Why Does the Omicron Variant Largely Spare Olfactory Function? Implications for the Pathogenesis of Anosmia in Coronavirus Disease 2019

Abstract

The omicron variant of severe acute respiratory syndrome coronavirus 2 causes much less olfactory dysfunction than the previous variants. There are several potential mechanisms for how omicron may change tissue tropism and spare olfactory function. The new mutations make omicron more hydrophobic and alkaline than previous variants, which may reduce penetration of the mucus layer. Overall, the new mutations minimally change receptor binding affinity, but entry efficiency into host cells is reduced in cells expressing transmembrane serine protease 2 (TMPRSS2). Because the support cells in the olfactory epithelium abundantly express TMPRSS2, these main target cells in the olfactory epithelium may become infected less by the new omicron variant.

Keywords: ACE2; COVID-19; D614G mutation; SARS-CoV-2; TMPRSS2; anosmia; loss of smell; mucus; omicron; prevalence.

Figure 1.

Anosmia prevalences associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants (A) and proposed experimental strategy to elucidate the mechanism underlying varying anosmia prevalences in an animal model (B). A, Graph shows pooled anosmia prevalence for the original D614 strain [2], the G614 variant according to multiple meta-analyses [2, 5], and the alpha [6, 7] and delta [7] variants and our pooled estimate for the omicron variant according to the first 12 studies from 4 continents (Table 1). The approximate time periods of variant predominance are indicated on the x-axis. These periods overlap somewhat, because variants were dominant in different regions of the world at different times. For data compiled from multiple studies, error bars indicate the 95% confidence interval. Note that the D614G mutation generally leads to higher anosmia prevalence but not for omicron. B, As a strategy to elucidate mechanisms, a suitable mouse model expressing the viral entry receptor (human angiotension-converting enzyme [hACE2]) is infected with either a virus variant inducing a high prevalence of anosmia (eg, alpha or G614) or a virus variant inducing low anosmia prevalence (eg, omicron). The animals undergo standard behavioral testing to measure and verify the time needed to find a hidden cookie. The olfactory epithelium and brains (olfactory bulbs) of the same animals are then processed for various morphological, histochemical, and biochemical analyses to quantify the amount of virus that infected the olfactory epithelium, to identify infected cell types, and to measure the extent and timing of damage and other parameters in the olfactory system.