TDP-43 promotes efficient HSV-1 replication in human DRG-derived neurons

TAR DNA-binding protein 43 (TDP-43) is a versatile nuclear RNA-binding protein that performs important functions in RNA localization, processing and stability. In the neurodegenerative disease amyloid lateral sclerosis (ALS) TDP43 forms toxic, insoluble cytoplasmic aggregates that ultimately lead to neuronal loss. Although TDP-43 is expressed in every cell type, its function and subcellular localization are particularly important for neuronal homeostasis. However, it is unknown if TDP-43 has a role during herpesviral infection. Herpes simplex virus type-1 (HSV-1), a ubiquitous neurotrophic pathogen considered a contributing factor to neurodegenerative disorders. In this study, we tested the requirement for TDP-43 during HSV-1 infection in neuronal and non-neuronal cells. HSV-1 infection of epithelial cells and fibroblasts did not change overall TDP-43 abundance, nor did TDP-43 depletion detectably alter HSV-1 replication in a multicycle growth experiment. By contrast, when TDP-43 was depleted in differentiated HD10.6 cells , HSV-1 infectious virus production was significantly reduced in both single- and multicycle growth experiments. Notably, TDP-43 depletion restricts viral lytic gene expression at the immediate-early phase. Through nanopore direct RNA-sequencing we uncovered enhanced intron retention in two essential viral genes upon TDP-43 depletion. Thus, while depletion of TDP-43 does not affect replication in epithelial cells and fibroblasts, TDP-43 is required for efficient replication in HD10.6 cells through modifying the abundance and splicing of viral genes.