Evolution of nasal and olfactory infection characteristics of SARS-CoV-2 variants
Mengfei Chen, … , Nicholas R. Rowan, Andrew P. Lane
Mengfei Chen, … , Nicholas R. Rowan, Andrew P. Lane
Published March 14, 2024
Citation Information: J Clin Invest. 2024;134(8):e174439. https://doi.org/10.1172/JCI174439.
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Research Article COVID-19 Neuroscience

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

Abstract

SARS-CoV-2 infection of 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 nasal tropism from olfactory to respiratory epithelium as the virus evolved. Analyzing each variant revealed that SARS-CoV-2 WA1 or Delta infect a proportion of olfactory neurons in addition to the primary target sustentacular cells. The Delta variant possessed broader cellular invasion capacity into the submucosa, while Omicron displayed enhanced nasal respiratory infection and longer retention in the sinonasal epithelium. The olfactory neuronal infection by WA1 and the subsequent olfactory bulb transport via axon were more pronounced in younger hosts. In addition, the observed viral clearance delay and phagocytic dysfunction in aged olfactory mucosa were accompanied by a decline of phagocytosis-related genes. Further, robust basal stem cell activation contributed to neuroepithelial regeneration and restored ACE2 expression postinfection. Together, our study characterized the nasal tropism of SARS-CoV-2 strains, immune clearance, and regeneration after infection. The shifting characteristics of viral infection at the airway portal provide insight into the variability of COVID-19 clinical features, particularly long COVID, and may suggest differing strategies for early local intervention.

Authors

Mengfei Chen, Andrew Pekosz, Jason S. Villano, Wenjuan Shen, Ruifeng Zhou, Heather Kulaga, Zhexuan Li, Amy Smith, Asiana Gurung, Sarah E. Beck, Kenneth W. Witwer, Joseph L. Mankowski, Murugappan Ramanathan Jr, Nicholas R. Rowan, Andrew P. Lane

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Figure 4

Age-associated SARS-Cov-2 infection in olfactory sensory neurons.

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Age-associated SARS-Cov-2 infection in olfactory sensory neurons. (A–C) ...
(A–C) Confocal images showing WA1-infected hamster olfactory epithelium at 4 dpi. Insert in A highlighting a NP-stained axon bundle (horizontal section). Arrowheads indicate virus-infected TUBB3+ immature (B) or OMP+ mature (C) sensory neurons (coronal sections). White line indicated the basal layer of epithelium. (D and E) NP+ axon travel from neuroepithelium to laminar propria and merge into TUBB3+ axon bundle. (F–H), Quantification of NP+ axons in young and old hamsters at 6 dpi. Representative images show horizontal (F) or coronal sections (G). NP+ axons were quantified per μm of the diameter of axon bundle. (I and J) Representative images showing NP located in TUBB3+ human olfactory neurons (J) and the percentage of NP+ cells in TUBB3+ population (I). Dotted line in J indicates virus infected NP+ axon. Arrowheads denote NP+/TUBB3+ neurons compared with uninfected cells (empty arrowhead). Infected biopsies from 3 young donors (age 25–33 years) and 5 biopsies from older donors (age 54–72 years) were quantified for TUBB3+ neuronal infection. (K and L) Representative images of NRP1 expression in human olfactory epithelium (K) and quantification of NRP1+ cells in TUBB3+ population (L). 3 biopsies from young (age 20–30 years) and 4 biopsies from older donors (age 68–79 years) were examined for NRP1 expression. Images in A–G were captured with 2 μm Z-stack and exported by maximum intensity projections. Each data point represents an individual sample from hamster (H, n = 3), or human (I and L, n = 3-5). Details of human biopsies can be found in Supplemental Table 1. Data are represented as mean ± SD. Statistical significance was determined by unpaired 2-tailed t test. Scale bars: 20 μm.