ALS/FTD-linked TDP-43 alterations prevent HSV-1 infection by disrupting cell-adhesion pathways

The article discusses how alterations in TDP-43, a protein associated with neurodegenerative disorders such as ALS and FTD, can prevent herpes simplex virus type-1 (HSV-1) infection. TDP-43 alterations are a key feature of these conditions, and research has now linked them to viral infections as well. The study found that ALS/FTD-linked forms of human TDP-43 hinder HSV-1 infection, and this effect was consistent across different mutations, sporadic ALS, and C9ORF72-ALS.

This protective mechanism was observed in both neural and non-neural cell types, using patient-derived cells and animal models.

In addition to hindering infection, TDP-43 mutations also prevented inflammatory and cell stress-related responses to HSV-1 exposure. The protective effect was attributed to a loss-of-function mechanism, as TDP-43 knockdown but not overexpression was sufficient to protect cells from HSV-1 infection. Moreover, neurons with TDP-43 mutation exhibited disruptions in adhesion-related pathways, leading to reduced early-stage viral binding and entry.

These disruptions were linked to alternative RNA splicing and impairment of focal adhesion kinase (FAK/PTK2), a critical mediator of cell-adhesion pathways.

Inhibition of FAK was found to decrease HSV-1 infection, while genetic enhancement of functional FAK promoted infectivity in cells with TDP-43 mutation. In conclusion, this study highlights the role of TDP-43 in affecting virus-host interactions by influencing adhesion pathways required for viral infection.