Single-cell multiomic profiling of human lungs reveals cell-type-specific and age-dynamic control of SARS-CoV2 host genes.

Allen Wang,Joshua Chiou,Yan Xu,Justin Buchanan,Minzhe Guo,Xin Sun,Cory Poole,Parul Kudtarkar,Xiaomeng Hou,Heidie Huyck,Kai Zhang,Justinn Barr,Sharvari Narendra,Ja Whitsett ,Dina A Faddah ,Sebastian Preißl ,Olivier Poirion ,Enikö Sajti ,Michael J Valdez ,Kyle J Gaulton ,Ravi S Misra ,Gloria S Pryhuber ,Jacklyn Newsome ,Jamie M Verheyden ,Lisa M Rogers ,Randee E Young

doi:10.7554/elife.62522

Abstract

Respiratory failure associated with COVID-19 has placed focus on the lungs. Here, we present single-nucleus accessible chromatin profiles of 90,980 nuclei and matched single-nucleus transcriptomes of 46,500 nuclei in non-diseased lungs from donors of ~30 weeks gestation,~3 years and ~30 years. We mapped candidate cis-regulatory elements (cCREs) and linked them to putative target genes. We identified distal cCREs with age-increased activity linked to SARS-CoV-2 host entry gene TMPRSS2 in alveolar type 2 cells, which had immune regulatory signatures and harbored variants associated with respiratory traits. At the 3p21.31 COVID-19 risk locus, a candidate variant overlapped a distal cCRE linked to SLC6A20, a gene expressed in alveolar cells and with known functional association with the SARS-CoV-2 receptor ACE2. Our findings provide insight into regulatory logic underlying genes implicated in COVID-19 in individual lung cell types across age. More broadly, these datasets will facilitate interpretation of risk loci for lung diseases.

Highlights

Amidst the ongoing COVID-19 pandemic, understanding how SARS-CoV-2 infects and impacts the lungs has become an urgent priority
We identified 19 clusters representing epithelial (AT1alveolar type 1, alveolar type 2 cells (AT2s)-alveolar type 2, club, ciliated, basal, and pulmonary neuroendocrine), mesenchymal, endothelial, and hematopoietic cell types (Figure 1A)
We corroborated recent findings that the host entry genes ACE2, encoding the receptor for the viral spike protein, and TMPRSS2, encoding a serine protease for priming of the spike protein, were detected in a higher proportion of AT2 cells in adult lungs compared to pediatric lungs (Muus et al, 2020; Schuler et al, 2020), and identified candidate cis-regulatory elements (cCREs) linked to TMPRSS2 and highlighted 19 cCREs with age-increased accessibility

Summary

Introduction

Amidst the ongoing COVID-19 pandemic, understanding how SARS-CoV-2 infects and impacts the lungs has become an urgent priority. The human airway epithelium is composed of luminal cells and basal cells (Tata and Rajagopal, 2017). Luminal cells include club cells and goblet cells that moisturize the air and trap pathogens, as well as ciliated cells that sweep out inhaled particles. These luminal cells are underlined by basal cells, which serve as progenitors when luminal cells are lost after infection (Hogan et al, 2014; Kim, 2017). The alveolar epithelium is composed of alveolar type 1 cells (AT1s), which are flat and line the gas–blood interface to facilitate gas exchange; and alveolar type 2 cells (AT2s), which produce surfactant to reduce surface tension and protect against pathogens (Whitsett and Weaver, 2015). While SARS-CoV-2 likely infects both the airway and alveolar regions of the lungs, it is the damage to the alveolar region that causes ARDS (Du et al, 2020)

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Results

Conclusion