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Anosmia is one of the most prevalent symptoms of SARS-CoV-2 infection during the COVID-19 pandemic. However, the cellular mechanism behind the sudden loss of smell has not yet been investigated. The initial step of odour detection takes place in the pseudostratified olfactory epithelium (OE) mainly composed of olfactory sensory neurons surrounded by supporting cells known as sustentacular cells. The olfactory neurons project their axons to the olfactory bulb in the central nervous system offering a potential pathway for pathogens to enter the central nervous system by bypassing the blood brain barrier. In the present study, we explored the impact of SARS-COV-2 infection on the olfactory system in golden Syrian hamsters. We observed massive damage of the OE as early as 2 days post nasal instillation of SARS-CoV-2, resulting in a major loss of cilia necessary for odour detection. These damages were associated with infection of a large proportion of sustentacular cells but not of olfactory neurons, and we did not detect any presence of the virus in the olfactory bulbs.We observed massive infiltration of immune cells in the OE and lamina propria of infected animals, which may contribute to the desquamation of the OE. The OE was partially restored 14 days post infection. Anosmia observed in COVID-19 patient is therefore likely to be linked to a massive and fast desquamation of the OE following sustentacular cells infection with SARS-CoV-2 and subsequent recruitment of immune cells in the OE and lamina propria.

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.

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The primary function of the respiratory tract is to exchange gases. The upper respiratory tract includes the nasal cavity, which plays a role in the detection of odorants via the olfactory neuroepithelium (Cole, 1954). Inhalation can also lead to the transmission of harmful environmental agents, such as bacteria and viruses. The inhaled microorganisms and particles first pass through the nasal cavity, which is covered in large parts by the respiratory epithelium. The olfactory epithelium is present in the caudal and upper part of the nasal cavity and is pseudostratified. It mainly contains olfactory sensory neurons (OSNs) which have cilia exposed to the environment, allowing contact with odors. As OSNs projects their axons to the olfactory bulb (OB), these cilia provide a direct pathway from the external environment to the central nervous system (CNS). Some viruses, including Japanese encephalitis virus, Influenza, and Herpes simplex exploit this olfactory pathway to access the OB. From here, they can spread to other brain regions including the hypothalamus and cortical areas, as described in various animal models of infection (Dando et al.,

Detection and discrimination of odorants by the olfactory system plays a pivotal role in animal survival. Olfactory-based behaviors must be adapted to an ever-changing environment. Part of these adaptations includes changes of odorant detection by olfactory sensory neurons localized in the olfactory epithelium. It is now well established that internal signals such as hormones, neurotransmitters, or paracrine signals directly affect the electric activity of olfactory neurons. Furthermore, recent data have shown that activity-dependent survival of olfactory neurons is important in the olfactory epithelium. Finally, as olfactory neurons are directly exposed to environmental toxicants and pathogens, the olfactory epithelium also interacts closely with the immune system leading to neuroimmune modulations. Here, we review how detection of odorants can be modulated in the vertebrate olfactory epithelium. We choose to focus on three cellular types of the olfactory epithelium (the olfactory sensory neuron, the sustentacular and microvillar cells) to present the diversity of modulation of the detection of odorant in the olfactory epithelium. We also present some of the growing literature on the importance of immune cells in the functioning of the olfactory epithelium, although their impact on odorant detection is only just beginning to be unravelled.

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