Asthmatic Bronchial Smooth Muscle Decreases Epithelial Response to Rhinovirus Infection Through a CCL20-EIF2AK2 Dependent Pathway

Asthma is a very frequent airway disease affecting 6 to 20% of the population of western European countries. The disease is characterized by an increase of bronchial smooth muscle (BSM) mass correlated with the severity of asthma. Recent clinical investigations have shown a link between BSM mass and the exacerbations rate. Exacerbations are mainly the consequence from inhalation of aero-contaminant acting on bronchial epithelium cells with the most important trigger being the human rhinovirus (RV). However, the role of the BSM in infections of the epithelium by the RV is still unknown. Asthmatic and non-asthmatic BSM cells and bronchial epithelial cells (BEC) were obtained from patient biopsies (COBRA cohort). BEC were cultured and differentiated in Air-Liquide- Interface. RV infection was measured using qPCR. Cytokines concentrations were assessed using ELISA assays. Proteomic and transcriptomic data were analyzed using IPA (Qiagen). Using a co-culture model between BEC and BSM cells, we found an increased RV replication in BEC induced by asthmatic BSM cells. These findings were related to an increased production of CCL20 by asthmatic BSM cells. Moreover, we demonstrated a down regulation of the epithelial PKR/eIF2α antiviral pathway through this BSM-related CCL20 overproduction. Using both in vitro and ex vivo experiments, we demonstrated, for the first time, a direct bottom-up effect of BSM cells in severe asthmatic patients on BE susceptibility to RV infection. Asthmatic BSM cells are able to increase RV infection in BEC. Proteomic analysis highlight modified expression of CCL20 in BSM cells, showing that asthmatic BSM cells increase RV replication in BE through CCL-20 production.