vasculopathy that furthers our understanding of the pathogenesis of AIS.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available