Abstract Rationale Respiratory syncytial virus (RSV) is a common respiratory virus that results in over 80,000 hospitalizations of children younger than 5 years in the U.S. annually. Type-III interferon (IFN), a primarily epithelial cell secreted cytokine, plays a key role in antiviral defense against pathogens such as RSV. Inflammation, resulting from the release of additional signaling molecules, results in chemotaxis of immune cells, contributing to increased airway inflammation. In this study, the goal was to define the response of airway epithelial cells (AECs) from infant donors with high baseline type-III IFN production in the context of viral infection. Methods We generated 20 cell lines derived from infants with a history of viral induced wheezing (n = 20, median age 0.95 years). Nasal aspirates (n = 40, median 1.11 years) were also collected from children experiencing a clinically confirmed viral respiratory infection. Type III IFN, pro-inflammatory cytokines and gene expression (RNA-seq) of interferon-stimulated genes (ISGs) were quantified at baseline and after exposure to dsRNA (Poly I:C, 10ng). An ISG module score was generated for baseline samples using gene expression, the samples were then classified into high (≥50th percentile of ISG module score) or low (≤50th percentile of ISG module score), for further downstream analysis. Results We found that AECs exhibiting elevated baseline ISGs signaling via transcriptomic analysis also demonstrated elevated baseline type-III IFN production. We also observed that after exposure to viral stimuli, AECs from “type-III IFN High” donors responded with significantly increased pro-inflammatory cytokine production, including IL-18 (p-value: 0.004), IL-1B (p-value= 0.009), IL-15 (p = 0.001), IL-6 (p-value= 0.002) and IL-7 (p = 0.001). Notably, in nasal aspirates, high type-III IFN response during viral respiratory infection was linked to elevated pro-inflammatory with significantly higher levels of IL-6 (p-value= 0.012), IL-15 (p-value= 0.024), and IL-18 (p-value= 0.047). Conclusion Our data demonstrate that infants with a history of severe viral-induced respiratory illness and have elevated type-III IFN at baseline, also present with elevated pro-inflammatory signaling in the upper airways during viral respiratory infection. This suggests that the upper airways of these children may be experiencing significantly increased airway inflammation, rather than an anti-viral response, contributing to poor clinical outcomes including hypoxemia, respiratory failure, and intensive care admission. Our findings also suggest that type-III IFN may play a role in orchestrating and directing the local immune response in the pediatric airways in the context of viral infection. This abstract is funded by: None
Brito et al. (Fri,) studied this question.