Role of IL-13-induced Th2 inflammation in host responses to SARSCoV-2

ABSTRACT

Background: Chronic lung inflammation affects the response to respiratory viruses such as SARS-CoV-2 in airway epithelia. Based on the pattern associated with disease endotype, airway inflammation can be simplified into type 2 and type 17. Half of asthmatics have type 2 high endotype driven by IL-13/IL-4 cytokine signaling that induces goblet cell metaplasia. Other inflammatory diseases such as cystic fibrosis, chronic bronchitis, and sarcoidosis are associated with the type 17 cytokines IL-17 and TNF-α. Recent case-control studies have suggested that asthma may protect against or at least not worsen SARS-CoV-2 infection. However, the effect of inflammation on COVID-19 outcomes is unclear. Although interferons and cytokine-driven inflammation may modulate antiviral response, epithelial remodeling might also affect susceptibility to viruses.We applied a singlecell RNA-seq approach to investigate responses to SARS-CoV-2 in primary human airway epithelia treated with inflammatory cytokines. We hypothesized that IL-13-induced type 2 inflammation and IL-17-induced type 17 inflammation would respond differently to SARS-CoV-2-infected human airway epithelia and that IL-13 would protect the epithelia from SARS-CoV-2 infection through goblet cell-secreted factors Methods: We infected primary human airway epithelia (n = 3 donors) grown at the air–liquid interface with 0.1 multiplicity of infection of SARSCoV- 2 and obtained viral titers and single-cell suspensions at 6 and 72 hours after infection. The epitheliawere pretreated with IL-13 or IL-17 plus TNF-α for a short (4 days) or long (56 days) course to differentiate the early effects of cytokine response from late goblet cell metaplasia that develops over weeks. We then performed single-cell RNA-seq to analyze viral transcripts Results: We found that IL-13, but not IL17 plus TNF-α, protected epithelia from SARS-CoV-2 at 72 hours after infection. Moreover, the protection seemed to be independent of interferons because interferon-stimulated genes, induced by short IL-13 exposure, failed to protect the epithelia from viral infection. Our analysis shows that the genes with the largest expression change in long-course IL-13-treated epithelia were mediated by the appearance of goblet cells andwere goblet-specific genes. Using our single-cell RNA-seq data, we analyzed how cytokines change response in each cell type after viral infection. We found that, when cells become infected, their response is not abnormal. Conclusion: IL-13 protects human airway epithelia from SARS-CoV-2 infection in vitro;the protective mechanism may involve secreted products from goblet cells. IL-13-treated airway epithelial cells have an otherwise normal response to SARS-CoV-2. Our findings suggest that products secreted by goblet cells may have potential therapeutic applications for respiratory viral diseases.