Persistent post–COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium

SARS-CoV-2 causes profound changes in the sense of smell, including total smell loss. Although these alterations are often transient, many patients with COVID-19 exhibit olfactory dysfunction that lasts months to years. Although animal and human autopsy studies have suggested mechanisms driving acute anosmia, it remains unclear how SARS-CoV-2 causes persistent smell loss in a subset of patients. To address this question, we analyzed olfactory epithelial samples collected from 24 biopsies, including from nine patients with objectively quantified long-term smell loss after COVID-19. This biopsy-based approach revealed a diffuse infiltrate of T cells expressing interferon-γ and a shift in myeloid cell population composition, including enrichment of CD207+ dendritic cells and depletion of anti-inflammatory M2 macrophages. Despite the absence of detectable SARS-CoV-2 RNA or protein, gene expression in the barrier supporting cells of the olfactory epithelium, termed sustentacular cells, appeared to reflect a response to ongoing inflammatory signaling, which was accompanied by a reduction in the number of olfactory sensory neurons relative to olfactory epithelial sustentacular cells. These findings indicate that T cell–mediated inflammation persists in the olfactory epithelium long after SARS-CoV-2 has been eliminated from the tissue, suggesting a mechanism for long-term post–COVID-19 smell loss. Description Single-cell analysis of olfactory tissue biopsies from COVID-19 patients suggests T cell–mediated mechanisms underlying smell loss associated with SARS-CoV-2 infection. Smelling success in elucidating COVID-19 anosmia Smelling success in elucidating COVID-19 anosmia Loss of the sense of smell due to COVID-19 can last for months but the underlying pathogenic mechanisms remain unclear. In new work, Finlay et al. analyze biopsies of olfactory mucosa collected from COVID-19 patients with persistent smell loss using single cell RNA-sequencing and immunohistochemistry. The authors report that, compared with controls, biopsies from hyposmic individuals exhibited fewer olfactory sensory neurons and altered immune cell populations including T cells producing interferon-gamma, CD207+ dendritic cell enrichment, and depletion of M2 macrophages. These findings suggest that altered immune cell populations in olfactory epithelia contribute to long-term smell loss after COVID-19. ---OMS