The immune mechanism of the nasal epithelium in COVID-19–related olfactory dysfunction

Abstract

During the first waves of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, olfactory dysfunction (OD) was reported as a frequent clinical sign. The nasal epithelium is one of the front-line protections against viral infections, and the immune responses of the nasal mucosa may be associated with OD. Two mechanisms underlying OD occurrence in COVID-19 have been proposed: the infection of sustentacular cells and the inflammatory reaction of the nasal epithelium. The former triggers OD and the latter likely prolongs OD. These two alternative mechanisms may act in parallel; the infection of sustentacular cells is more important for OD occurrence because sustentacular cells are more likely to be the entry point of SARS-CoV-2 than olfactory neurons and more susceptible to early injury. Furthermore, sustentacular cells abundantly express transmembrane protease, serine 2 (TMPRSS2) and play a major role in the olfactory epithelium. OD occurrence in COVID-19 has revealed crucial roles of sustentacular cells. This review aims to elucidate how immune responses of the nasal epithelium contribute to COVID-19–related OD. Understanding the underlying immune mechanisms of the nasal epithelium in OD may aid in the development of improved medical treatments for COVID-19–related OD.

Prevalence and Factors Associated with Olfactory Dysfunction in Individuals with COVID-19 in Brazil: A Study of 20,669 Cases from 2020 to 2021

“…Among individuals who reported anosmia, there was a higher proportion of females, with 61.1% (n = 564) in 2020 and 61.7% (n = 1,713) in 2021. The median age did not differ significantly in the 2 years, with values of 36 years (IQR 27-46) in 2020 and 35 years (IQR [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] in 2021 (Mann-Whitney; p = 0.203) (Fig. 1b).…”

“…This is due to the fact that olfactory disturbance is a symptom that is only detectable when reported by the individual, unlike other verifiable complaints such as fever and dyspnea. Signs of severity, such as fever and cough, were found to have a negative association with olfactory disorders [ 44 ]. Furthermore, patients suffering from COVID-19-related anosmia tend to exhibit significantly lower serum levels of interleukin-6 (IL-6) than patients without anosmia, although this is controversial [ 44 ].…”

“…Signs of severity, such as fever and cough, were found to have a negative association with olfactory disorders [ 44 ]. Furthermore, patients suffering from COVID-19-related anosmia tend to exhibit significantly lower serum levels of interleukin-6 (IL-6) than patients without anosmia, although this is controversial [ 44 ]. Lower levels of interleukin-6 are associated with a milder course of the disease [ 45 ].…”

Type 2 and Non-type 2 Inflammation in the Upper Airways: Cellular and Molecular Alterations in Olfactory Neuroepithelium Cell Populations

“…Evidences in experimental models and in human samples have confirmed that sustentacular cells are the main target for SARS-CoV-2 [ 88 , 89 ••, 90 ]. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), the entry point for SARS-CoV-2, are expressed in the sustentacular cells being more susceptible than ONs to early infection [ 89 ••, 90 , 91 ••]. The lack of ONs support due to the death of infected sustentacular cells may compromise neuronal function leading to LoS in COVID-19 [ 49 ••, 92 ].…”

Olfactory immune response to SARS-CoV-2

“…What could explain the differences in this regenerative capacity? Evidence suggests that sustained inflammation may prevent olfactory stem cells from repopulating the tissue with functional neurons [118] (Fig. 1c).…”