Summary
A bioRxiv preprint reports that ALS- and FTD-linked TDP-43 alterations reduce HSV-1 infection in experimental models. The researchers connect the effect to changes in cell-adhesion signalling involving focal adhesion kinase.
A bioRxiv preprint reports that forms of TDP-43 associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) make experimental cells less susceptible to herpes simplex virus type 1 (HSV-1). The researchers link this effect to changes in cell-adhesion pathways that appear to reduce the virus’s early binding and entry into cells.
The authors report the protective effect across several TDP-43 alterations, including mutations, sporadic ALS and C9ORF72-associated ALS. They describe findings in neural and non-neural cell types, patient-derived cells and animal models. The work is preclinical: it does not report clinical measurements of HSV-1 infection in people with ALS or FTD.
TDP-43 changes affect early infection steps
TDP-43 is a protein whose alterations are a hallmark of ALS, FTD and some other neurodegenerative disorders. In the experiments described in the preprint, neurons with TDP-43 mutations showed changes in pathways involved in cell adhesion and had less viral binding and entry at an early stage of infection.
The researchers also found that reducing TDP-43 through knockdown was sufficient to protect cells from HSV-1, while increasing TDP-43 through overexpression was not. They interpret this pattern as pointing to a loss of normal TDP-43 function, rather than simply an effect of having more of the protein.
The study connects the cell-adhesion changes to focal adhesion kinase, or FAK (also known as PTK2), a protein involved in adhesion-related signalling. Inhibiting FAK reduced HSV-1 infection. In cells with TDP-43 mutations, boosting functional FAK promoted infection, while boosting an inactive form did not. The authors also report alternative RNA splicing associated with the pathway changes.
A possible link between neurodegeneration and viral susceptibility
HSV-1 is a common virus with the capacity to infect nervous tissue. The findings suggest that changes in a host cell’s adhesion machinery can influence how readily the virus binds and enters—not just how the cell responds after exposure. The authors also report that TDP-43 alterations prevented inflammatory and cell-stress responses to HSV-1 exposure in their models.
This offers a potential route for studying interactions between neurodegenerative disease biology and viral infection. The evidence is from experimental models, including patient-derived cells and animals; it does not establish that people with ALS or FTD have lower rates of HSV-1 infection. The bioRxiv article is a preprint, and its abstract does not provide sample sizes or numerical effect estimates.