Suppression of the host antiviral response by non-infectious varicella zoster virus extracellular vesicles

Author:

Niemeyer Christy S.1,Frietze Seth2ORCID,Coughlan Christina1,Lewis Serena W. R.1,Bustos Lopez Sara1,Saviola Anthony J.3,Hansen Kirk C.3,Medina Eva M.1,Hassell James E.1,Kogut Sophie2,Traina-Dorge Vicki4,Nagel Maria A.15,Bruce Kimberley D.6,Restrepo Diego7,Mahalingam Ravi1,Bubak Andrew N.1ORCID

Affiliation:

1. Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

2. Department of Biomedical and Health Sciences, University of Vermont, Burlington, Vermont, USA

3. Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

4. Division of Microbiology, Tulane National Primate Research Center, Tulane University, Covington, Louisiana, USA

5. Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

6. Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

7. Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

Abstract

ABSTRACT Varicella zoster virus (VZV) reactivates from ganglionic sensory neurons to produce herpes zoster (shingles) in a unilateral dermatomal distribution, typically in the thoracic region. Reactivation not only heightens the risk of stroke and other neurological complications but also increases susceptibility to co-infections with various viral and bacterial pathogens at sites distant from the original infection. The mechanism by which VZV results in complications remote from the initial foci remains unclear. Small extracellular vesicles (sEVs) are membranous signaling structures that can deliver proteins and nucleic acids to modify the function of distal cells and tissues during normal physiological conditions. Although viruses have been documented to exploit the sEV machinery to propagate infection, the role of non-infectious sEVs released from VZV-infected neurons in viral spread and disease has not been studied. Using multi-omic approaches, we characterized the content of sEVs released from VZV-infected human sensory neurons (VZV sEVs). One viral protein was detected (immediate-early 62), as well as numerous immunosuppressive and vascular disease-associated host proteins and miRNAs that were absent in sEVs from uninfected neurons. Notably, VZV sEVs are non-infectious yet transcriptionally altered primary human cells, suppressing the antiviral type 1 interferon response and promoting neuroinvasion of a secondary pathogen in vivo . These results challenge our understanding of VZV infection, proposing that the virus may contribute to distant pathologies through non-infectious sEVs beyond the primary infection site. Furthermore, this study provides a previously undescribed immune-evasion mechanism induced by VZV that highlights the significance of non-infectious sEVs in early VZV pathogenesis. IMPORTANCE Varicella zoster virus (VZV) is a ubiquitous human virus that predominantly spreads by direct cell-cell contact and requires efficient and immediate host immune evasion strategies to spread. The mechanisms of immune evasion prior to virion entry have not been fully elucidated and represent a critical gap in our complete understanding of VZV pathogenesis. This study describes a previously unreported antiviral evasion strategy employed by VZV through the exploitation of the infected host cell’s small extracellular vesicle (sEV) machinery. These findings suggest that non-infectious VZV sEVs could travel throughout the body, affecting cells remote from the site of infection and challenging the current understanding of VZV clinical disease, which has focused on local effects and direct infection. The significance of these sEVs in early VZV pathogenesis highlights the importance of further investigating their role in viral spread and secondary disease development to reduce systemic complications following VZV infections.

Funder

HHS | NIH | National Institute on Aging

Publisher

American Society for Microbiology

Reference83 articles.

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