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

Rybak-Wolf, A.; Wyler, E.; Legnini, I.; Loewa, A.; Glazar, P.; Joon Kim, S.; Pentimalli, T. M.; Oliveras Martinez, A.; Beyersdorf, B.; Woehler, A.; Landthaler, M.; Rajewsky, N.

doi:10.1101/2021.03.05.434122

bioRxiv · 10.1101/2021.03.05.434122

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

Rybak-Wolf, A.·Wyler, E.·Legnini, I.·Loewa, A.·Glazar, P.·Joon Kim, S.·Pentimalli, T. M.·Oliveras Martinez, A.·Beyersdorf, B.·Woehler, A.·Landthaler, M.·Rajewsky, N.

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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.

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Rybak-Wolf, A., Wyler, E., Legnini, I., Loewa, A., Glazar, P., Joon Kim, S., Pentimalli, T. M., Oliveras Martinez, A., Beyersdorf, B., Woehler, A., Landthaler, M., Rajewsky, N.. 2021-03-07. Neurodegeneration in human brain organoids infected with herpes simplex virus type 1. https://doi.org/10.1101/2021.03.05.434122

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