IL-13 Regulates Transcriptional Changes in SARS-CoV-2-Associated Genes in Asthma

ABSTRACT

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. 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 compiled a list of 342 SARS-CoV-2-associated genes. We cultured primary HBECs at air-liquid interface in the absence of cytokine, or with interleukin (IL)-13, IL-17, interferon (IFN)-α, or IFN-γ. 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 on cytokine exposure in vitro with gene expression changes in transcriptomic profiling datasets derived from individuals with mild-to-moderate asthma and chronic obstructive pulmonary disease (COPD). Results: Transcripts encoding 332 of 342 (97%) SARS-CoV-2-associated proteins were detected in HBECs (≥1 RPM in 50% samples);85 (26%) were regulated by at least one cytokine (>1.5-fold change, FDR < 0.05). 21 and 19 of the 41 IL-13 responsive, SARS-CoV-2-associated genes identified in HBECs 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). 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.