Tu184 - Duration and Mechanisms of Rhinovirus-mediated Viral Interference in Differentiated Human Bronchial Epithelium

Abstract Text: Viral interference occurs when infection with one virus temporarily protects against infection with an antigenically distinct 2nd virus. Rhinovirus (RV) is the most common human respiratory virus and commonly co-circulates with other respiratory viruses, suggesting it may be a significant cause of viral interference. While animal models and in vitro work support the ability of RV to interfere with pathogenic respiratory viruses during acute infection, the duration of interference and specific mechanisms of protection are not well characterized. Here, we use a model of differentiated human bronchial epithelium to study acute and chronic transcriptomic and proteomic changes following RV infection. We find that RV infection induces a persistent antiviral state that leads to a 19-fold reduction in influenza A virus (IAV) replication upon challenge two weeks post-RV. This antiviral state persists after cessation of RV virus shedding and coincides with elevation of a small subset of interferon-stimulated genes (ISGs) and RV RNA. We find that protection against IAV does not require reinduction of a new interferon response upon challenge, suggesting that cells are in a long-term antiviral state likely mediated by direct antiviral effectors. Persistent ISGs in bronchial epithelial cells result from ongoing cytosolic dsRNA-sensing RLR signaling which can be reversed through inhibition of TBK1. Together, these findings show that RV induces a long-term antiviral state in airway epithelium through persisting RLR-signaling that protects against IAV through elevation of direct antiviral effectors.