Rhinovirus C causes heterogeneous infection and gene expression in airway epithelial cell subsets

Abstract

Rhinoviruses (RV) infect ciliated airway epithelial cells and RV nonstructural proteins quickly inhibit and divert cellular processes for viral replication. Yet, the epithelium can mount a robust innate antiviral immune response. Therefore, we hypothesized that uninfected cells contribute significantly to the antiviral immune response in the airway epithelium. Using single-cell RNA sequencing, we demonstrate that both infected and uninfected cells upregulate antiviral genes (e.g., MX1, IFIT2, IFIH1, OAS3) with nearly identical kinetics, while uninfected non-ciliated cells are the primary source of proinflammatory chemokines. Furthermore, we identified a subset of highly infectable ciliated epithelial cells with minimal interferon responses and determined that interferon responses originate from distinct subsets of ciliated cells with moderate viral replication. These findings suggest that the composition of ciliated airway epithelial cells and coordinated responses of infected and uninfected cells could determine the risk of more severe viral respiratory illnesses in children with asthma, COPD, and genetically susceptible individuals.