Viral destruction of the olfactory mucosa elicits immune residence, bone metaplasia, and long-term smell loss.

The upper airway is comprised of two distinct mucosal surface tissues, the respiratory mucosa (RM) and the olfactory mucosa (OM), both of which are constantly being exposed to airborne pathogens. The olfactory mucosa is responsible for detecting and conveying odorant information into the central nervous system, and infection poses serious neuroinvasion risk. Using vesicular stomatitis virus (VSV) as a model of olfactotropic viral infection,(1) we identify long-term cellular and functional changes within the olfactory mucosa following infection. VSV infection rapidly destroys the neuroepithelium causing extensive tissue damage to the olfactory mucosa. Infection drives recruitment of numerous immune cell types to the olfactory mucosa where many continue to reside after viral resolution. Specifically, antigen-specific resident T cells are recruited and remain in the olfactory mucosa where they can produce inflammatory cytokines upon rechallenge. We also find following viral clearance, viral mediated damage results in ectopic bone growth within the nasal airway, significant olfactory tissue loss, and neurogenic failure leading to metaplastic conversion of olfactory mucosa into respiratory mucosa. This mucosal damage in previously infected animals results in functional olfaction deficits. Despite damage to the tissue and loss of olfactory surface area, an infection-based fate mapping approach demonstrated that previously infected precursor cells can survive infection, retain neuro-regenerative potential, and generate mature olfactory sensory neurons that synapse onto the olfactory bulb. Recent studies from SARS-CoV2 infected individuals indicate that long-term immune activity within the olfactory tissues can drive functional changes that impair olfaction. Our data provide an animal model for viral infection of the olfactory mucosa, one that leads to long-term immune residence and tissue architectural changes that suggest underlying commonalities with human studies linking immune activity following infection to permanent smell loss.