Varicella zoster virus-induced autophagy in human neuronal and hematopoietic cells exerts antiviral activity

Johanna L. Heinz, Daniëla M. Hinke, Muyesier Maimaitili, Jiayi Wang, Ira K.D. Sabli, Michelle Thomsen, Ensieh Farahani, Fanghui Ren, Lili Hu, Thomas Zillinger, Anna Grahn, Joanna von Hofsten, Georges M.G.M. Verjans, Søren R. Paludan, Abel Viejo-Borbolla, Vanessa Sancho-Shimizu, Trine H. Mogensen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Autophagy is a degradational pathway with pivotal roles in cellular homeostasis and survival, including protection of neurons in the central nervous system (CNS). The significance of autophagy as antiviral defense mechanism is recognized and some viruses hijack and modulate this process to their advantage in certain cell types. Here, we present data demonstrating that the human neurotropic herpesvirus varicella zoster virus (VZV) induces autophagy in human SH-SY5Y neuronal cells, in which the pathway exerts antiviral activity. Productively VZV-infected SH-SY5Y cells showed increased LC3-I-LC3-II conversion as well as co-localization of the viral glycoprotein E and the autophagy receptor p62. The activation of autophagy was dependent on a functional viral genome. Interestingly, inducers of autophagy reduced viral transcription, whereas inhibition of autophagy increased viral transcript expression. Finally, the genotype of patients with severe ocular and brain VZV infection were analyzed to identify potential autophagy-associated inborn errors of immunity. Two patients expressing genetic variants in the autophagy genes ULK1 and MAP1LC3B2, respectively, were identified. Notably, cells of both patients showed reduced autophagy, alongside enhanced viral replication and death of VZV-infected cells. In conclusion, these results demonstrate a neuro-protective role for autophagy in the context of VZV infection and suggest that failure to mount an autophagy response is a potential predisposing factor for development of severe VZV disease.

Original languageEnglish
Article numbere29690
Number of pages18
JournalJournal of Medical Virology
Volume96
Issue number6
Early online date28 May 2024
DOIs
Publication statusPublished - Jun 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.

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