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

Area of Science:

• Neurovirology
• Molecular Biology
• RNA Biology

Background:

• TAR DNA-binding protein 43 (TDP-43) is vital for RNA processing and neuronal homeostasis.
• TDP-43 aggregates are implicated in neurodegenerative diseases like ALS.
• Herpes simplex virus type-1 (HSV-1) is a neurotropic pathogen linked to neurodegeneration.

Purpose of the Study:

• To investigate the role of TDP-43 in HSV-1 infection across different cell types.
• To determine if TDP-43 influences viral replication and gene expression in neurons.

Main Methods:

• HSV-1 infection assays in epithelial cells, fibroblasts, and neuron-derived HD10.6 cells.
• TDP-43 depletion using RNA interference.
• Analysis of viral replication via multicycle growth experiments.
• Nanopore direct RNA sequencing to assess viral mRNA processing.

Main Results:

• TDP-43 depletion did not affect HSV-1 replication in epithelial cells or fibroblasts.
• HSV-1 replication was significantly reduced in TDP-43-depleted neuron-derived HD10.6 cells.
• TDP-43 depletion impaired viral immediate-early gene expression and caused intron retention in ICP0 and UL15 viral genes.

Conclusions:

• TDP-43 is essential for efficient HSV-1 replication specifically in neuronal cells.
• TDP-43 influences HSV-1 gene expression and mRNA splicing, impacting viral propagation.
• Targeting TDP-43 may offer a novel antiviral strategy against severe HSV-1 infections.