Mechanisms of SARS-CoV-2-associated anosmia

Abstract

Anosmia, the loss of the sense of smell, is one of the main neurological manifestations of COVID-19. Although the SARS-CoV-2 virus targets the nasal olfactory epithelium, current evidence suggests that neuronal infection is extremely rare in both the olfactory periphery and the brain, prompting the need for mechanistic models that can explain the widespread anosmia in COVID-19 patients. Starting from work identifying the non-neuronal cell types that are infected by SARS-CoV-2 in the olfactory system, we review the effects of infection of these supportive cells in the olfactory epithelium and in the brain and posit the downstream mechanisms through which sense of smell is impaired in COVID-19 patients. We propose that indirect mechanisms contribute to altered olfactory system function in COVID-19-associated anosmia, as opposed to neuronal infection or neuroinvasion into the brain. Such indirect mechanisms include tissue damage, inflammatory responses through immune cell infiltration or systemic circulation of cytokines, and downregulation of odorant receptor genes in olfactory sensory neurons in response to local and systemic signals. We also highlight key unresolved questions raised by recent findings.

Keywords: COVID-19; SARS-CoV-2; anosmia; neuroinflammation; olfaction.

Graphical abstract

FIGURE 1.

Cell types in the olfactory epithelium and potential mechanisms of COVID-19-induced anosmia. Top: schematic of the olfactory epithelium with major cell types. Bottom: 3 primary effects of SARS-CoV-2 infection: loss of OSN cilia and receptor downregulation, immune cell infiltration, and tissue detachment (complete lesion), which activates horizontal basal cells (HBCs) and triggers regeneration. Sustentacular cells, Bowman’s gland, and microvillar cells (colored in gray at bottom) are the primary targets of SARS-CoV-2. Image created with BioRender.com, with permission.

FIGURE 2.

Experimental models used in COVID-19-related studies. Hamsters have been used as an animal model because their ACE2 can bind to SARS-CoV-2 spike protein and wild-type animals can be efficiently infected with SARS-CoV-2. Mice have also been used but researchers need to use either 1) transgenic animals that express human ACE2 from KRT18 promoters (active in epithelial cells) or from endogenous mouse Ace2 promoter or 2) SARS-CoV-2 variants that have mutations in the spike protein and other viral genes that allow for binding to mouse ACE2 and facilitate cell entry. Human autopsies and biopsies have also been used, but samples from anosmic COVID-19 patients are limited. Image created with BioRender.com, with permission.

FIGURE 3.

Effects of SARS-CoV-2 infection in the brain. Top: schematic of human brain with vasculature, with the olfactory bulb highlighted in yellow and the structure and cell types of the vasculature depicted on right. Bottom: 3 possible central mechanisms that may contribute to COVID-19-associated anosmia. Although both direct infection to neurons and viral invasion to the brain are unlikely based on recent studies, inflammatory responses due to microglial activation and cytokine circulation are suggested to affect neurological functions in COVID-19 patients. Image created with BioRender.com, with permission.