Mechanistic Understanding of the Olfactory Neuroepithelium Involvement Leading to Short-Term Anosmia in COVID-19 Using the Adverse Outcome Pathway Framework

Abstract

Loss of the sense of smell (anosmia) has been included as a COVID-19 symptom by the World Health Organization. The majority of patients recover the sense of smell within a few weeks postinfection (short-term anosmia), while others report persistent anosmia. Several studies have investigated the mechanisms leading to anosmia in COVID-19; however, the evidence is scattered, and the mechanisms remain poorly understood. Based on a comprehensive review of the literature, we aim here to evaluate the current knowledge and uncertainties regarding the mechanisms leading to short-term anosmia following SARS-CoV-2 infection. We applied an adverse outcome pathway (AOP) framework, well established in toxicology, to propose a sequence of measurable key events (KEs) leading to short-term anosmia in COVID-19. Those KEs are (1) SARS-CoV-2 Spike proteins binding to ACE-2 expressed by the sustentacular (SUS) cells in the olfactory epithelium (OE); (2) viral entry into SUS cells; (3) viral replication in the SUS cells; (4) SUS cell death; (5) damage to the olfactory sensory neurons and the olfactory epithelium (OE). This AOP-aligned approach allows for the identification of gaps where more research should be conducted and where therapeutic intervention could act. Finally, this AOP gives a frame to explain several disease features and can be linked to specific factors that lead to interindividual differences in response to SARS-CoV-2 infection.

Advances in Animal Models and Cutting-Edge Research in Alternatives: Proceedings of the Third International Conference on 3Rs Research and Progress, Vishakhapatnam, 2022

“…In addition to being used for food safety and chemical risk assessment, NAMs can also be used to assess the effects of pathogens like SARS-CoV-2. [13][14][15][16][17][18] Session 1: Adoption of the 3Rs in research…”

Embryology and Clinical Development of the Human Olfactory System

“…Olfactory Loss in Coronavirus, Zika, and Other Viral Infections Loss of sense of smell and taste is a frequent finding in both adult and pediatric patients with coronavirus (COVID-19) infections, [57][58][59][60] but is not specific for this virus and also occurs in other viral infections, particularly those affecting the respiratory system. The olfactory mucosa and primary olfactory neurons within in are the primary target, 61 but the olfactory bulb also may be involved. Because of the regenerative capability of olfactory neurons and resident progenitor cells in the olfactory bulb throughout life, the loss of olfaction is not permanent.…”

Report of the 3rd and 4th Mystery of Reactive Oxygen Species Conference

“…Over three years (2020-2023), CIAO involved over 70 scientists from different countries and backgrounds, including toxicology, virology, computer science, and pharmacology. Numerous COVID-19 related AOPs were developed, resulting in various AOs such as respiratory symptoms (e.g., acute respiratory distress and lung fibrosis), short-term anosmia and other neurological syndromes (Hogberg et al, 2022;Shahbaz et al, 2022), intestinal disorders (Clerbaux et al, 2022c), gut dysbiosis (Clerbaux et al, 2022b), or liver disorders (Vinken, 2021). Oxidative stress has been identified…”