Rhinovirus triggers distinct host responses through differential engagement of epithelial innate immune signaling [RNA-Seq]

Rhinovirus (RV) is the most frequent cause of common colds, but also a major cause of serious respiratory illness in high-risk groups (e.g. smokers and asthmatics). The molecular mechanisms leading to disparate outcomes of infection are not fully understood. Variation in the host epithelial interferon response has been implicated susceptibly to RV illness. We performed single cell sequencing air-liquid interface (ALI) cultured human nasal epithelial cells (HNECs) with infection of HRV-01A in the presence of IRF3 activation inhibitor BX795. We showed that the epithelial interferon response restricts RV infection to <2% of cells, however, inhibiting IRF3 activation increases the proportion of infected cells to >30%, and leads to a distinct NFKB-dependent pro-inflammatory response, with production of neutrophil-attracting chemokines, increased mucus, and IL-1b. Bulk RNA sequencing further revealed that inhibiting both IRF3 and NFKB induce ER stress and squamous metaplasia genes. Overall, our study demonstrates how distinct forms of epithelial defense responses impact RV-induced inflammation.