PROJECT SUMMARY: The sudden loss of smell and taste are among the defining features of COVID-19 that set it apart from other viral respiratory syndromes with an incidence of up to 70% with some SARSCoV2 variants. Importantly, in some patients smell and taste disturbances persist for longer than 12 months after recovery from COVID-19. Furthermore, classical anti-inflammatory treatment therapies are ineffective for COVID19 chemosensory dysfunction. To inform targeted treatments, it is critical to elucidate the specific pathways that lead to persistent disruption of chemosensory function. Our preliminary data show that persistent COVID19 chemosensory dysfunction involves persistently disordered neuroepithelial composition and infiltration with immune cells with features of immunosuppressive macrophages. The dysregulated inflammatory milieu prominently features linoleic acid metabolites and glioma-associated proteins with direct effect on olfactory stem cell proliferation and differentiation and olfactory sensory neuron survival. This study will determine how the inflammatory but steroid-resistant immune cells drive chemosensory dysfunction that plagues patients with persistent COVID19 disruption of smell and taste. In Aim 1 we will define the phenotype of the infiltrating immune cells using both transcriptional and mediator studies. In Aim 2, we will determine how immune mediators defined in Aim 1 disrupt olfactory stem cell and sensory neuron development and apoptosis trajectories using a mouse in vitro system and relate these findings to the disordered epithelial composition of subjects with persistent COVID19 chemosensory dysfunction. Thus, we use complementary approaches with molecular tools and cell systems and samples from carefully phenotyped human subjects. The studies should reveal new potential strategies for therapeutic development that are based on the novel underlying mechanism that we identified here.