Supporting Cells of the Human Olfactory Epithelium Co-Express the Lipid Scramblase TMEM16F and ACE2 and May Cause Smell Loss by SARS-CoV-2 Spike-Induced Syncytia

Abstract

Background/Aims: Quantitative and qualitative alterations in the sense of smell are well established symptoms of COVID-19. Some reports have shown that non-neuronal supporting (also named sustentacular) cells of the human olfactory epithelium co-express ACE2 and TMPRSS2 necessary for SARS-CoV-2 infection. In COVID-19, syncytia were found in many tissues but were not investigated in the olfactory epithelium. Some studies have shown that syncytia in some tissues are formed when SARS-CoV-2 Spike expressed at the surface of an infected cell binds to ACE2 on another cell, followed by activation of the scramblase TMEM16F (also named ANO6) which exposes phosphatidylserine to the external side of the membrane. Furthermore, niclosamide, an approved antihelminthic drug, inhibits Spike-induced syncytia by blocking TMEM16F activity. The aim of this study was to investigate if proteins involved in Spike-induced syncytia formation, i.e., ACE2 and TMEM16F, are expressed in the human olfactory epithelium. Methods: We analysed a publicly available single-cell RNA-seq dataset from human nasal epithelium and performed immunohistochemistry in human nasal tissues from biopsies. Results: We found that ACE2 and TMEM16F are co-expressed both at RNA and protein levels in non-neuronal supporting cells of the human olfactory epithelium. Conclusion: Our results provide the first evidence that TMEM16F is expressed in human olfactory supporting cells and indicate that syncytia formation, that could be blocked by niclosamide, is one of the pathogenic mechanisms worth investigating in COVID-19 smell loss.

Post-viral olfactory loss and parosmia

“… 61 ACE2 and TMEM16F were shown to be coexpressed both at RNA and protein levels in sustentacular cells, supporting the hypothesis of pathological syncytia formation. 62 …”

“…61 ACE2 and TMEM16F were shown to be coexpressed both at RNA and protein levels in sustentacular cells, supporting the hypothesis of pathological syncytia formation. 62 Acute sustentacular injury might account for early phase olfactory dysfunction, but more widespread changes induced in the olfactory pathway by SARS-CoV-2 could account for longlasting symptoms. After infection, SARS-CoV-2 has been observed to disrupt the nuclear architecture and interfere with olfactory sensory neurons' transcriptome, influencing a persistent downregulation of olfactory receptor proteins and olfactory receptors signalling genes in human olfactory sensory neurons.…”