IL-13 regulates transcriptional changes in SARS-CoV-2-associated genes in asthma

Luke R Bonser1*, Walter L Eckalbar1,2,3*, Stephanie A Christenson2, Jiangshan Shen1, Kyung Duk Koh1, Lorna T Zlock4, Walter E Finkbeiner4, and David J Erle1,3,5,6

*These authors contributed equally.
1Lung Biology Center and 2Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine; 3UCSF CoLabs; 4Department of Pathology; 5Cardiovascular Research Institute; and 6ImmunoX Initiative; University of California, San Francisco

Rationale: SARS-CoV-2, the virus that causes COVID-19, exhibits an ACE2-dependent airway epithelial tropism, and exploits host cell proteins to replicate and evade detection. The impact of asthma on COVID-19 susceptibility and severity is unclear.

Objectives: We sought to discover how genes encoding SARS-CoV-2-associated host proteins are expressed in primary human bronchial epithelial cells (HBECs), and how these genes are regulated by cytokines important in asthma.

Methods: We cultured primary HBECs at air-liquid interface in the absence of cytokine, or with IL-13, IL-17, IFN-a, or IFN-g. We used bulk RNA-seq and single cell RNA-sequencing to identify changes in gene expression. We correlated cytokine-regulated changes in SARS-CoV-2-associated transcripts with gene expression changes in transcriptomic profiling datasets derived from individuals with mild-to-moderate asthma and chronic obstructive pulmonary disease (COPD).

Measurements and Main Results: Transcripts encoding 332 of 342 (97%) SARS-CoV-2-associated proteins were detected in HBECs (≥1 RPM in 50% samples). 85 (26%) of these mRNAs were regulated by at least one cytokine (>1.5-fold change, FDR < 0.05). 21 and 19 of the 41 SARS-CoV-2-associated genes regulated by IL-13 in HBECs were correlated with type 2 inflammatory gene signature scores in transcriptomic profiling datasets derived from individuals with mild-to-moderate asthma and COPD (p < 0.05). Few IL-17 or interferon-responsive genes were correlated with their respective signatures in either dataset. Single cell RNA-sequencing revealed that 143 of the 332 (43%) SARS-CoV-2-associated transcripts detected in HBECs were differentially expressed between cell types (FDR < 0.05); some of these genes were associated with SARS-CoV-2 proteins predicted to co-opt host trafficking pathways. 11 SARS-CoV-2-associated genes were modulated by IL-13 in a cell type-specific manner (>1.25-fold change, FDR < 0.05).

Conclusions: Many genes encoding proteins associated with SARS-CoV-2 infection are expressed in HBECs, with substantial differences among cell subsets. IL-13 induces extensive changes in the expression of SARS-CoV-2-related genes that correlated with a measure of type-2 inflammation in vivo, providing a plausible basis for differences in outcome of COVID-19 in individuals with asthma.

Luke Russell Bonser PhD

UCSF

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