Peripheral viral detection induces an antimicrobial program in olfactory bulb immature neurons

Abstract

Abstract The immune and nervous systems have co-evolved to sense and eliminate danger. Neuroimmune interactions occur bidirectionally between the periphery and the central nervous system (CNS) in physiological and disease states. In the olfactory periphery, olfactory sensory neurons (OSNs) are exposed to environmental pathogens and project their axons onto the olfactory bulb. Previous studies have shown that the olfactory bulb participates in the immune response when a pathogen directly invades the CNS. We hypothesize that immune responses occur in the olfactory bulb in response to peripheral pathogen detection by OSNs. We have leveraged zebrafish as a model organism to study neuronal signaling in response to peripheral viral stimuli without infection of the olfactory bulb. Using single cell RNA sequencing we demonstrate that microglia respond to peripheral viral stimuli within 15 min, while a population of immature neurons expressing the neurotransmitter adcyap1(PACAP-38) and scg5(secretogranin V) expands within one day. PACAP-38 is a highly conserved neuropeptide with immunomodulatory and antimicrobial functions in mammals, suggesting that immature neurons participate in the antiviral state of the olfactory bulb. Neuronal transcriptional responses to olfactory viral stimuli were coupled to neuronal activation in the olfactory bulb. Furthermore, neuronal changes are translated into behavioral responses, as shown by a reduced mean velocity in an open field test after one day in virally treated compared to control animals. Taken together, these results indicating that peripheral viral stimuli induce a neuropeptide-based antimicrobial program in the olfactory bulb of adult zebrafish.