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

Area of Science:

• Neurovirology
• Molecular Biology
• Cell Biology

Background:

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

Purpose of the Study:

• To investigate the role of TDP-43 in HSV-1 infection across different human cell types.
• To elucidate the mechanism by which TDP-43 influences viral replication in neurons.

Main Methods:

• HSV-1 infection assays in epithelial cells, primary fibroblasts, and a human neuron-derived cell line (HD10.6).
• TDP-43 depletion using RNA interference.
• Viral replication and gene expression analysis.
• Nanopore direct RNA sequencing to assess mRNA processing.

Main Results:

• TDP-43 depletion did not affect HSV-1 replication in epithelial cells or fibroblasts.
• In neuron-derived HD10.6 cells, TDP-43 depletion significantly reduced HSV-1 production.
• TDP-43 depletion inhibited viral lytic gene expression during the immediate-early phase.
• Nanopore sequencing revealed enhanced intron retention in essential viral genes upon TDP-43 depletion.

Conclusions:

• TDP-43 is cell-type specifically required for efficient HSV-1 replication in human neurons.
• TDP-43 promotes HSV-1 gene expression and viral mRNA splicing.
• This interaction may contribute to the understanding of neurodegenerative disease etiology.