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Neurodegeneration in human brain organoids infected with herpes simplex virus type 1

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Title:Neurodegeneration in human brain organoids infected with herpes simplex virus type 1
Creators Name:Rybak-Wolf, A. and Wyler, E. and Legnini, I. and Loewa, A. and Glažar, P. and Kim, S.J. and Pentimalli, T.M. and Oliveras Martinez, A. and Beyersdorf, B. and Woehler, A. and Landthaler, M. and Rajewsky, N.
Abstract:Herpes simplex virus type 1 (HSV-1) infection of the nervous system may lead to brain damage, including neurodegeneration. However, lack of suitable experimental models hinders understanding molecular mechanisms and cell-type-specific responses triggered by HSV-1. Here, we infected human brain organoids with HSV-1. Known features of HSV-1 infection such as alteration of neuronal electrophysiology and induction of antisense transcription were confirmed. Full-length mRNA-sequencing revealed aberrant 3’ end formation and poly(A)-tail lengthening. Single-cell RNA-seq and spatial transcriptomics uncovered changes in the cellular composition of the infected organoids caused by viral replication and dysregulation of molecular pathways in cell-type specific manner. Furthermore, hallmarks of early neurodegeneration were observed, namely extracellular matrix disruption, STMN2 and TARDBP/TDP43 downregulation, and upregulation of the AD-related non-coding RNA BC200/BCYRN1. These hallmarks were weaker/absent when infecting with a mutant HSV-1 control. Together, our data indicate that brain organoids serve as a powerful model to study mechanisms of HSV-1-driven neurodegeneration.
Keywords:Herpes Simplex Virus Type 1, HSV-1, Brain Organoids, Single-Cell RNA-seq, Neurodegeneration
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2021.03.05.434122
Date:7 March 2021
Official Publication:https://doi.org/10.1101/2021.03.05.434122

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