Single-Cell and Population Transcriptomics Reveal Pan-epithelial Remodeling in Type 2-High Asthma

Jackson, Nathan D.; Everman, Jamie L.; Chioccioli, Maurizio; Feriani, Luigi; Goldfarbmuren, K.C.; Sajuthi, Satria; Rios, Cydney; Powell, Roger; Armstrong, Michael; Gomez, Joe; Michel, Cole; Eng, Celeste; Oh, Sam S.; Rodríguez‐Santana, José; Cicuta, Pietro; Reisdorph, Nichole; Burchard, Esteban G.; Seibold, Max A.

doi:10.1016/j.celrep.2020.107872

Cited by 93 publications

(103 citation statements)

References 72 publications

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“…Variance stabilization transformation (VST) implemented in DESeq2 56 (v1.22.2) was then carried out on the raw gene count matrix to create a variance stabilized gene expression matrix suitable for downstream analyses. These RNA-seq data were analyzed and published for other analyses 57 .…”

Section: Methodsmentioning

confidence: 99%

Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium

et al. 2020

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Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2, that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

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Section: Methodsmentioning

confidence: 99%

Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium

et al. 2020

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“…We suggest that type 2 T helper cells were higher in the in ltrate in the C2 subtype, while type 1 T helper cells were higher in the in ltrate in the C1 subtype. It is known that chronic IL-3 stimulation can produce a Type 2-asthma model [7]. We hypothesized that one of the two secretory cells (secretory cell 1 and secretory cell 2) may be associated with Th2 in ammation.…”

Section: Consensus Clustering Based On the Ve Cell Marker Genesmentioning

confidence: 99%

“…We downloaded the pediatric asthma scRNA-seq describing chronic stimulation with IL-13 in the GSE145013 dataset from the GEO database (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE145013) [7]. Single cell sequencing analysis was performed on epithelial cells from tracheal donors after chronic (11 days) IL-13 stimulation.…”

Section: Data Acquisitionmentioning

confidence: 99%

Identification of Type 2-pediatric Asthma Based on Single-cell Transcriptomic Analysis

Dai

Sun

Yang

et al. 2021

Preprint

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Type 2-pediatric asthma characterized by T2 cytokine-driven airway inflammation is the most common type of asthma. Recently, T2 cytokine inhibitors have reduced the exacerbation rates of asthma, but their ability to improve lung function is limited. Screening novel therapeutic strategies for Type 2-pediatric asthma patients is imperative. We obtained single-cell RNA sequencing (scRNA-seq) describing the chronic stimulation GSE145013 dataset with IL-13. Consensus clustering was performed to classify pediatric asthmatic patients from validation datasets GSE65204 and GSE40888, based on the cell marker genes. We found three cellular subtypes including ciliated cells, secretory cell 1, and secretory cell 2. The expression of CCL26, PRB1, and SLC9B2 was higher in secretory cell 1, while SCGB3A1 and BPIFA1 were higher in secretory cell 2. Consensus clustering based on the five cell marker genes produced two patient subtypes (C1 and C2). The expression of SCGB3A1 and BPIFA1 was higher in C2 subtypes, while CCL26, PRB1, and SLC9B2 was higher in C1 subtypes. Patients in C2 subtypes may more secretory cell 2, while the patients in C1 may have higher secretory cell 1 in the infiltrate. More Type 2 T helper cells were in the infiltrate in the C2 subtype, while type 1 T helper cells were higher in the C1 subtype. T2 cytokines (IL-13, IL-33, IL-3, IL-4, and TSLP) were expressed more in the C2 subtype, corresponding to Type 2-pediatric asthma. This study identified five cell marker genes to screen Type 2-pediatric asthma that could potentially be therapeutic targets for Type 2-pediatric asthma.

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“…The cellular composition and structure of large airway epithelia have been well - established through histological and immunofluorescence imaging, flow cytometry, single-cell RNA sequencing, and other techniques (Bonser et al, 2021; Hackett et al, 2008; Jackson et al, 2020; Maestre-Batlle et al, 2017; Montoro et al, 2018; Nakajima et al, 1998; Okuda et al, 2020; Plasschaert et al, 2018). The large airway epithelium is a pseudostratified columnar epithelium consisting of basal cells in the basal layer, and secretory and ciliated cells residing in an apical/surface layer.…”

Section: Introductionmentioning

confidence: 99%

Topography-dependent gene expression and function of common cell archetypes in large and small porcine airways

Pezzulo

Thurman

et al. 2021

Preprint

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The small airways of humans are affected early in several lung diseases. However, because they are relatively inaccessible, little is known about the epithelial cells that line these airways. We performed a single cell RNA-seq census of small and large airways of wild-type pigs and pigs with disrupted cystic fibrosis transmembrane conductance regulator (CFTR) gene. The sequencing data showed that small airway epithelia had similar major cell types as large airways but no ionocytes; moreover, lack of CFTR expression had minimal effect on the transcriptome. Small airway epithelial cells expressed a different transcriptome than large airway cells. Quantitative immunohistochemistry showed that small airway basal cells participate in epithelial barrier function. Finally, sequencing data and in vitro electrophysiologic studies suggest that small airway epithelia have a water and ion transport advantage. Our data highlight the archetypal nature of basal, secretory, and ciliated airway cells with location-dependent gene expression and function.

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Single-Cell and Population Transcriptomics Reveal Pan-epithelial Remodeling in Type 2-High Asthma

Cited by 93 publications

References 72 publications

Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium

Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium

Identification of Type 2-pediatric Asthma Based on Single-cell Transcriptomic Analysis

Topography-dependent gene expression and function of common cell archetypes in large and small porcine airways

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