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A3846 - Over-Production of Growth Differentiation Factor 15 (GDF15) Promotes Human Rhinovirus Infection and Virus-Induced Inflammation in the Lung
Author Block: Q. Wu1, D. Jiang2, N. Schaefer2, L. Harmacek3, B. P. O’Connor3, T. E. Eling4, O. Eickelberg1, H. Chu2; 1Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States, 2Medicine, National Jewish Health, Denver, CO, United States, 3Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, United States, 4The Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States.
RATIONALE: Human rhinovirus (HRV) is the most common virus contributing to acute exacerbations of chronic obstructive pulmonary disease (COPD) nearly year-round, but the mechanisms have not been well elucidated. Our prior study shows that growth differentiation factor 15 (GDF15) is up-regulated in airway epithelial cells of COPD smokers. Recent clinical studies suggest that high GDF15 protein levels in the blood are associated with an increased yearly rate of all-cause COPD exacerbations. However, little is known about the role of GDF15 in regulating host defense and inflammation in response to HRV infection. Therefore, we hypothesized that over-production of GDF15 promotes HRV infection and subsequently enhances virus-induced inflammation in the lung. METHODS: We first examined the role of GDF15 in regulating host defense and HRV-1B-induced inflammation using human GDF15 transgenic (hGDF15 Tg+) mice and cultured hGDF15 Tg+ mouse tracheal epithelial cells. Next, we determined the effect of GDF15 on viral replication, antiviral responses, and inflammation in well-differentiated normal primary human bronchial epithelial cells (HBEs) at air-liquid interface (ALI) with GDF15 knockdown and HRV-16 infection. Finally, we explored the signaling pathways involved in airway epithelial responses to HRV infection in the context of GDF15 by performing a pSmad1 ChIP assay followed by next-generation sequencing. RESULTS: First, compared to WT mice, HRV-induced pro-inflammatory cytokines (e.g., IL-6, KC, IP-10) and neutrophils in the lung were significantly higher in hGDF15 Tg+ mice. These effects were linked with a notably higher HRV-1B load and lower IFN-λ2/3 (IL-28A/B) expression in the lung. Cultured hGDF15 Tg+ mouse tracheal epithelial cells exhibited a higher HRV-1B release, but not inhibition of IFN-λ2/3 (IL-28A/B) and the increase of KC and IP-10. Second, compared to HRV-infected shControl HBEs, knockdown of GDF15 significantly reduced HRV-16 replication and release in apical side of ALI cultures. This reduction of viral load was accompanied by an enhanced IFN-λ1/IL-29 protein production and an attenuated production of HRV-induced IP-10, IL-6, and IL-8 protein. Lastly, interferon regulatory factor 7 (IRF7) binding site was identified in the promoter regions of 137 pSmad1-regulated genes, which were further enriched into the defense response, antimicrobial humoral response, inflammatory response, regulation of apoptosis, and other cellular processes by the Gene Ontology (GO) analysis. CONCLUSIONS: Our results reveal a novel function of GDF15 in promoting lung HRV infection and virus-induced inflammation, which may be a new mechanism for the increased susceptibility and severity of respiratory viral (i.e., HRV) infection in cigarette smoke-exposed airways with GDF15 over-production.