Evolution of nasal and olfactory infection characteristics of SARS-CoV-2 variants

Abstract

SARS-CoV-2 infection in the upper airway and the subsequent immune response are early, critical factors in COVID-19 pathogenesis. By studying infection of human biopsies in vitro and in a hamster model in vivo, we demonstrated a transition in tropism from olfactory to respiratory epithelium as the virus evolved. Analyzing each variants revealed that SARS-CoV-2 WA1 or Delta infects a proportion of olfactory neurons in addition to the primary target sustentacular cells. The Delta variant possesses broader cellular invasion capacity into the submucosa, while Omicron displays longer retention in the sinonasal epithelium. The olfactory neuronal infection by WA1 and the subsequent olfactory bulb transport via axon is more pronounced in younger hosts. In addition, the observed viral clearance delay and phagocytic dysfunction in aged olfactory mucosa is accompanied by a decline of phagocytosis related genes. Furthermore, robust basal stem cell activation contributes to neuroepithelial regeneration and restores ACE2 expression post-infection. Together, our study characterized the nasal tropism of SARS-CoV-2 strains, immune clearance, and regeneration post infection. The shifting characteristics of viral infection at the airway portal provides insight into the variability of COVID-19 clinical features and may suggest differing strategies for early local intervention.

Changes in Symptoms Experienced by SARS-CoV-2-Infected Individuals – From the First Wave to the Omicron Variant

“…Sustentacular cells of the olfactory epithelium have been shown to express high levels of both ACE2 and TMPRSS2 (57), making them direct target cells of the previous SARS-CoV-2 variants as demonstrated both in the mouse model (10) and in human tissue (11). It could be shown in vivo in the hamster model that in comparison to G614 and delta, the infection of the olfactory epithelium by the omicron variant was markedly reduced and infection of nasal tissue shifted to the respiratory epithelium (58), which is in accordance with the significantly reduced frequency of loss of smell in omicron infected individuals shown in this study as well as by others.…”

The nervous system during COVID‐19: Caught in the crossfire

“…Once airborne infectious SARS‐CoV‐2 virions are inhaled, the SARS‐CoV‐2 virus attempts to infect cells along the nasal respiratory epithelium and olfactory neuroepithelium. 102 , 172 , 173 Sustentacular cells are especially vulnerable to SARS‐CoV‐2 infection because they display TMPRSS2 and ACE2 on their apical surface. 101 , 174 Electron microcopy of the SARS‐CoV‐2‐infected hamster neuroepithelium shows that sustentacular cells lose their cilia as SARS‐CoV‐2 fuses with the cell membrane.…”

“…SARS‐CoV‐2 (A‐D) infection of sustentacular cells is observed across species, including humans, 172 , 173 , 175 humanized mice, 176 wildtype mice, 137 , 138 and hamsters. 172 , 175 Interestingly, not all sustentacular cells are ACE2‐expressing in mice—ACE2 is only localized to the apical surface of sustentacular cells residing in the NAD(P)H Quinone Dehydrogenase‐rich dorsal ethmoid turbinates.…”

“…SARS‐CoV‐2 (A‐D) infection of sustentacular cells is observed across species, including humans, 172 , 173 , 175 humanized mice, 176 wildtype mice, 137 , 138 and hamsters. 172 , 175 Interestingly, not all sustentacular cells are ACE2‐expressing in mice—ACE2 is only localized to the apical surface of sustentacular cells residing in the NAD(P)H Quinone Dehydrogenase‐rich dorsal ethmoid turbinates. 101 , 174 However, SARS‐CoV‐2 (A‐D) infection is observed throughout the ethmoid turbinates of wildtype mice, implying that SARS‐CoV‐2 (A‐D) can infect sustentacular cells through an ACE2‐independent pathway.…”

“… 214 In the incipient stages of SARS‐CoV‐2 (A‐D) infection, levels of macrophage chemoattractants, including CCL5 and CXCL10, become elevated in the ethmoid turbinates of hamsters 177 , 211 (Figure 3 ). As the infection of the ethmoid turbinates progresses, an increasing number of Iba1 + macrophages infiltrate the neuroepithelium and swarm the sites of SARS‐CoV‐2 infection 172 , 175 , 215 , 216 (Figure 4 ). This robust macrophage response in the olfactory neuroepithelium is consistent with the high levels of Macrophage Inflammatory Protein‐1 Alpha (MIP‐1a) detected in the ethmoid turbinates of SARS‐CoV‐2 (A‐D) ‐infected hamsters.…”