IL-13 Modulates Antiviral Effector and Proinflammatory Pathways in Rhinovirus-Infected Pediatric Bronchial Epithelium

Rhinovirus (RV) is the most common trigger of viral-induced pediatric asthma exacerbations. The impact of IL-13-driven inflammation, common in pediatric asthma, on airway epithelial antiviral and inflammatory responses to RV remain unclear.

Determine how IL-13-driven T2 inflammation modulates pediatric bronchial epithelial cell responses to RV infection.

Bronchial epithelial cells (BECs) were collected from children with (n=50) and without (n=11) asthma. They were differentiated at an air-liquid interface for 21 days, pretreated with IL-13 (10ng/mL) for 7 days to model T2 inflammation, then infected with RV-A16 (MOI 0.5). RNA sequencing of BECs was performed prior to and on days 2, 4, 7, and 10 post infection. Linear and generalized additive models partnered with pathway analysis identified differentially expressed gene clusters.

RV infection, IL-13 stimulation, and their interaction each induced differentially expressed genes (7,808; 10,251; and 7,095 genes, respectively; FDR<0.05). IL-13 pretreatment did not alter RV load or a cluster enriched for interferon response and regulation genes, including IFNB1, IFNL1-3, STAT1/2, and CXCL10/11. In contrast, IL-13 reduced expression of distinct antiviral effectors (e.g. MX1/2, RSAD2, IFITM1-3; FDR=1.85×10^-4) and increased a secondary proinflammatory response cluster enriched for IL-15, TNF, ER stress, and cell-death pathways (FDR=3.63×10^-6). These clusters correlated with viral load in RV-infected cells, but IL-13 pretreatment eliminated those associations.

IL-13 does not modify viral load or interferon induction but selectively suppresses epithelial antiviral effector programs and enhances secondary inflammatory pathways during RV infection. These findings provide mechanistic insight into how T2 inflammation contributes to viral-triggered asthma morbidity.