The Type 2 Asthma Mediator IL-13 Inhibits Severe Acute Respiratory Syndrome Coronavirus 2 Infection of Bronchial Epithelium

Abstract

Asthma is associated with chronic changes in the airway epithelium, a key target of SARS-CoV-2. Many epithelial changes, including goblet cell metaplasia, are driven by the type 2 cytokine IL-13, but the effects of IL-13 on SARS-CoV-2 infection are unknown. We found that IL-13 stimulation of differentiated human bronchial epithelial cells (HBECs) cultured at air-liquid interface reduced viral RNA recovered from SARS-CoV-2 infected cells and decreased dsRNA, a marker of viral replication, to below the limit of detection in our assay. An intact mucus gel reduced SARS-CoV-2 infection of unstimulated cells, but neither a mucus gel nor SPDEF, which is required for goblet cell metaplasia, were required for the anti-viral effects of IL-13. Bulk RNAseq revealed that IL-13 regulated 41 of 332 (12%) mRNAs encoding SARS-CoV-2-associated proteins that were detected in HBECs (>1.5-fold change, FDR < 0.05). Although both IL-13 and IFN- each inhibit SARS-CoV-2 infection, their transcriptional effects differed markedly. Single cell RNA-seq revealed cell type-specific differences in SARS-CoV-2-associated gene expression and IL-13 responses. Many IL-13-induced gene expression changes were seen in airway epithelium from individuals with type 2 asthma and COPD. IL-13 effects on airway epithelial cells may protect individuals with type 2 asthma from COVID-19 and could lead to identification of novel strategies for reducing SARS-CoV-2 infection.

SARS-CoV-2 infection of airway cells causes intense viral and cell shedding, two spreading mechanisms affected by IL-13

“…A recent study showed that, despite mucus removal, IL-13 treatment had protective effects against SARS-CoV-2 infections ( 37 ). Our infections were performed via bolus (200 µL) incubation for 2 h, and this approach was shown to remove the majority of the mucus from the cell surfaces ( 40 ).…”

“…Relative abundance of MUC5AC was analyzed by mucin Western blotting ( 55 ). Gene expression data were obtained from NCBI GEO and processed using R. CBF was determined by taking phase contrast videos of the field of view and performing Fourier spectral analysis ( 37 ). MCT velocity was obtained by tracking hardened red blood cells.…”

“…The variability within the asthmatic population may originate from pathophysiologic differences based on Th2-low (nonallergic) and Th2-high (allergic) inflammatory profiles, with allergic asthma being protective ( 32 , 33 ). IL-13, a type 2 cytokine associated with allergic asthma, has been shown to increase MUC5AC secretion ( 34 , 35 ) and down-regulate ACE2 expression ( 30 , 36 ), and the effects of IL-13 on SARS-CoV-2 infection are only beginning to be explored ( 37 ).…”

COVID‐19 test positivity by occupation using the Delphi US COVID‐19 trends and impact survey, September–November 2020

“…One possible mechanism is the reduction of angiotensinconverting enzyme-2, the host cell entry receptor for SARS-CoV-2 in people with asthma. 25 Although there were differences in percent tested among the occupational groups, the correlation between the percent tested work and in situations outside of work. 27,28 Information on trends in infection risk for detailed occupations and for major occupational groups can help target messaging and future studies on specific working or social conditions contributing to risk of infection and lead to improved mitigation strategies.…”

Regulation of mRNA transcripts, protein isoforms, glycosylation and spatial localization of ACE2 and other SARS-CoV-2-associated molecules in human airway epithelium upon viral infection and type 2 inflammation

“…It is suggested that allergic inflammation and the type 2 (T2)-high asthma might convey some forms of protection from SARS-CoV-2 infection, whereas T2-low asthma might be a risk factor of COVID-19 13 . It is based on the contrasting epidemiological observations in COVID-19 cohorts from different parts of the world 11, 13 , and a few mechanistic studies showing that IL-13, the major type 2 cytokine, decreases ACE2 expression and inhibits SARS-CoV-2 infection in airway epithelium 14, 15 . However, IL-13 has been also shown to be a major driver of COVID-19 severity and anti-IL-4/13 treatment is showing positive effects in COVID-19 clinical trials 16, 17 .…”