Nasal ciliated cells are primary targets for SARS-CoV-2 replication in the early stage of COVID-19
Ji Hoon Ahn, … , Chang-Seop Lee, Gou Young Koh
Ji Hoon Ahn, … , Chang-Seop Lee, Gou Young Koh
Published May 18, 2021
Citation Information: J Clin Invest. 2021;131(13):e148517. https://doi.org/10.1172/JCI148517.
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Research Article Infectious disease

Nasal ciliated cells are primary targets for SARS-CoV-2 replication in the early stage of COVID-19

Abstract

The upper respiratory tract is compromised in the early period of COVID-19, but SARS-CoV-2 tropism at the cellular level is not fully defined. Unlike recent single-cell RNA-Seq analyses indicating uniformly low mRNA expression of SARS-CoV-2 entry–related host molecules in all nasal epithelial cells, we show that the protein levels are relatively high and that their localizations are restricted to the apical side of multiciliated epithelial cells. In addition, we provide evidence in patients with COVID-19 that SARS-CoV-2 is massively detected and replicated within the multiciliated cells. We observed these findings during the early stage of COVID-19, when infected ciliated cells were rapidly replaced by differentiating precursor cells. Moreover, our analyses revealed that SARS-CoV-2 cellular tropism was restricted to the nasal ciliated versus oral squamous epithelium. These results imply that targeting ciliated cells of the nasal epithelium during the early stage of COVID-19 could be an ideal strategy to prevent SARS-CoV-2 propagation.

Authors

Ji Hoon Ahn, JungMo Kim, Seon Pyo Hong, Sung Yong Choi, Myung Jin Yang, Young Seok Ju, Young Tae Kim, Ho Min Kim, MD Tazikur Rahman, Man Ki Chung, Sang Duk Hong, Hosung Bae, Chang-Seop Lee, Gou Young Koh

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Figure 1

The mismatch between protein and mRNA expression pattern of SARS-CoV-2 entry molecules in human nasal mucosa epithelium.

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The mismatch between protein and mRNA expression pattern of SARS-CoV-2 e...
(A–F) Representative images of cross-sectional view of human nasal epithelium showing robust ACE2, TMPRSS2, and FURIN protein in acetylated α-tubulin+ ciliated epithelium (yellow arrowheads). Scale bars: 50 μm. Similar findings were observed in n = 3 normal human tissues from 3 independent experiments. (B, D, and F) Profile analysis of relative signal intensity of ACE2, TMPRSS2, and FURIN along the white line in A, C, and E. (G, I, and K) Representative images of cross-sectional views of human nasal epithelium showing that ACE2, TMPRSS2, and FURIN were not distinctly detected in MUC5AC+ goblet cells (white arrowheads). Scale bars: 50 μm. Similar findings were observed in 3 human tissues from 3 independent experiments. (H, J, and L) Comparison of relative ACE2 signal intensity between ciliated cells and goblet cells. Each dot indicates a value measured from 1 section in 3 human tissues (n = 10 sections per tissue) from 3 independent experiments. Horizontal bars indicate the mean ± SD. P value versus ciliated cells was obtained by 2-tailed Mann-Whitney U test. (M) Unsupervised clustering of 1721 pooled human nasal epithelial cells projected on a 2D UMAP plot, and donut plot showing 5 major clusters and cellular composition of the epithelial cells. (N) UMAP plot showing distribution of ACE2+, ACE2+/TMPRSS2+, ACE2+/FURIN+, ACE2+/TMPRSS2+/FURIN+, and ACE2– cells across all clustered epithelial cells. (O) Dot plot heatmap showing expression of SARS-CoV-2 entry–related host molecule genes per each indicated cluster. (P–S) Comparison of the average of normalized expression level of each SARS-CoV-2 entry–related host molecule gene per each indicated cluster.