Microparticle-mediated VZV propagation and endothelial activation: Mechanism of VZV vasculopathy

Despina Eleftheriou; Elena Moraitis; Ying Hong; Mark Turmaine; Cristina Venturini; Vijeya Ganesan; Judith Breuer; Nigel Klein; Paul Brogan

doi:10.1212/WNL.0000000000008885

Microparticle-mediated VZV propagation and endothelial activation: Mechanism of VZV vasculopathy

Neurology. 2020 Feb 4;94(5):e474-e480. doi: 10.1212/WNL.0000000000008885. Epub 2019 Dec 31.

Authors

Despina Eleftheriou¹, Elena Moraitis², Ying Hong², Mark Turmaine², Cristina Venturini², Vijeya Ganesan², Judith Breuer², Nigel Klein², Paul Brogan²

Affiliations

¹ From the Infection, Immunology and Rheumatology Section (D.E., E.M., Y.H., C.V., J.B., N.K., P.B.) and Clinical Neurosciences (V.G.), University College London GOS Institute of Child Health; Arthritis Research UK Centre for Adolescent Rheumatology (D.E.); and Department of Cell and Developmental Biology (M.T.), University College London, UK. d.eleftheriou@ucl.ac.uk.
² From the Infection, Immunology and Rheumatology Section (D.E., E.M., Y.H., C.V., J.B., N.K., P.B.) and Clinical Neurosciences (V.G.), University College London GOS Institute of Child Health; Arthritis Research UK Centre for Adolescent Rheumatology (D.E.); and Department of Cell and Developmental Biology (M.T.), University College London, UK.

Abstract

Objective: Varicella zoster virus (VZV) can spread anterogradely and infect cerebral arteries causing VZV vasculopathy and arterial ischemic stroke. In this study, we tested the hypothesis that virus-infected cerebrovascular fibroblasts undergo phenotypic changes that promote vascular remodeling and facilitate virus transmission in an in vitro model of VZV vasculopathy. The aims of this project were therefore to examine the changes that virus-infected human brain adventitial vascular fibroblasts (HBVAFs) undergo in an in vitro model of VZV vasculopathy and to identify disease biomarkers relating to VZV-related vasculopathy.

Methods: HBVAFs were infected with VZV, and their ability to migrate, proliferate, transdifferentiate, and interact with endothelial cells was studied with flow cytometry. Microparticles (MPs) released from these cells were isolated and imaged with transmission electron microscopy, and their protein content was analyzed with mass spectrometry. Circulating MP profiles were also studied in children with VZV and non-VZV vasculopathy and compared with controls.

Results: VZV-infected HBVAFs transdifferentiated into myofibroblasts with enhanced proliferative and migratory capacity. Interaction of VZV-infected HBVAFs with endothelial cells resulted in endothelial dysfunction. These effects were, in part, mediated by the release of MPs from VZV-infected HBVAFs. These MPs contained VZV virions that could transmit VZV to neighboring cells, highlighting a novel model of VZV cell-to-cell viral dissemination. MPs positive for VZV were significantly higher in children with VZV-related vasculopathy compared to children with non-VZV vasculopathy (p = 0.01) and controls (p = 0.007).

Conclusions: VZV-infected HBVAFs promote vascular remodeling and facilitate virus transmission. These effects were mediated by the release of apoptotic MPs that could transmit VZV infection to neighboring cells through a Trojan horse means of productive viral infection. VZV+ MPs may represent a disease biomarker worthy of further study.

MeSH terms

Adolescent
Adventitia
Cell Movement*
Cell Proliferation*
Cell Transdifferentiation*
Cell-Derived Microparticles / ultrastructure
Cell-Derived Microparticles / virology*
Cerebral Arteries
Cerebrovascular Disorders / physiopathology
Cerebrovascular Disorders / virology*
Child
Child, Preschool
Endothelial Cells
Female
Fibroblasts / physiology
Fibroblasts / ultrastructure
Fibroblasts / virology*
Herpesvirus 3, Human
Humans
In Vitro Techniques
Male
Mass Spectrometry
Microscopy, Electron, Transmission
Myofibroblasts / physiology
Myofibroblasts / ultrastructure
Myofibroblasts / virology*
Stroke / physiopathology
Stroke / virology
Vascular Remodeling*
Virus Cultivation