Understanding olfactory dysfunction in COVID-19: Expression of ACE2, TMPRSS2 and Furin in the nose and olfactory bulb in human and mice

Abstract

Background Anosmia is a frequent symptom in patients with the coronavirus disease 2019 (COVID-19) driven by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mostly recovers within weeks. This clinical figure is significantly different from that of anosmia after upper respiratory infection, which occurs in only a small proportion of patients and does not recover or requires months to recover. The background mechanisms of COVID-19 induced olfactory dysfunction have not been elucidated.Methods To address the unique pathophysiology of olfactory dysfunction associated with COVID-19, we examined the existence and distribution of ACE2 (virus binding receptor), TMPRSS2 and Furin (proteases to facilitate virus entry) in the nasal mucosa, composed of the respiratory mucosa (RM) and olfactory mucosa (OM), and the olfactory bulb (OB) in mouse and human tissues by immunohistochemistry and gene analyses.Results Ace2, Tmprss2, and Furin gene expressions were confirmed in the nasal mucosa and OB. ACE2 was widely expressed all in the RM, OM and OB. Co-expression of ACE2, TMPRSS2, and Furin was observed in the RM including the RE and subepithelial glands and in the OM, especially in the supporting cells on the olfactory epithelium and the Bowman’s glands. Notably, the olfactory receptor neurons (ORNs) in the OM were positive for ACE2 but almost negative for TMPRSS2 and Furin. The cells in the OB expressed ACE2 strongly and Furin weakly and did not express TMPRSS2.Conclusions ACE2 was widely expressed in the RM, OM and OB, but TMPRSS2 and Furin were expressed in certain types of cells and were absent in the ORNs. These findings, together with clinically reported ones, suggest that COVID-19 related anosmia can occur due to mainly sensorineural and central dysfunction and, to some extent, conductive olfactory dysfunction. That the ORNs express ACE2 but not TMPRSS2 or Furin may explain the early recovery of anosmia.Short Summary Protein expression patterns of ACE2, TMPRSS, and Furin suggest that COVID-19 related anosmia can occur due to mainly sensorineural dysfunction without olfactory neuronal damage.Competing Interest StatementThe authors have declared no competing interest.View Full Text