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.

Comparison of Brain Activation Patterns during Olfactory Stimuli between Recovered COVID-19 Patients and Healthy Controls: A Functional Near-Infrared Spectroscopy (fNIRS) Study

“…On the other hand, analysis of cerebral spinal fluid samples and post-mortem brain tissues has provided inconsistent evidence for the neuroinvasion of COVID-19 [42]. When reviewing findings from animal models, Butowt et al [43] concluded that the evidence for the olfactory route to brain infection is weak, and that the loss of smell does not indicate that the virus has entered the brain. In short, the mechanisms behind the neurological symptoms in COVID-19 infection and the potential for neuroinvasion of the virus in humans is still not clear [44].…”

Expression of the ACE2 Virus Entry Protein in the Nervus Terminalis Reveals the Potential for an Alternative Route to Brain Infection in COVID-19

“…Many previous reports have suggested that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gains access to the brain by using an olfactory route from the nose to the brain ( Bougakov et al, 2020 ; Briguglio et al, 2020 ; Butowt and Bilinska, 2020 ; Li et al, 2020 ; Natoli et al, 2020 ; Zubair et al, 2020 ; Burks et al, 2021 ; Meinhardt et al, 2021 ), similar to some other neuro-invasive viruses that are known to infect olfactory receptor neurons and spread from these first-order olfactory neurons to secondary and tertiary olfactory targets in the brain ( Barnett and Perlman, 1993 ; van Riel et al, 2015 ; Dubé et al, 2018 ). Indeed, it has been shown that SARS-CoV-2 can accumulate in various brain regions, in animal models (reviewed in: Butowt and von Bartheld, 2020 ; Rathnasinghe et al, 2020 ; Butowt et al, 2021 ) and in a small number of human patients with COVID-19 ( Ellul et al, 2020 ; Matschke et al, 2020 ; Meinhardt et al, 2021 ; Mukerji and Solomon, 2021 ; Solomon, 2021 ; Thakur et al, 2021 ).…”

“…However, the route along the olfactory nerve from the nose to the brain is controversial for SARS-CoV-2, primarily for two reasons: (1) the olfactory receptor neurons do not express the obligatory virus entry receptor, angiotensin-converting enzyme 2 (ACE2), or expression is restricted to a very small subset of these neurons ( Butowt and von Bartheld, 2020 ; Cooper et al, 2020 ; Brechbühl et al, 2021 ; Butowt et al, 2021 ). Because sustentacular cells tightly enwrap olfactory receptor neurons ( Liang, 2020 ), these ACE2-expressing support cells can easily be mistaken for olfactory receptor neurons, resulting in false positive identification.…”

“…(2) The timeline of appearance of SARS-CoV-2 in the brain is inconsistent with a “neuron-hopping” mode: infection of third-order olfactory targets should occur with a significant delay after infection of the olfactory epithelium, as has been reported for other neuro-invasive viruses ( Barnett et al, 1995 ), but instead the hypothalamus and brainstem are reported to be infected as early as, or even earlier than, the olfactory bulb ( de Melo et al, 2021 ; Zheng et al, 2021 ), and SARS-CoV-2 may even skip the olfactory nerve and olfactory bulb on its way to brain infection ( Winkler et al, 2020 ; Zhou et al, 2020 ; Carossino et al, 2021 ). These findings have raised doubt about the notion that the olfactory nerve serves as a major conduit for brain infection in COVID-19 ( Butowt et al, 2021 ).…”

“…With few exceptions ( Briguglio et al, 2020 ; Butowt and von Bartheld, 2020 ; Butowt et al, 2021 ), studies suggesting an olfactory route for SARS-CoV-2 to achieve brain infection fail to consider the potential for an alternative route from the nose to the brain, the route via the nervus terminalis. Many peripheral processes of the nervus terminalis innervate the olfactory epithelium, the blood vessels below this epithelium, as well as cells in Bowman’s glands ( Larsell, 1950 ), and the central processes of some of these neurons extend to various targets in the forebrain as far caudal as the hypothalamus ( Pearson, 1941 ; Larsell, 1950 ; Schwanzel-Fukuda et al, 1987 ; Demski, 1993 ; von Bartheld, 2004 ).…”