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

Abstract

BackgroundAnosmia is a frequent symptom in coronavirus disease 2019 (COVID-19) patients that generally resolves within weeks. In contrast, the anosmia caused by other upper respiratory infections affects a small proportion of patients and may take months to resolve or never resolve. The mechanisms behind COVID-19-induced olfactory dysfunction remain unknown. Here, we address the unique pathophysiology of COVID-19-associated olfactory dysfunction.MethodsThe expression of ACE2 (virus binding receptor) and TMPRSS2 and Furin (host cell proteases facilitating virus entry) was examined in the nasal mucosa, composed of respiratory mucosa (RM), olfactory mucosa (OM), and olfactory bulb (OB) of mouse and human tissues using immunohistochemistry and gene analyses.ResultsCo-expression of ACE2, TMPRSS2, and Furin was observed in the RM and in the OM, especially in the supporting cells of 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. Cells in the OB expressed ACE2 strongly and Furin weakly, and did not express TMPRSS2. All three gene expressions were confirmed in the nasal mucosa and OB.ConclusionsACE2 was widely expressed in all tissues, whereas TMPRSS2 and Furin were expressed only in certain types of cells and were absent in the ORNs. These findings, together with clinical reports, suggest that COVID-19-related anosmia occurs mainly through sensorineural and central dysfunction and, to some extent, conductive olfactory dysfunction. The expression of ACE2, but not TMPRSS2 or Furin, in ORNs may explain the early recovery from anosmia.

A Review on the Neurological Manifestations of COVID-19 Infection: a Mechanistic View

“…2b). In this scene, Furin and the transmembrane protease serine 2 (TMPRSS2) are two key players [54]. TMPRSS2 locating in the cell membrane primes the spike protein to facilitate viral uptake by ACE2.…”

Evidence of SARS-CoV2 entry protein ACE2 in the human nose and olfactory bulb

“…Different cell types and their interconnections, like interneurons and projection neurons are located in deeper layers of the olfactory bulb and lead to processed and fine-tuned sensory information ( Figure 4A) [20]. The olfactory bulb has been analyzed on RNA level and on protein level with mouse tissue so far [8,9]. In the human olfactory bulb, ACE2 could be found widely distributed, with high expression in the glomerular layer ( Figure 4D).…”

“…Up to date, there is no clear evidence which cell types of the olfactory and respiratory epithelium express ACE2 and TMPRSS2. Transcriptional but also data from murine and human olfactory tissue show as of now report conflicting data [7][8][9][10]. In addition, the reports on localization of the viral entry proteins in different cell types from the epithelia vary [7,8].…”

“…Transcriptional but also data from murine and human olfactory tissue show as of now report conflicting data [7][8][9][10]. In addition, the reports on localization of the viral entry proteins in different cell types from the epithelia vary [7,8]. Protein expression was found in sustentacular cells in all publications, but only one paper claims a low ACE2 expression in ORN [8].…”

“…In addition, the reports on localization of the viral entry proteins in different cell types from the epithelia vary [7,8]. Protein expression was found in sustentacular cells in all publications, but only one paper claims a low ACE2 expression in ORN [8]. TMPRSS2 was found in murine and human respiratory epithelium and murine olfactory epithelium [7].…”