Th2 cytokine-induced mucociliary remodeling in chronic rhinosinusitis: implications for antiviral defense and epithelial function

Chronic rhinosinusitis (CRS) is a sinonasal inflammatory disease, often complicated by aberrant Th2-driven immunologic responses and increased susceptibility to viral infections. Th2-induced epithelial remodeling has been proposed to facilitate viral entry and replication, thereby increasing susceptibility to infection and exacerbating inflammation in CRS. This exploratory study investigated if chronic Th2-mediated remodeling alters the transcriptional response to rhinoviral infection between individuals with and without CRS. We hypothesized that Th2 cytokine exposure of human primary nasal epithelial cells during their differentiation disrupts mucociliary function, impairing the antiviral response to rhinovirus. Primary nasal epithelial cells from patients with and without CRS were differentiated at air-liquid interface while being exposed to Th2 cytokines (IL-4, IL-13, or IL-4/13; 10 ng/mL) followed by a rhinovirus (RV-A16) infection. RNA sequencing and inflammatory cytokine profiling revealed significant downregulation of pathways involved in cilia structure, development, and function, as well as lower rhinovirus reads in Th2 cytokine-exposed cultures, with similar trends observed in CRS and non-CRS samples. Chronic Th2 cytokine exposure also altered cytokine release, shifting toward an anti-inflammatory profile. Notably, sex-specific differences were observed in unexposed cultures, with male-derived cultures exhibiting higher levels of inflammatory cytokines and accompanying more inflammatory transcriptomic profiles, thus highlighting intrinsic sex-specific immune variability. These findings underscore how Th2 cytokine-driven epithelial remodeling may compromise mucociliary function and antiviral defenses across CRS and non-CRS cultures. Understanding these mechanisms may inform therapeutic strategies aimed at restoring epithelial integrity and mitigating chronic inflammation.