Long term Immune Residence and Cellular Remodeling Follow Viral Infection of the Olfactory Neuroepithelial Barrier

Abstract

Abstract Barrier immunity, particularly at mucosal surfaces, provides a first line of defense against invading pathogens. Unlike the more classical barrier surfaces in the gut, respiratory tract, genital tract, and skin, the olfactory epithelium within the nose is a specialized barrier structure containing layers of olfactory sensory neurons (OSNs) dedicated to our sense of smell. Because OSNs must contact the nasal airways, they are vulnerable to infection. Upper respiratory viral infection is known to damage the olfactory neuroepithelium and is associated with loss of olfaction. Neurotropic viruses, such as vesicular stomatitis virus (VSV), readily infect OSNs, yet the olfactory epithelial response to infection is unknown. Using a newly generated VSV expressing Cre recombinase, we tracked the fate of virus infected cells after clearance. Numerous cell types, including neural precursors and olfactory ensheathing cells, survived infection. In addition, several months after infection, we detected clonal patches of regenerated mature OSNs derived from previously infected neuroepithelial precursors. VSV infection drove a massive influx of CD45+ hematopoietic cells into the olfactory epithelium that established residence after viral clearance. This included antigen presenting cells and tissue resident CD4+ and CD8+ T cells that localized in and around the regenerating neuroepithelium. We postulate that these immune cells provide a barrier defense against viral rechallenge and might play a role in supporting neuronal regeneration. Collectively, these studies offer insights into how the nasal barrier remodels its neural-immune architecture to restore function and provide enhanced protection following a viral challenge.