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.

Exploring the research landscape of COVID-19-induced olfactory dysfunction: A bibliometric study

“…Sodagar et al (2022) reviewed the pathological features, neuroinflammatory mechanisms, and potential treatments of SARS-CoV-2 in the brain, finding strong infection of the olfactory bulb, thalamus, and brainstem. Karimian et al (2022) explored the molecular mechanism of SARS-CoV-2-induced olfactory deficit, suggesting that OD may be a temporary or long-term complication caused by olfactory neuroepithelial disorders, with the Delta and Omicron strains relying on TMPRSS2 to enter cells and inducing inflammation, apoptosis, and neuronal damage.…”

Prevalence of Olfactory Dysfunction with the Omicron Variant of SARS-CoV-2: A Systematic Review and Meta-analysis

“…Second, due to reduced furin cleavage, the omicron variant prefers an endosomal route via cathepsin for entering host cells rather than a surface membrane fusion via the protease TMPRSS2 [103]. Sustentacular cells and Bowman gland cells are the cells in the olfactory epithelium which most abundantly express not only ACE2, but also TMPRSS2 [104,105] and for this reason these support cells were the prime target of previous SARS-CoV-2 variants for host cell entry via the route using cell surface membrane fusion enabled by TMPRSS2 [106]. Since the support cells – similar to many other host cells – have evolved more potent defense mechanisms for the endosomal route of infection [102,107], for example, the antiviral IFITM2 gene is the most highly upregulated gene in support cells at 3 days after infection [108], this may lead to a lower efficiency in omicron infection of the support cells of the olfactory epithelium, and therefore reduced olfactory dysfunction [102,109].…”

The Luminescence Hypothesis of Olfaction

“…COVID-19 has a high prevalence of anosmia of 38% [ 81 ]. The source has not been discovered to be related to the transmembrane serine protease TMPRSS2 which is involved with cell entry [ 82 ]. The main finding in multiple research efforts is that it is the sustentacular cells that mediate the dysfunction, and not the neural cells of ONs or the brain [ 80 , 83 ].…”