Single-cell analysis of lung epithelial cells reveals age and cell population-specific responses to SARS-CoV-2 infection in ciliated cells.

Abstract

Introduction: The ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to evade antiviral immune signaling in the airway contributes to the severity of coronavirus disease 2019 (COVID-19). Additionally, COVID-19 is influenced by age and has more severe presentations in older individuals. Hence we investigate the role of innate immune signaling as a function of lung development and age.

Method: We investigated the transcriptome of the airway epithelium using pediatric and adult lung tissue samples from the LungMAP Human Tissue Core Biorepository. Specifically, lung lobes were digested and cultured into a biomimetic model of the airway epithelium on an air-liquid interface. Cells were then infected with SARS-CoV-2 and subjected to single-cell RNA sequencing. The data was analyzed using Seurat, scType, Monacle and tools to infer cell-cell communication.

Results: The clustering analysis identified following six cell populations: club cells, proliferating epithelial cells, multiciliated precursor cells, ionocytes, and two biologically distinct clusters of ciliated cells (FOXJ1high and FOXJ1low). Interestingly, the two ciliated cell clusters showed different infection rates and enrichment of processes involved in ciliary biogenesis and function; we observed a cell-type-specific suppression of innate immunity in infected cells from the FOXJ1low subset. We also identified a significant number of genes that were differentially expressed in lung cells derived from children as compared to adults, suggesting the differential pathogenesis of SARS-CoV-2 infection in children versus adults.

Conclusion: This work reveals age dependent differences in the lung epithelial cell response to SARS-CoV-2 infection. The results can be used to identify drug targets to modulate molecular signaling cascades that mediate an innate immune response.