Peripheral detection of viruses shapes brain immunity and behavior in zebrafish

Olfactory sensory neurons (OSNs) are constantly exposed to pathogens, including viruses. However, serious infection of the brain by the olfactory route rarely occurs. When OSNs detect a virus, they coordinate local antiviral immune responses to stop virus progression into the brain. Despite effective immune control at the olfactory periphery, pathogen-triggered neuronal signals reach the CNS via initial outputs in the olfactory bulb (OB). We hypothesized that neuronal detection of a virus by OSNs initiates neuroimmune responses in the OB that prevent pathogen invasion. Using zebrafish (Danio rerio) as a model, we demonstrate viral-specific neuronal activation of OSNs projecting into the OB, indicating that OSNs are electrically activated by viruses. Further, behavioral changes are seen in both adult and larval zebrafish after viral exposure. By profiling the transcription of single cells in the OB after OSNs are exposed to virus, we found that both microglia and neurons enter a protective state. Cells with microglia and macrophage markers in the OB respond within minutes of nasal viral delivery followed by striking responses in neuronal clusters characterized by decreased expression of neuronal differentiation factors and enrichment of genes in the neuropeptide signaling pathway, especially the known antimicrobial pacap. We confirm that PACAP is antiviral in vitro and that PACAP expression increases in the OB 1 day post-viral treatment. Our work reveals how encounters with viruses in the olfactory periphery shape the vertebrate brain by inducing antimicrobial programs in neurons and by altering host behavior. ### Competing Interest Statement The authors have declared no competing interest.