Rhinovirus infection of airway epithelial cells uncovers the non-ciliated subset as a likely driver of genetic risk to childhood-onset asthma
Sarah Djeddi, Daniela Fernandez‐Salinas, George Huang, Vitor R. C. Aguiar, Chitrasen Mohanty, Christina Kendziorski, Steven Gazal, Joshua A. Boyce, Carole Ober, James E. Gern, Nora A. Barrett, María Gutiérrez‐Arcelus
Abstract
Asthma is a complex disease caused by genetic and environmental factors. Studies show that wheezing during rhinovirus infection correlates with childhood asthma development. Over 150 non-coding risk variants for asthma have been identified, many affecting gene regulation in T cells, but the effects of most risk variants remain unknown. We hypothesized that airway epithelial cells could also mediate genetic susceptibility to asthma given they are the first line of defense against respiratory viruses and allergens. We integrated genetic data with transcriptomics of airway epithelial cells subject to different stimuli. We demonstrate that rhinovirus infection significantly upregulates childhood-onset asthma-associated genes, particularly in non-ciliated cells. This enrichment is also observed with influenza infection but not with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or cytokine activation. Overall, our results suggest that rhinovirus infection is an environmental factor that interacts with genetic risk factors through non-ciliated airway epithelial cells to drive childhood-onset asthma.