Infection by herpes simplex virus (HSV-1) is lifelong with frequent recurrent episodes. During recurrent herpes infections, HSV-1 travels along sensory nerves to reinfect the epidermis. Once in the epidermis, HSV-1 induces the production of interferons (IFNs) from both infected epithelial cells as well as from resident and infiltrating immune cells. The presence of IFNs is crucial for control and clearance of the virus from the lesions. However, there is limited research on whether IFNs produced by infected epidermal cells or resident/infiltrating immune cells exert an inhibitory effect on the nerves innervating the lesions.
Using an innovative compartmentalised neuronal culture system, we recently showed that direct treatment of sensory axons with recombinant IFNs (IFNα1, α14, β, γ or λ3) activates STAT1/3 locally in axons and inhibits HSV-1 exit from infected axons. Neurons are capable of local protein translation in the axon terminals, and hence, IFNs are likely to induce local changes to the axonal proteome to inhibit virus exit. Therefore, we aim to identify proteins, phosphoproteins and signalling pathways, altered by IFN, leading to virus inhibition from axons. For this, we performed proteomic and phosphoproteomic analysis of HSV-1 infected axons directly treated or untreated with IFN⍺14. We identified ~ 100 host axonal proteins, which were differentially expressed and ~70 axonal proteins and kinases with significantly altered phosphosites in IFN⍺14-treated infected axons. These proteins are involved in cellular processes critical for virus exit from axons including actin organisation, calcium regulation, vesicle transport, membrane tethering and exocytosis in axons. We are determining which proteins and/or their phosphorylation are critical for virus exit from axons.
There is currently no cure or vaccine available for HSV-1 Therefore, this study will identify new targets for new classes of antivirals to prevent virus shedding from nerves and subsequent virus transmission, where current antiviral drugs have limited efficacy.