Title: Persistent post-COVID-19 smell loss is associated with immune infiltration and altered olfactory epithelial gene expression Code to perform analyses in Finlay et al. 2022 Publication abstract: SARS-CoV-2 causes profound changes in the sense of smell, including total smell loss. While these alterations are often transient, many COVID-19 patients exhibit olfactory dysfunction that lasts months to years. Although animal and human autopsy studies have suggested mechanisms driving acute anosmia, it remains unclear how SARSCoV- 2 causes persistent smell loss in a subset of patients. To address this question, here we analyze olfactory epithelial samples derived from patients suffering from objectively quantified long-term smell loss following COVID-19. This biopsy-based approach reveals a diffuse infiltrate of T cells expressing interferon-gamma, and a myeloid cell shift including enrichment of CD207+ dendritic cells and depletion of antiinflammatory M2 macrophages. Despite the absence of detectible SARS-CoV-2 RNA or protein, gene expression in sustentacular cells appears to reflect a response to ongoing inflammatory signaling, which is accompanied by a reduction in the number of olfactory sensory neurons relative to support cells. These data suggest that T-cell mediated inflammation persists in the olfactory epithelium long after the virus has been eliminated from the tissue, identify a mechanism underlying long-term post-COVID smell loss, and raise the possibility that sterile epithelial infiltration by immune cells participates in other long COVID symptoms. Data: All datasets used in this manuscript are available on NCBI GEO at accession numbers GSE201620, GSE139522, and GSE184117. Raw data are provided as CellRanger Count output matrices. Raw fastq files can be found on the SRA. Code also available on GitHub at https://github.com/Goldstein-Lab/Finlay_long_COVID_smell_loss