Molecular mechanisms involved in anosmia induced by SARS-CoV-2, with a focus on the transmembrane serine protease TMPRSS2

Abstract

Since 2020, SARS-CoV-2 has caused a pandemic virus that has posed many challenges worldwide. Infection with this virus can result in a number of symptoms, one of which is anosmia. Olfactory dysfunction can be a temporary or long-term viral complication caused by a disorder of the olfactory neuroepithelium. Processes such as inflammation, apoptosis, and neuronal damage are involved in the development of SARS-CoV-2-induced anosmia. One of the receptors that play a key role in the entry of SARS-CoV-2 into the host cell is the transmembrane serine protease TMPRSS2, which facilitates this process by cleaving the viral S protein. The gene encoding TMPRSS2 is located on chromosome 21. It contains 15 exons and has many genetic variations, some of which increase the risk of disease. Delta strains have been shown to be more dependent on TMPRSS2 for cell entry than Omicron strains. Blockade of this receptor by serine protease inhibitors such as camostat and nafamostat can be helpful for treating SARS-CoV-2 symptoms, including anosmia. Proper understanding of the different functional aspects of this serine protease can help to overcome the therapeutic challenges of SARS-CoV-2 symptoms, including anosmia. In this review, we describe the cellular and molecular events involved in anosmia induced by SARS-CoV-2 with a focus on the function of the TMPRSS2 receptor.

Fig. 1

TMPRSS2 gene map and features of two common gene variations, rs12329760 and rs75603675. The TMPRSS2 gene contains 15 exons, and rs12329760 and rs75603675 are located on exons 1 and 6, respectively. The position of the rs12329760 polymorphism in the three-dimensional structure of the protein suggests an effect on enzyme function.

Fig. 2

Effects of the rs12329760 polymorphism on protein and mRNA function and gene expression. A Potential deleterious impact of rs12329760 on the TMPRSS2 protein. B RNAsnp analysis showing no impact on mRNA structure. C Effect of this genetic variation on TMPRSS2 expression.

Fig. 3

Inhibitory effect of camostat and nafamostat on SARS-CoV-2 entry into the cell. Because TMPRSS2 plays a key role in virus entry, the serine protease inhibitors camostat and nafamostat can inhibit virus cell entry by blocking TMPRSS2.