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 1

Time-series scRNA-seq of developing mouse lung.

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Time-series scRNA-seq of developing mouse lung. (A) Overview of murine d...
(A) Overview of murine developmental stages and time points for scRNA-seq time series. (B) Workflow of scRNA-seq time series. Single-cell suspensions were generated from at least 4 mice at each time point. Viable, Cd45–, Ter119– cells were selected for scRNA-seq library preparation using the 10X Genomics Chromium 5′ platform. Uniform Manifold Approximation and Projection (UMAP) embedding of 67,629 cells annotated by (C) developmental time point and (D) cell-type. (E) Violin plot depicting expression of key SARS-CoV2 receptor Ace2 and coreceptor Tmprss2 across cell types. (F) UMAP embedding of 4,369 epithelial cells after subsetting and reclustering. (G, H) UMAP plots depicting relative expression of Ace2 and Tmprss2. (I) Relative expression of putative SARS-CoV-2 priming proteases during development, shown as violin plots to indicate relative expression, with individual cells shown as dots. *P < 3.125 × 10–3 by 1-way ANOVA across developmental time points.