The olfactory nerve is not a likely route to brain infection in COVID-19: a critical review of data from humans and animal models

Abstract

One of the most frequent symptoms of COVID-19 is the loss of smell and taste. Based on the lack of expression of the virus entry proteins in olfactory receptor neurons, it was originally assumed that the new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) does not infect olfactory neurons. Recent studies have reported otherwise, opening the possibility that the virus can directly infect the brain by traveling along the olfactory nerve. Multiple animal models have been employed to assess mechanisms and routes of brain infection of SARS-CoV-2, often with conflicting results. We here review the current evidence for an olfactory route to brain infection and conclude that the case for infection of olfactory neurons is weak, based on animal and human studies. Consistent brain infection after SARS-CoV-2 inoculation in mouse models is only seen when the virus entry proteins are expressed abnormally, and the timeline and progression of rare neuro-invasion in these and in other animal models points to alternative routes to the brain, other than along the olfactory projections. COVID-19 patients can be assured that loss of smell does not necessarily mean that the SARS-CoV-2 virus has gained access to and has infected their brains.

Keywords: Brain infection; COVID-19; Neuro-invasion; Olfactory system; SARS-CoV-2; Virus.

Fig. 1

SARS-CoV-2 nucleocapsid protein (red) immunolabeled in the olfactory epithelium, double-labeled for olfactory marker protein (OMP, green) and stained with Hoechst nuclear stain (blue). a The SARS-CoV-2 (red) is present in a sustentacular cell that partially overlaps with an OMP-labeled olfactory receptor neuron. b When in the same image the sustentacular cell body is invisible (black ellipsoid shadow with white arrows), as it would be when the plane of section is not entirely perpendicular to the epithelium, then the SARS-CoV-2 protein would be erroneously interpreted to be co-localized within the OMP-expressing olfactory receptor neuron. Scale bar = 10 µm. Image is adapted from Bryche et al. [15]

Fig. 2

Probability of brain infection after nasal inoculation in animal models or in SARS-CoV-2 infected patients. Note that the probability of brain infection in humans resembles that in non-transgenic animal models and in the newer human ACE2 (hACE2) mouse models, but not the infection probability in the older transgenic mouse models that use the K18 cytokeratin promoter