LSC Abstract – Punching above their weight: Plasmacytoid dendritic cells play a critical role in regulating rhinovirus induced gene expression pathways

Human rhinoviruses (HRV) often trigger exacerbations of chronic lung diseases. Host defence against HRV involves multiple interferons (IFNs), IFN-stimulated genes and cytokines, though how this is regulated is poorly understood. This project aimed to examine HRV-induced gene expression patterns and the extent to which these are regulated by plasmacytoid dendritic cells (pDC). Blood mononuclear cells were isolated from 18 healthy donors, depleted of pDC or left intact, and cultured with HRV for 24h. Global patterns of gene expression were determined using Illumina HT-12 microarray chips. Selected genes identified by micro-array were validated by RT-qPCR and/or ELISA. In pDC depleted cultures, there was a profound perturbation of the gene expression program, with 3856 differentially expressed genes identified in pDC-depleted versus intact mononuclear cells. Pathways analysis demonstrated that these genes were enriched in multiple canonical pathways including EIF2 signalling, mitochondrial dysfunction, IFN signalling, mTOR signalling, IFN regulatory factors, pattern recognition receptors and oxidative phosphorylation. Using RT-qPCR or ELISA, we confirmed that pDC depleted cells expressed significantly less IL-27, IL-27B (EBI3), IL-15RA, IRF7, IL-6, and IFNγ than intact mononuclear cells, and showed that these cytokines and receptors are key regulators of IFNα production.Though pDC represent a rare subset of migratory leukocytes, they exert a major influence on the immune response to HRV. Future studies will assess the extent to which these genes and pathways are dysregulated in asthma.