IL-13 decreases suceptibility to airway epithelial SARS-CoV-2 infection but increases disease severity in vivo [scRNA-seq]

Human airway epithelia (HAE) undergo inflammation-induced remodeling in chronic lung diseases such as asthma and chronic bronchitis. The role of type 2 inflammation-induced epithelial remodeling in SARS-CoV-2 infection and the course of COVID-19 is unclear, moreover, there is discrepancy in the literature regarding the potential benefit of treatments that modulate type 2 inflammation. We investigated the role of IL-13-induced inflammation on SARS-CoV-2 binding/entry, replication, and host response in primary HAE cells in vitro and in a model of mouse-adapted SARS-CoV-2 in vivo. IL-13 protected airway epithelial cells from SARS-CoV-2 infection in vitro by decreasing the abundance of ACE2- expressing ciliated cells rather than by neutralization in the airway surface liquid or by interferon-mediated antiviral effects. In contrast, IL-13 worsened the severity of disease in mice in vivo; the effects were mediated by eicosanoid signaling and were abolished in mice deficient in the phospholipase A2 enzyme PLA2G2D. We conclude that IL-13-induced inflammation affects multiple steps of SARS-CoV-2-induced disease pathogenesis. Whereas IL-13-induced inflammation may be protective against initial infection at the airway epithelium, it enhances disease severity once infection progresses in vivo; blockade of IL-13 and/or eicosanoid signaling may be protective against progression to severe lung disease. Overall design: To investigate the role of IL-13 induced inflammation on SARS-CoV-2 in vitro, we treated HAE from 2 donors with 20 ng/mL recombinant IL-13 or 20 ng/mL recombinant IL-17 combined with 10 ng/mL tumor necrosis factor alpha (TNFa) for 4 or 55 days. The cytokines were applied to both apical and basolateral side of HAE. The cells were then infected with SARS-CoV-2 (MOI 0.1), the strain isolated from the first US patient (2019-nCoV/USA-WA1/2020, GenBank:MN985325.1) for 6 or 72 hours.