Anosmia in COVID-19: Underlying Mechanisms and Assessment of an Olfactory Route to Brain Infection

Rafal Butowt, Christopher S von Bartheld, Rafal Butowt, Christopher S von Bartheld

Abstract

In recent months it has emerged that the novel coronavirus-responsible for the COVID-19 pandemic-causes reduction of smell and taste in a large fraction of patients. The chemosensory deficits are often the earliest, and sometimes the only signs in otherwise asymptomatic carriers of the SARS-CoV-2 virus. The reasons for the surprisingly early and specific chemosensory dysfunction in COVID-19 are now beginning to be elucidated. In this hypothesis review, we discuss implications of the recent finding that the prevalence of smell and taste dysfunction in COVID-19 patients differs between populations, possibly because of differences in the spike protein of different virus strains or because of differences in the host proteins that enable virus entry, thus modifying infectivity. We review recent progress in defining underlying cellular and molecular mechanisms of the virus-induced anosmia, with a focus on the emerging crucial role of sustentacular cells in the olfactory epithelium. We critically examine the current evidence whether and how the SARS-CoV-2 virus can follow a route from the olfactory epithelium in the nose to the brain to achieve brain infection, and we discuss the prospects for using the smell and taste dysfunctions seen in COVID-19 as an early and rapid diagnostic screening tool.

Keywords: ACE2; COVID-19; SARS-CoV-2; anosmia; brain infection; diagnosis; hyposmia; olfactory epithelium; prevalence; smell loss; taste.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Prevalence of chemosensory deficits in COVID-19 patients. (A) World map based on 68 studies with a total of 30,264 patients (updated version, original from: von Bartheld and others 2020). (B) Prevalence of chemosensory dysfunction in COVID-19 patients in Western countries and East Asia according to a recent meta-analysis (von Bartheld and others 2020). Error bars are 95% confidence intervals. Data are based on a total of 22,011 Caucasian and 8253 East Asian patients with COVID-19 from n = 61 cohorts and n = 12 cohorts, respectively.
Figure 2.
Figure 2.
The time course and frequency of chemosensory dysfunctions in COVID-19 patients according to a study from Italy (Vaira and others 2020a). Note that dysfunction of smell peaked slightly earlier than dysfunction of taste, and most deficits resolved within 8 to 10 days after the peak.
Figure 3.
Figure 3.
Schematic of the olfactory pathway to the brain with four different scenarios how the SARS-CoV-2 virus may cause anosmia or hyposmia. (A) Normal pathway: odorant molecules bind to the olfactory receptor neuron (ORN), the ORN transmits the smell sensation through the cribriform plate (bone) to the mitral cell (MC) in the olfactory bulb of the brain. Olfactory epithelium also contains support cells (sustentacular cells, SuC) and stem cells (SC) that can regenerate SuCs and ORNs. (B) Odors may not reach the ORNs, because of nasal obstruction/congestion by increased mucus. (C) The transmission of odor sensation may be blocked because of damage and/or death of ORNs. (D) The sensation of smell may be compromised because the virus affects neurons in the brain. (E) The transmission of odor sensation may be compromised, because the SuC (which assists the ORN with odor processing) is damaged by the virus.
Figure 4.
Figure 4.
Entry of the SARS-CoV-2 virus in the olfactory epithelium and the virus’ predicted effects that may explain the anosmia in COVID-19 patients. Coronavirus enters (pink arrows) and accumulates in the sustentacular cells (SuC) which abundantly express ACE2 and TMPRSS2 proteins, the entry proteins of the virus. SuCs normally partake in the processing of the odorants by endocytosing the odorant-binding protein complex (green-black symbol), by detoxifying, by maintaining the cilia of mature olfactory receptor neurons (mORN), and by maintaining epithelial integrity. Olfactory sensation is impaired when these essential SuC functions are disrupted. It is unknown whether the virus may transfer from SuC to mature olfactory receptor neurons (mORN) which lack ACE2 and TMPRSS2 proteins (Table 2), but have axons extending to the brain. Both the SuC and mORN can be replaced by stem cells (SC—blue arrows), although SuC replacement is much faster than replacement of mORN where SC first generates immature ORN (iORN) whose axons have to grow through the bone to the brain.
Figure 5.
Figure 5.
Time course of cellular events that may cause loss of smell and its recovery in COVID-19 patients. Day 0 = day of infection. Symbols and abbreviations are the same as explained in Figures 3 and 4. SuC, sustentacular cell; ORN, olfactory receptor neuron; SC, stem cell.
Figure 6.
Figure 6.
Four potential routes of SARS-CoV-2 virus from the nose to the brain through the cribriform plate. (A) Olfactory circuits. (B) Nervus terminalis. (C) Cerebrospinal fluid. (D) Vasculature. BS, brainstem; CVOs, circumventricular organs; HY, hypothalamus; OB, olfactory bulb; OE, olfactory epithelium.

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