Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium
Bryce A. Schuler, … , Jonathan A. Kropski, Jennifer M.S. Sucre
Bryce A. Schuler, … , Jonathan A. Kropski, Jennifer M.S. Sucre
Published November 12, 2020
Citation Information: J Clin Invest. 2021;131(1):e140766. https://doi.org/10.1172/JCI140766.
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Concise Communication Pulmonology

Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) novel coronavirus 2019 (COVID-19) global pandemic has led to millions of cases and hundreds of thousands of deaths. While older adults appear at high risk for severe disease, hospitalizations and deaths due to SARS-CoV-2 among children have been relatively rare. Integrating single-cell RNA sequencing (scRNA-seq) of developing mouse lung with temporally resolved immunofluorescence in mouse and human lung tissue, we found that expression of SARS-CoV-2 Spike protein primer TMPRSS2 was highest in ciliated cells and type I alveolar epithelial cells (AT1), and TMPRSS2 expression increased with aging in mice and humans. Analysis of autopsy tissue from fatal COVID-19 cases detected SARS-CoV-2 RNA most frequently in ciliated and secretory cells in airway epithelium and AT1 cells in peripheral lung. SARS-CoV-2 RNA was highly colocalized in cells expressing TMPRSS2. Together, these data demonstrate the cellular spectrum infected by SARS-CoV-2 in lung epithelium and suggest that developmental regulation of TMPRSS2 may underlie the relative protection of infants and children from severe respiratory illness.

Authors

Bryce A. Schuler, A. Christian Habermann, Erin J. Plosa, Chase J. Taylor, Christopher Jetter, Nicholas M. Negretti, Meghan E. Kapp, John T. Benjamin, Peter Gulleman, David S. Nichols, Lior Z. Braunstein, Alice Hackett, Michael Koval, Susan H. Guttentag, Timothy S. Blackwell, Steven A. Webber, Nicholas E. Banovich, Vanderbilt COVID-19 Consortium Cohort, Human Cell Atlas Biological Network, Jonathan A. Kropski, Jennifer M.S. Sucre

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Figure 2

Spatial and temporal localization of Tmprss2 expression across lung development.

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Spatial and temporal localization of Tmprss2 expression across lung deve...
(A) RNA-ISH of Tmprss2 expression (white) with epithelial markers Scgb1a1 (secretory cells, blue), Foxj1 (ciliated cells, magenta), Sftpc (surfactant protein C, AT2 cells, green), Hopx (type 1 alveolar epithelial cells, red). FFPE tissue from lungs at E18, P0, P7, P14, 2 months, 12 months, and 24 months was used, with representative image data from P0, P7, 2 months, 12 months, and 24 months shown in the figure. Lungs from 3 mice at each time point were used, with ten ×40 images obtained per slide. Scale bars: 100 μm. (B, C) Quantification of Tmprss2 expression in each epithelial subtype across development by automated image analysis (HALO, Indica Labs) measured as (B) percentage of cellular area covered by Tmprss2 probe in each cell expressing both Tmprss2 and the epithelial marker (all data points are shown with mean ± SD) and (C) percentage of cells expressing the epithelial marker that also express Tmprss2, with positive Tmprss2 expression defined as having 5 or more copies of Tmprss2 probe (box and whisker plots are shown with mean and error bars reflecting minimum and maximum values for each time point). More than 1000 cells were counted at each time point. ****P < 0.0001 by 1-way ANOVA. (D) RNA-ISH of Foxj1 expression (red) or Hopx expression (red) with protein immunofluorescence for TMPRSS2 protein (white). Five ×40 images per slide were obtained. Scale bars: 100 μm.