COVID-19 Anosmia: High Prevalence, Plural Neuropathogenic Mechanisms, and Scarce Neurotropism of SARS-CoV-2?

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of coronavirus disease 2019 (COVID-19). It is known as a respiratory virus, but SARS-CoV-2 appears equally, or even more, infectious for the olfactory epithelium (OE) than for the respiratory epithelium in the nasal cavity. In light of the small area of the OE relative to the respiratory epithelium, the high prevalence of olfactory dysfunctions (ODs) in COVID-19 has been bewildering and has attracted much attention. This review aims to first examine the cytological and molecular biological characteristics of the OE, especially the microvillous apical surfaces of sustentacular cells and the abundant SARS-CoV-2 receptor molecules thereof, that may underlie the high susceptibility of this neuroepithelium to SARS-CoV-2 infection and damages. The possibility of SARS-CoV-2 neurotropism, or the lack of it, is then analyzed with regard to the expression of the receptor (angiotensin-converting enzyme 2) or priming protease (transmembrane serine protease 2), and cellular targets of infection. Neuropathology of COVID-19 in the OE, olfactory bulb, and other related neural structures are also reviewed. Toward the end, we present our perspectives regarding possible mechanisms of SARS-CoV-2 neuropathogenesis and ODs, in the absence of substantial viral infection of neurons. Plausible causes for persistent ODs in some COVID-19 convalescents are also examined.

Keywords: COVID-19; SARS-CoV-2; anosmia; olfactory dysfunction; pathogenesis.

Figure 1

Electron micrographs showing perpendicular (A) and tangential/oblique section (B) of the apical part of the rat OE. Dotted line in panel A denotes sustentacular cell (S) apical surface from which the long thin sustentacular-cell microvilli protrude into the nasal cavity for about 2–3 µm. ORN dendritic knobs (DN) and cilia (C) at apical ends of ORN dendrites (D) are mostly found among the sustentacular microvilli (most of the unlabeled small profile structures in (B) and in area above the dotted line in (A). Human OE is similarly organized [52,53,54]. Scale bars = 0.5 µm.

Figure 2

Schematic diagrams showing possible mechanisms of olfactory neuropathogenesis in COVID-19. (A) A schematic overview to illustrate relations among nasal cavity, olfactory epithelium (OE), olfactory nerve (ON), olfactory bulb (OB), and the brain. (B) At the OE, SARS-CoV-2 mainly infects olfactory sustentacular cells (OSCs) that express high levels of SARS-CoV-2 receptor ACE2 on the luminal surface. Sustentacular cell infection and damage may lead to inflammation, immune reactions, release of cytokines, and signaling through pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and pattern recognition receptors (PRRs) which in turn may cause dysfunctions (such as anosmia or hyposmia) and damage and/or anterograde degeneration of olfactory receptor neuronal cells (ORNs). In the case of post-COVID-19 persistent olfactory dysfunctions, pathogenic mechanisms may include damage of basal cells, continuous inflammation, or chronic SARS-CoV-2 infection in the OE. (C) Anterograde degeneration, signaling, and transport of pathogenic molecules from the OE to the OB along ORN axons may result in dysfunction and transsynaptic degeneration of neural structures in the OB. (D) SARS-CoV-2 infection of endothelial cells or pericytes, and microthrombi in capillary blood vessels, may compromise the blood–brain barrier, and give rise to hematogenous neuropathology and dysfunctions in various brain regions, including the OB.